link
stringlengths 41
45
| date
stringlengths 9
9
| paper
dict | reviews
listlengths 1
6
| version
int64 1
5
| main
stringlengths 38
42
|
|---|---|---|---|---|---|
https://f1000research.com/articles/11-113/v1
|
28 Jan 22
|
{
"type": "Research Article",
"title": "Comparison of invasive histological and molecular methods in the diagnosis of Helicobacter pylori from gastric biopsies of Sudanese patients: a cross-sectional study",
"authors": [
"Maram Elnosh",
"Hisham Altayb",
"Yousif Hamedelnil",
"Wafa Elshareef",
"Aliaa Abugrain",
"Esraa Osman",
"Aalaa Albasha",
"Abdelhamid Abdelhamid",
"Ehssan Moglad",
"Ahmed AbdAlla",
"Ahmed Ismail",
"Hisham Altayb",
"Yousif Hamedelnil",
"Wafa Elshareef",
"Aliaa Abugrain",
"Esraa Osman",
"Aalaa Albasha",
"Abdelhamid Abdelhamid",
"Ehssan Moglad",
"Ahmed AbdAlla",
"Ahmed Ismail"
],
"abstract": "Background: The continuous rise in the number of patients suffering from Helicobacter pylori is probably due to the changes in modern life. Nowadays, patients suffering from gastrointestinal problems are diagnosed through invasive and non-invasive techniques. The choice of a diagnostic test is influenced by factors such as the tests' sensitivity and specificity, the clinical conditions, and the cost-effectiveness of the testing strategy. This study aimed to compare molecular detection methods of H. pylori by polymerase chain reaction (PCR) targeting the 16S rRNA, ureA and glmM genes with an invasive histopathological technique. Methods: 290 gastric biopsies were collected using gastrointestinal endoscopy from patients with gastritis symptoms in different hospitals in Khartoum state. Two gastric biopsies were collected from each patient for PCR and histopathology. Results: A total of 103 (35.5%) samples were positive by histopathological examination, 88 (30.3%) by 16S rRNA, 39 (13.4%) by glmM gene, and 56 (19.3%) by ureA gene. The highest sensitivity was observed in 16S rRNA (46.6%), followed by glmM (24.3%) and ureA (23.3%). While the best specificity was observed in glmM gene (92.5%), followed by ureA (82.3%) and 16S rRNA (78.6%). Conclusion: PCR test targeting the 16S rRNA gene exhibited the best results for molecular detection of H. pylori compared to other genes.",
"keywords": [
"Helicobacter pylori",
"Histopathology",
"16S rRNA",
"PCR",
"ureA",
"sensitivity",
"specificity",
"Khartoum."
],
"content": "Introduction\n\nHelicobacter pylori (H. pylori) is a Gram-negative, microaerophilic, spiral, and motile bacterium that colonizes the human gastric mucosa.1,2 It has been associated with the development of various clinical disorders of the upper gastrointestinal tract, such as aseptic ulcers, chronic gastritis, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, which is classified as type I cancer-causing agent by the World Health Organization (WHO).3–5 Its distribution is worldwide and affects more than 90% of the world population, but it is more common in developing countries with the highest prevalence found in Africa,6,7 probably due to the possible transmission through the fecal-oral route and the unsafe sanitation conditions in these countries.1,8 Clinically, a variety of various invasive techniques (requiring endoscopy and biopsy which include, culture, histological examination, and rapid urease test, CLO (Campylobacter like organism) test, smear examination, and molecular studies) or noninvasive techniques (including serology, respiratory urea breath test, or the detection of fecal antigen) are often performed to detect H. pylori infection.9–11 The sensitivity of any of those techniques in detecting H. pylori relays on how the density of the bacterial cells within the specimens taken by biopsy (recent use of disease-related medications, specifically antibiotics and proton-pump inhibitors (PPI) can reduce the density of the cells), pathologist expertise, also the type and quality of the stain used for detection purposes.10 Many studies reported that the gold standard method for the diagnosis is the detection of H. pylori in biopsy material.12,13\n\nCurrently, many clinical laboratories use urease tests and histological analysis as a gold standard approach.13,14 In routine practice, hematoxylin and eosin (H and E), Giemsa, and immunohistochemistry staining techniques are commonly used to identify H. pylori following endoscopy; however, these techniques normally fails in identifying low numbers or coccoid forms of bacteria.15\n\nThe polymerase Chain Reaction (PCR) method offers advantages over culture and histopathology because it can detect the coccoid form of the H. pylori. PCR-based methods have been developed to detect the organism directly in clinical specimens alongside virulence and drug resistance analysis due to the high sensitivity and specificity of this technique.16 The targets of these PCR methods include the 16S rRNA gene, the urease (ureA) gene, the ureC gene, renamed phosphoglucosaminemutase (glmM), the random chromosome sequence, and the 26-kDa species-specific antigen (SSA) gene. H. pylori ureA gene is an important virulence factor that ensures that bacteria can resist acidity of the gastric mucosa.17\n\nIn Sudan, many studies were carried out to investigate the seroprevalence of H. pylori using ELISA and rapid immunochromatographic tests.18 The prevalence of H. pylori infection was estimated to be 80% among patients with gastritis symptoms, 56% with duodenal ulcer, while 60% with duodenitis and 16% apparently healthy individuals.19 In another study in Eastern Sudan high prevalence of H. pylori infection, 80% among patients with gastritis and Barrett's esophagus was reported.20 In Sudan and probably many third-world countries, the cost of diagnosis plays a major role rather than the accuracy of the diagnostic method. Hence, diagnosis of H. pylori infections is largely based on serology, detection of stool antigen and rarely endoscopy and culture. The present study aimed to compare the use of histopathology (gold standard method) with polymerase chain reaction (PCR) approach for the detection and prevalence of H. pylori infections in Khartoum State.\n\n\nMethods\n\nThis was a cross-sectional study conducted at Khartoum State, Sudan between March 2018 to January 2020. The project was approved by the Ethics Committee of the Ministry of Health Research Department, Khartoum State (3/2018) (specimens were collected from patients undergoing endoscopic examination). The study aims were explained to the recruits, and a consent form was obtained and signed prior to sample collection.\n\nGastric tissue samples were collected by physicians from 290 patients (both gender of different age groups) undergoing endoscopic examination and suffering from dyspepsia and other gastritis-related symptoms. Patients who had received antibiotics, PPI, H2 blockers, or colloidal bismuth sulfate within the previous two months of endoscopy for treatment of gastritis or peptic ulcer, patients with a history of gastric resection, patients with complicated peptic ulcer disease, i.e. hemorrhage, were excluded.4 Two biopsy specimens were collected from the antrum and the corpus of each patient, one sample was immediately placed in tubes containing saline and transported for molecular study, while the other was fixed in 10% buffered formalin for at least 24 hours and then embedded in paraffin wax for histopathological examination.\n\nHematoxylin and Eosin (H and E) staining and modified Giemsa staining were performed for all samples. Three sections for each specimen were deparaffinized and hydrated in descending grades of alcohol and cut in sequential 4 μm sections. One slide was stained by routine H and E stain, and the other slide was stained by modified Giemsa stain to demonstrate the presence of H. pylori. Cover slips with DPX mounted on slides and then later examined by a histopathologist and assigned to each morphological variable.\n\nDNA extraction of gastric biopsies was performed using the guanidine chloride method as described by Abd Al Rahem and Elhag.21 Biopsies were grounded by sterile blades and tips and then washed with phosphate buffer saline (PBS). 2 ml of lysis buffer were added, followed by 10 μl of proteinase K, 1 ml of guanidine chloride, and 300 μl of ammonium (NH4) acetate, then vortexed and incubated at 65°C for 2 hours. The mixture was cooled to room temperature, and then 2 ml of pre-cooled chloroform was applied, vortexed, and centrifuged for 5 minutes at 3000 revolutions per minute (rpm). The upper layer of the mixture was moved to a new tube, and 10 ml of absolute cold ethanol were added, shaken, and held for 2 hours or overnight at −20°C. The tube was then centrifuged for 15–20 minutes at 3000 rpm, the supernatant was carefully removed, and the tube was inverted for 5 minutes on tissue paper. The pellet was washed with 70% ethanol, centrifuged for 5 minutes at 3000 rpm. The supernatant was poured away, allowing the pellet to dry for 10 minutes. Then re-suspended into 50 μl of distilled water, briefly vortexed, and held overnight at −20°C. The extracted DNA was stored at −80°C until use.\n\nThree different primers were used for the detection of the bacteria, targeting specific H. pylori 16S rRNA (532 bp), glmM (294 bp), and ureA (217 bp). PCR was carried out in 25 μl of reaction mixture containing 5 μl of ready to use master mix (Taq DNA polymerase, dNTPs and MgCl2) (Intron Biotechnology, Korea), 2 μl of DNA template, 1 μl of forward (F) primer, 1 μl of reverse (R) primer and 16μl distilled water (DW). For each batch of PCR assay, DW was used as negative control instead of the genomic DNA templates. The reaction mixtures were cycled in an automated thermocycler. The PCR for the specific H. pylori 16S rRNA gene was performed using the forward primer (5′-GCTAAGAGATCAGCCTATGTCC-3′) and reverse primer (5′-TGGCAATCAGCGTCAGGTAAT-3′). The PCR condition for the 16S rRNA gene was performed as follows: initial denaturation at 94°C for 3 minutes, 35 cycles of denaturation at 94°C for 30 seconds, annealing at 53°C for 30 seconds, extension at 72°C for 45 seconds, and a final extension at 72°C for 5 minutes.22 The PCR for the ureA gene of H. pylori was performed using the forward primer (5′-AACCGGATGATGTGATGGAT-3′) and reverse primer (5′-GGTCTGTCGCCAACATTTTT-3′) reported by Ye et al., which results in an amplicon of 217 bp. The PCR condition for the ureA gene was performed as follows: initial denaturation at 94°C for 3 minutes, 35 cycles of denaturation at 94°C for 30 seconds, annealing at 53°C for 30 seconds, extension at 72°C for 45 seconds, and a final extension at 72°C for 5 minutes.22\n\nThe PCR for the glmM gene was performed using the forward primer (5′-GGATAAGCTTTTAGGGGTGTTAGGGG-3′) and reverse primer (5′-GCTTACTTTCTAACACTAACGCGC-3′).23 The PCR condition for the glmM gene was performed as follows: initial denaturation at 94°C for 3 minutes, 35 cycles of denaturation at 94°C for 30 seconds, annealing at 58°C for 30 seconds, extension at 72°C for 30 seconds, and a final extension at 72°C for 3 minutes.\n\nAfter amplification, 5 μl of the product was run in electrophoreses on a 1.5% agarose gel containing Ethidium bromide (0.5 μg/ml), then visualized under an ultraviolet illuminator and photographed. A 100-bp DNA ladder was used as a size marker.\n\nStatistical analysis was done using IBM Statistical Package for Social Sciences (SPSS) software version 20.0 (RRID: SCR_019096 URL: https://www.ibm.com/products/spss-statistics). Chi-squared test was done for the analysis of categorical variables. A p-value of <0.05 was considered statistically significant.\n\n\nResults\n\nThe sociodemographic and clinical data of 290 patients recruited in this study are shown in Table 1.\n\nGastric biopsies were obtained from 290 patients suffering from various gastric conditions through Oesophago-Gastro-Duodenoscopy (OGD). H. pylori were clearly detected in positive samples as curved bacilli on the surface of the gastric epithelial cells; the bacteria appear as light bluish rods in H and E slides with varying sizes (3–6 μ) on the luminal surface of mucosal cells. In Giemsa’s stain H. pylori appear dark blue in a light blue background.3\n\nFrom a total of 290 samples, H. pylori were found in 103 samples (35.5%). The highest number of positive H. pylori samples were observed in the active chronic gastritis followed by patients of the duodenal ulcer, gastric ulcer, and normal gastric findings in the following frequencies: 75 (25.9%), 13 (4.5%), 6 (2.1%) and 6 (2.1%) respectively, while the lowest frequency was noticed in patients with esophagitis 3 (1.0%) cases.\n\nAmong the samples analyzed by the PCR method for H. pylori 88 (30.3%) were positive using HP 16S rRNA gene, 39 (13.4%) samples were positive using glmM gene, 56 (19.3%) samples were positive using ureA gene, and the rest of samples 234 (80.7%) were negative (Figure 1).\n\na. 16S rRNA gene. Lane 8 marker (100–1500 bp), lane 7 positive control, lanes 2–5 contain positive samples (532 bp), lanes 1 and 6 are negative samples. b. glmM gene, lane 5 marker (100–1500 bp), lane 4 positive control, lanes 1,6, and 7 contain amplicons of glmM (294 bp), lanes 2 and 3 are negative samples. c. ureA gene. Lane 1 marker (100–1500 bp), lane 8 positive control, lanes 4 and 7 contain amplicons of ureA (217 bp), lanes 2, 3, 5, and 6 are negative samples.\n\nThe calculated results were statistically significant when comparing histopathological technique results with 16S rRNA and glmM genes (p-value = 0.000) (Table 2).\n\n\nDiscussion\n\nCurrently, there are many diagnostic methods for the diagnosis of H. pylori infections; each method has its advantages and disadvantages, so it is recommended to use at least a combination of two methods based on different principles to detect colonization by H. pylori.24 Although, the culture method is regarded as the most appropriate technique, it has limitations, particularly in case of slow-growing or fastidious bacteria, due to complicated identification and time-consuming methods. In addition to the need for immediate transport of the biopsy specimens to the designated laboratory to assure the viability of H. pylori and prevent the formation of coccoid forms of the microorganism.24–26 The histological technique and culturing of gastric biopsy specimens have been considered a gold standard method under optimal conditions.24\n\nHistological staining enables identifying bacteria and evaluating the type and intensity of the gastric mucosa's inflammation and associated pathology, such as, atrophic gastritis (AG), intestinal metaplasia (IM), and gastric cancer or lymphoma.27\n\nIn this study, the prevalence of H. pylori infection was 35.5%. H. pylori was detected in (103/290) patients using histopathological examination with 35.5% sensitivity. There are many previous studies done in this field with various pictures of the disease. Mohamed et al. reported that 16/69 (23.2%) positive patients for H. pylori infection among Sudanese patients with colon polyps and colon cancer patients.18 Redéen et al. reported that 97/304 (31.9%) positive patients for H. pylori infection.28 In another study, Salman et al. reported that 115/210 (54.7%) samples were positive for H. pylori via histopathology, 57 (62.6%) of positive H. pylori samples were observed in patients with chronic gastritis, 11 (50%) with adenocarcinoma and 31 (44.2%) with superficial gastritis, while only one H. pylori-positive out of 5 cases observed in atrophy gastritis patient.29 Histopathology is the first diagnostic method for detection of H. pylori and is still widely used as the main diagnostic tool; nevertheless, it has limitations including higher cost, longer turnaround time, and inter-observer variation assessment; experience and skills of the pathologist do matter for the specificity and sensitivity of histopathological diagnosis of H. pylori,2 false-positive results can occur due to presence of structures similar to H. pylori24 and failure to detect all the positive samples might occur in case of intestinal metaplasia.29 The density and irregular distribution of H. pylori can vary at different sites on the gastric mucosa, which might lead to sampling error.24,27 Moreover, the sensitivity of histology may decrease in patients taking antisecretory therapy, such as, proton pump inhibitor (PPI).27\n\nMolecular tests should be applied as replacements to the traditional method for the identification of H. pylori, which are sensitive, rapid, and precise techniques for the specific recognition of H. pylori from gastric biopsy specimens and to discover particular mutations related to antimicrobial resistance.24–26\n\nIn this study, identification of H. pylori was applied to all biopsies by PCR using specific primers. Specific H. pylori 16S rRNA gene is a conserved region of prokaryotic DNA that allows specific identification. However, H. pylori 16S rRNA gene's sensitivity and specificity were 46.6% and 78.6%, respectively. The glmM gene shows 24.3% sensitivity and 92.5% specificity. In our study, the ureA gene showed the lowest sensitivity (23.3%), and 82.3% specificity. Our result aligned with a study conducted by AlNaji et al. in 2018, which found that the glmM gene is 38.8% lower than the 16S rRNA gene 95.9%.30 Helaly et al. reported similar results (38.5%) for glmM gene.31 This low percent of glmM (ureC) gene may be due to sequence polymorphism or/in variation to the diversity of strains within the patients that reported in previous studies.30 Also, housekeeping genes are affected by geographical regions and point mutations, Intragenic and recombination are another potential factors.32\n\nThe ureA gene is a housekeeping gene that is needed for urease enzyme activity. Espinoza et al. demonstrated that the amplification of the ureA gene was noticed in (86.36%) which was lower than that of the glmM gene (100%).17 Smith et al. reported that ureA gene PCR had a very poor specificity and sensitivity.33 The possible reasons for poor sensitivity of ureA and ureC (glmM) genes for the detection of H. pylori may be that both of them are single-step PCR and thus unable to identify the lower number of bacteria or they were unable to counteract PCR inhibitors in the clinical specimens.34\n\nThe 16S rRNA gene is a useful and commonly used for the primary finding of H. pylori use Hp1, Hp2 primers with sensitivity up to 100%.30 Sugimoto et al. and Farhadkhani et al. reported that the detection of H. pylori 16S rRNA gene was greater than the ureA gene. They determined that the difference could be due to discrepancy in the primer specificity and sensitivity. Using of 16S rRNA gene for the detection of H. pylori might be more sensitive but could not be as specific as ureA gene.35,36 The poor specificity may be explained by sequence conservation across the bacterial genera and also by possible amplification of nonspecifically human DNA.34 Yet, no 100% specificity or sensitivity for primer sets amplifies H. pylori ureA and 16SrRNA genes.35,36\n\n\nConclusions\n\nThere is an urgent need for a rapid, accurate, sensitive, and specific test to diagnose H. pylori infections, especially on the samples collected by invasive methods (gastric biopsy). The study results suggest that H. pylori 16S rRNA gene detection by the PCR method could be used to diagnose H. pylori infections. To avoid false-positive results and increase specificity, we recommend using two conserved target genes to detect H. pylori infections.\n\n\nData availability\n\nFigshare: Underlying data for ‘Comparison of invasive histological and molecular methods in the diagnosis of Helicobacter pylori from gastric biopsies of Sudanese patients: a cross-sectional study’.\n\nThe project contains the following underlying data:\n\n- Raw data collected from patients with gastritis symptoms: https://doi.org/10.6084/m9.figshare.17072012.v2.37\n\n- Raw gel electrophoresis images: [PCR amplification of H. pylori on agarose gel electrophoresis 1.5%]: https://doi.org/10.6084/m9.figshare.18482015.v1.38\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nNevoa JC, Rodrigues RL, Menezes GL, et al.: Molecular technique for detection and identification of Helicobacter pylori in clinical specimens: a comparison with the classical diagnostic method. Jornal Brasileiro de Patologia e Medicina Laboratorial. 2017; 53(1): 13–19. Publisher Full Text\n\nKhalifehgholi M, Shamsipour F, Ajhdarkosh H, et al.: Comparison of five diagnostic methods for Helicobacter pylori. Iran. J. Microbiol. 2013; 5(4): 396–401. PubMed Abstract\n\nLoharamtaweethong K, Puripat N: Comparison of Immunohistochemistry and Conventional Stains for Helicobacter Pylori Detection in Gastric Biopsies of Patients Receiving Proton Pump Inhibitors. J. Health Sci. Med. Res. 2020; 38(4): 321–330. Publisher Full Text\n\nRajan A, Ganguli P, Pathak N, et al.: Correlation of serology with morphological changes in gastric biopsy of H. pylori infection. Int. J. Res. Med. Sci. 2017; 5(5): 1851–1857. Publisher Full Text\n\nGao C, Du S-Y, Fang L, et al.: Eradication treatment of Helicobacter pylori infection based on molecular pathologic antibiotic resistance. Infect. Drug Resist. 2020; Volume 13: 69–79. PubMed Abstract | Publisher Full Text\n\nIdris AB, Idris EB, Ataelmanan AE, et al.: First insights into the molecular basis association between promoter polymorphisms of the IL1B gene and Helicobacter pylori infection in the Sudanese population: computational approach. BMC Microbiol. 2021; 21(1): 1–15. Publisher Full Text\n\nZamani M, Ebrahimtabar F, Zamani V, et al.: Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Aliment. Pharmacol. Ther. 2018; 47(7): 868–876. PubMed Abstract | Publisher Full Text\n\nEldeen LAT, Mohamed MA, Awad MM, et al.: A variety of Helicobacter pylori strains colonize the stomach of non-bleeding Egyptian patients with upper gastrointestinal disorders. Bull. Natl. Res. Cent. 2019; 43(1): 1–8. Publisher Full Text\n\nAkanda M, Rahman A: Comparative study of different methods for detection of Helicobacter pylori in gastric biopsies. Dinajpur Med. Col. J. 2011; 4(1): 1–6.\n\nMawlood AH, Kawther RS, Balaky STJ: Evaluation of Invasive and Non-Invasive Methods for the Diagnosis of H. pylori in Dyspepsia Patients. Diyala J. Med. 2019; 16(2): 55–63. Publisher Full Text\n\nWang Y-K, Kuo F-C, Liu C-J, et al.: Diagnosis of Helicobacter pylori infection: Current options and developments. World J. Gastroenterol: WJG. 2015; 21(40): 11221–11235. PubMed Abstract | Publisher Full Text\n\nHasosah M: Accuracy of invasive and noninvasive methods of Helicobacter pylori infection diagnosis in Saudi children. Saudi Journal of Gastroenterology: Official Journal of the Saudi Gastroenterology Association. 2019; 25(2): 126–131. PubMed Abstract | Publisher Full Text\n\nCosgun Y, Yildirim A, Yucel M, et al.: Evaluation of invasive and noninvasive methods for the diagnosis of Helicobacter pylori infection. Asian Pacific Journal of Cancer Prevention: APJCP. 2016; 17(12): 5265–5272. PubMed Abstract\n\nAhmad F, Jaffar R, Khan I: Helicobacter Pylori detection in chronic gastritis: A comparison of staining methods. J. Ayub Med. Coll. Abbottabad. 2011; 23(2): 112–114.\n\nTalebi Bezmin Abadi A: Diagnosis of Helicobacter pylori using invasive and noninvasive approaches. J. Pathog. 2018; 2018: 1–13. PubMed Abstract | Publisher Full Text\n\nSyahniar R, Wahid MH, Syam AF, et al.: Detecting the Helicobacter pylori 16S rRNA gene in dyspepsia patients using real-time PCR. Acta Med. Indones. 2019; 51(1): 34–41. PubMed Abstract\n\nEspinoza MGC, Vazquez RG, Mendez IM, et al.: Detection of the glmM gene in Helicobacter pylori isolates with a novel primer by PCR. J. Clin. Microbiol. 2011; 49(4): 1650–1652. PubMed Abstract | Publisher Full Text\n\nMohamed AK, Elhassan NM, Awhag ZA, et al.: Prevalence of Helicobacter pylori among Sudanese patients diagnosed with colon polyps and colon cancer using immunohistochemistry technique. BMC. Res. Notes. 2020; 13(1): 1–6.\n\nHamid O, Eldaif W: Association of Helicobacter pylori infection with life style chronic diseases and body-index. J. Sci. 2014; 4(4): 255–258.\n\nAbdallah TM, Mohammed HB, Mohammed MH, et al.: Sero-prevalence and factors associated with Helicobacter pylori infection in Eastern Sudan. Asian Pac. J. Trop. Dis. 2014; 4(2): 115–119. Publisher Full Text\n\nAbd Al Rahem SA, Elhag WI: Molecular Detection of Helicobacter pylori in Drinking Water in Khartoum State (Sudan). African J. Med. Sci. 2018; 3(5).\n\nYe F: The role of DNA supercoiling in the coordinated regulation of gene expression in Helicobacter pylori.2004.\n\nTomasini ML, Zanussi S, Sozzi M, et al.: Heterogeneity of cag genotypes in Helicobacter pylori isolates from human biopsy specimens. J. Clin. Microbiol. 2003; 41(3): 976–980. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRamis IB, Moraes EP, Fernandes MS, et al.: Evaluation of diagnostic methods for the detection of Helicobacter pylori in gastric biopsy specimens of dyspeptic patients. Braz. J. Microbiol. 2012; 43(3): 903–908. PubMed Abstract | Publisher Full Text\n\nDong Z, Chen B, Pan H, et al.: Detection of microbial 16S rRNA gene in the serum of patients with gastric cancer. Front. Oncol. 2019; 9: 608. PubMed Abstract | Publisher Full Text\n\nKisa O, Albay A, Mas MR, et al.: The evaluation of diagnostic methods for the detection of Helicobacter pylori in gastric biopsy specimens. Diagn. Microbiol. Infect. Dis. 2002; 43(4): 251–255. Publisher Full Text\n\nLee JY, Kim N: Diagnosis of Helicobacter pylori by invasive test: histology. Annals of translational medicine. 2015; 3(1).\n\nRedéen S, Petersson F, Törnkrantz E, et al.: Reliability of diagnostic tests for Helicobacter pylori infection. Gastroenterol. Res. Pract. 2011; 2011: 1–6. PubMed Abstract | Publisher Full Text\n\nSalman KD, Al-Thwaini AN, Askar BA: Evaluation of glmM Gene in Diagnosis of Helicobacter pylori with Another Invasive Methods. Iran. J. Biotechnol. 2019; 18(3).\n\nAlNaji HA, Omran R, AlSherify A: Molecular Detection of Helicobacter pylori Infection in Gastric Biopsy Specimens by PCR. Journal of University of Babylon for Pure and Applied Sciences. 2018; 26(2): 109–118.\n\nHelaly GH, El-Afandy NM, Hassan AA, et al.: Diagnostic Value of Housekeeping [glmM] Gene Expression in Antral Biopsies in Comparison to Rapid Urease Test and Histological Detection of Helicobacter Pylori Infection Egyptian. J. Med. Microbiol. 2009; 18(4).\n\nRaymond J, Thiberge J-M, Chevalier C, et al.: Genetic and transmission analysis of Helicobacter pylori strains within a family. Emerg. Infect. Dis. 2004; 10(10): 1816–1821. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSmith S, Oyedeji K, Arigbabu A, et al.: Comparison of three PCR methods for detection of Helicobacter pylori DNA and detection of cagA gene in gastric biopsy specimens. World J Gastroenterol: WJG. 2004; 10(13): 1958–1960. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSingh V, Mishra S, Rao G, et al.: Evaluation of nested PCR in detection of Helicobacter pylori targeting a highly conserved gene: HSP60. J. Helicobacter. 2008; 13(1): 30–34. PubMed Abstract | Publisher Full Text\n\nFarhadkhani M, Nikaeen M, Hassanzadeh A, et al.: Potential transmission sources of Helicobacter pylori infection: detection of H. pylori in various environmental samples. J. Environ. Health Sci. Eng. 2019; 17(1): 129–134. PubMed Abstract | Publisher Full Text\n\nSugimoto M, Wu J-Y, Abudayyeh S, et al.: Unreliability of results of PCR detection of Helicobacter pylori in clinical or environmental samples. J. Clin. Microbiol. 2009; 47(3): 738–742. PubMed Abstract | Publisher Full Text\n\nMaram E, Altayb Hisham N, Fadalla HY, et al.: Comparison of invasive histological and molecular methods in the diagnosis of Helicobacter pylori from gastric biopsies of Sudanese patients: a cross-sectional study. figshare. Dataset. 2021. Publisher Full Text\n\nMaram E, Altayb Hisham N, Fadalla HY, et al.: Comparison of invasive histological and molecular methods in the diagnosis of Helicobacter pylori from gastric biopsies of Sudanese patients: a cross-sectional study. figshare. Figure. 2022. Publisher Full Text"
}
|
[
{
"id": "121551",
"date": "11 Feb 2022",
"name": "Maxime Pichon",
"expertise": [
"Reviewer Expertise Medical microbiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript by Maram Elnosh et al. describes interesting data on the comparison between histology and molecular biology for the detection of Helicobacter pylori in gastric biopsies. If the publication is suitable for the editor, modifications remain to be made before indexing.\nIntroduction:\n\nThe introduction needs to be completed, adding information about testing another sample, non-invasive such as stool - for example, see Pichon et al., 20201 which demonstrates that invasive sampling is not the sole solution in recent times, especially searching for resistance to primary-line antibiotic resistance. In addition, this reference could provide information on the detection of CLA resistance, not described in this study without good reason.\nMethods:\nThe authors should justify the number of patients they included and their inclusion period.\n\nBecause the authors use a very homemade extraction and PCR process, they must use positive and negative controls. Please describe the results obtained.\n\nSpecify the manufacturers' information for the DNA ladder.\nResults:\nTable 1: Specify if age is min-max or IQR.\n\nTable 1: Specify the impact of the two different locations.\n\nItalicize all gene names.\n\nThe last sentence in the results section of the manuscript should be reworded. The sentence could lead the reader to misunderstand the results. Moreover, the authors indicate a p-value equal to 0 that is statistically impossible, so they have to limit their conclusion to p-value < threshold.\n\nEvaluation of the concordance between the different PCRs tested in this manuscript would be interesting (to be calculated and discussed).\n\nTable 2: Prefer likelihood ratio instead of PPV and NPV as prevalence was specific.\nConclusion:\nRephrase the first sentence, as many tests already exist in the world there is no urgency.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "136292",
"date": "25 May 2022",
"name": "Stella Ifeanyi Smith",
"expertise": [
"Reviewer Expertise Molecular epidemiology of infectious diseases including Helicobacter pylori"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the Introduction section, the authors have described invasive histological methods of diagnosis and compared them with basic molecular biology methods and did not include other molecular methods that have been used for H. pylori diagnosis and simultaneous detection of resistance including the Fluorescence in situ Hybridization (FISH). These other molecular methods should be included in this section.\nUnder the results table, it is expected to see the age of patients by groups, e.g. 1–10 years, and that immediately brings out the age most susceptible to H. pylori infection. I also want to believe still under Table 1, that the two hospitals were randomly chosen. The socio-demographic and clinical data are too scanty, kindly give more information.\nHelicobacter pylori should be italicized and some H. pylori have the species name starting with a capital letter, so the species name should start with small letters, not capital letters as the authors have written in some.\nIn the conclusion, the authors have written 'urgent need…', there are several available methods now which can be utilized to suit the particular country of origin depending on costs and accuracy. It would have been interesting to see the molecular method compared with both histology and or stool antigen test at the least since histology is not as specific as stool antigen test or urea breath test (the latter might be out of reach due to high cost).\nI, therefore, approve with reservations after my suggestions above have been incorporated into the manuscript.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-113
|
https://f1000research.com/articles/10-1101/v1
|
01 Nov 21
|
{
"type": "Research Article",
"title": "Frequency of anisometropia in children and adolescents",
"authors": [
"Amélia F Nunes",
"Maria Batista",
"Pedro Monteiro",
"Maria Batista",
"Pedro Monteiro"
],
"abstract": "Background: Our objective was to estimate the frequency of anisometropia at various educational stages, from pre-school to 9th school year, studying its association with gender, study cycle and area of residence.\nMethods: 749 children and adolescents (from 3 to 16 years old) participated in this study, 46.7% girls and 42.7% living in a rural environment. The refraction was performed with a paediatric, open field autorefractometer (PlusOptix), without cycloplegic and under binocular conditions.\nResults: The frequency rate of anisometropia in the studied sample was 6.1%, varying from 2.9% in pre-school education to 9.4% in the 3rd study cycle. Myopic anisometropia was the most frequent and hyperopic and astigmatic anisometropia showed identical proportions of occurrence. No statistical evidence was found to state that the occurrence of anisometropia differs between genders or between areas of residence. Regarding the school cycle, a significant association was found with spherical equivalent anisometropia, with an increase in its frequency with school progress (p=0,012), with myopic anisometropia being the main contributor to this variation. Conclusions: The increase in workload for near tasks has been identified as a risk factor for the increase in myopia. This fact may be related to the increase in anisometropia with the educational stage, found in this study. The high rate of anisometropia found in adolescents (9.4%) as well as the progressive increase in this rate throughout school progress (from 2.9% to 9.4%) suggests the need to extend the detection strategies of this condition to beyond childhood.",
"keywords": [
"Pediatrics",
"Child",
"Teenager",
"Refraction",
"School vision"
],
"content": "Introduction\n\nAnisometropia is an ocular disorder characterized by an interocular difference (IOD) in refractive error, representing a specific refractive condition insofar as the two eyes of an individual, with presumably similar sociodemographic, environmental and genetic influences, can have asymmetric eye growth.1 This condition can occur in situations of myopic, hyperopic or astigmatic asymmetry and is strongly associated with the development of other eye changes such as aniseiconia, amblyopia, diplopia and strabismus.2,3\n\nAlthough there is no uniformly defined dioptre value for its clinical classification, an IOD in the spherical equivalent (SE) of 1 diopter or more is accepted as the threshold, for most authors.1,4–8 However, even using this limit, the scientific literature presents a significant variation in the prevalence values of anisometropia in terms of age, gender and ethnicity.4,5,8,9 Factors associated with lifestyle and educational level have also been referred to as risk factors for anisometropia.7,8,10\n\nEarly detection and early treatment is crucial to prevent permanent visual loss. Although it is not clear what is the ideal age to perform the correction, in order to guarantee an ideal visual development and maturation,11 the early correction of anisometropia is important, either because it prevents the development of other changes such as aniseikonia, amblyopia and strabismus,3,12,13 and even in small degrees (<1D) facilitates emmetropization,11 whether because it improves quality of life, reducing or eliminating symptoms of visual discomfort. In this way, visual screening at a young age is useful in identifying who is most likely to benefit from early optical correction or preventive treatment.11,14,15\n\nThe clinical methods used to characterize anisometropia are refractive techniques, with autorefraction, using Plusoptix, one of the most recommended techniques for screening activities.16,17 This instrument allows quantifying the refractive error in open field, simultaneously in both eyes and under the same conditions, in a fast, easy, safe, non-invasive way, in which it is possible to obtain a very similar value to that obtained by cycloplegic refraction17–19 and with excellent precision in anisometropia signalling.19\n\nScientific studies on the prevalence of anisometropia focus on children or adults, with less research being found in adolescence. There is evidence that lifestyle, as well as educational level, may be risk factors for its development. The aim is to estimate the frequency of anisometropia (spherical and astigmatic) and to analyse its pattern of variation in a sample of children and adolescents, from preschool education (from three to six years old) to the various cycles of basic education (from the 1st to the 9th school year in Portugal, from six to fifteen years old).\n\n\nMethods\n\n749 children and adolescents aged between three and sixteen years participated. Students' data for which it was not possible to obtain refraction were excluded, due to technical issues associated with the performance of the instrument (presence of strabismus, opacities, retinal anomalies or when the refractive error exceeded the instrument's measurement limit - spherical measurement range or cylindrical from −7.00 to +5.00D) or due to lack of cooperation from the participant.\n\nThe refractive error was obtained with the paediatric autorefractometer model A09 by PlusOptix by the average of three consecutive measurements, binocular and without the use of a cycloplegic. The PlusOptix allows measuring the refractive error in real time and in both eyes at the same time, at a distance of one meter from the subject's eyes.\n\nIn order to calculate the average of the three refractive measurements, the power was converted from its spherical-cylindrical to its vector representation, described by Thibos,20 using the following expressions:\n\nWhere SE represents the spherical equivalent; J0 represents Jackson's crossed cylinders on the 90° or 180° axis, J45 represents Jackson's crossed cylinders on the 45° or 135° axis, S, C and α represent the spherical, cylindrical and cylinder axis component, respectively, of the autorefractometer measurement.\n\nThe participants were classified in emmetropes, myopes, hyperopes, astigmats or anisometropes, according to the average value of the autorefractometer. In order to carry out this classification, the criteria recommended for the autorefractometer used were applied (Table 1).\n\nThe absolute value of IOD of the refractive error in terms of SE was designated as spherical anisometropia (SA), the absolute IOD in astigmatism was designated as meridional anisometropia (MA) and the absolute IOD only in the astigmatic component was designated by simple meridional anisometropia (sMA), according to the cutoff points referred to in Table 1. The presence of at least one of the previous conditions was designated as total anisometropia (TA). Low anisometropia was considered for IOD values below 2.00D, high anisometropia for values between 2.00D and 6.00D and very high anisometropia for IOD values above 6.00D.\n\nAccording to the type of refractive error, anisometropia was classified as myopic, when both eyes were myopic or when one eye was myopic and the other was emmetropic; hyperopic, when both eyes were hyperopic or when one eye was hyperopic and the other emmetropic; antimetropic, when one eye was myopic and the other hyperopic; simple meridional anisometropia when there was no SA, but there was MA.\n\nA descriptive statistical analysis was carried out, using SPSS version 26 package, characterizing the sample in the variables of interest, sociodemographic and refractive, presenting means and standard deviations, frequencies and percentages both in the whole of the sample and also according to several stratifications to which it was subjected.\n\nIn all the sociodemographic factors in which the sample was categorized, groups with a large size (n > 30) were obtained and by applying the central limit theorem, it can be considered that the violation of the assumptions does not have serious consequences. Thus, the age differences between the groups were inferred by parametric tests: student’s t when the factor subdivides the sample into two groups and one way ANOVA when the factor subdivides the sample into more than two groups. To test the independence between two qualitative variables, the Chi-square independence test was applied.\n\nAll the results of the statistical inference tests were interpreted to a 95% confidence level, that is, the significance level of 0.05 was used.\n\nThis study was conducted in accordance with that the principles of the Declaration of HELSINKI and written informed consent were obtained from parents of each participant in the study. It was approved by the Ethics Committee from Universidade da Beira Interior (CE-UBI-Pj-2019-043).\n\nWritten informed consent was obtained from parents or legal gardians of all participants.\n\n\nResults\n\nIn Portugal the compulsory education includes basic education, which is divided into 3 cycles, followed by the secondary education. The 1st cycle of basic education includes the 1st to 4th school year (ages 6 to 10), the 2nd cycle includes the 5th and 6th year (ages 10 to 12) and the 3rd cycle includes the 7th to the 9th year (ages 12 to 15). The sample under study had students from preschool to the 3rd cycle of basic education and was characterized according to gender, area of residence and cycle of studies. Table 2 summarizes the characteristics of the sample.\n\n** Significant at the 0.01 level.\n\nIt can be seen that the sample has a similar average age between genders and between area of residence, but as can be expected, ages differ between study cycles, being higher in more advanced cycles, and this difference is statistically significant.27\n\nAccording to the classification criteria previously defined for the classification of refractive state, it was concluded that in the study sample 71.16% (n = 533) is emmetropic. Among subjects with significant refractive error (n = 216), it was found that hyperopia is the most frequent refractive error (50.5%, corresponding to 14.6% in the studied population) followed by myopia (22.7%, corresponding to 6.5% in the population), anisometropia (21.3%, corresponding to 6.1% in the population) and astigmatism (11.6% (n = 25) where 5.6% are cases of simple astigmatism and 6% compound astigmatism, corresponding to 3.3% in the population). Figure 1 shows graphically the distribution of the different refractive states in the study sample. The representation of astigmatism, refers only to the occurrence of simple astigmatism, without a significant SE.\n\n46 participants with anisometropia were identified (6.1% of the studied population). According to the magnitude of the refractive error, no child was found with very high anisometropia, 15 were registered with high anisometropia and 31 with low anisometropia, that is, of the anisometrope subjects, most (67.4%) had low anisometropia.\n\nIn the classification of anisometropia according to the type of refractive error, 37 subjects (80.4% of anisometropes, corresponding to 4.9% in the studied population) were found with SA, integrating 21 with myopia, 15 with hyperopia and 1 with antimetropia; and 15 subjects (32.6% of the anisometrope sample, corresponding to 2% in the population) with MA, and only 9 of these did not have SA, and it can be considered that about 20% of the anisometrope sample presents simple meridional anisometropia (sMA). This distribution is represented graphically in Figure 1. It is possible to observe that myopic anisometropia is the most frequent (46%), followed by hyperopic anisometropia (33%) and sMA (19%). Antimetropic anisometropia is the least frequent (2%).\n\nThe proportion of subjects with anisometropia was analysed according to gender, area of residence and school cycle, and through the Chi-square test it was evaluated whether these variables are associated with the occurrence of anisometropia in the studied population (Table 3). The Chi-square test indicates that there is no association between sMA and any of the factors under analysis, therefore this parameter is not in the table.\n\nTA – all anisometropia (spherical and meridional); SA - spherical anisometropia. The highest rates are shown in bold.\n\n* Significant at the 0.05 level.\n\nNo significantly different occurrence of anisometropia was found according to gender or area of residence. (p > 0.05), however, in relation to the school, there is a pattern of variation that increases with the cycle of studies, ranging from 2.9% in preschool education to 9.4% in the 3rd cycle of studies, however this association is only statistically significant for SA (χ2(3) = 10.918; p = 0.012), where there is a rate of 1% in preschool education and 8.6% in the 3rd cycle. It should be noted that the study cycle is dependent on age, as shown in Table 2, older children attend the more advanced study cycle.\n\nFigure 2 illustrates the distribution of anisometropia according to the type of refractive error, for each school cycle. It is observed that myopic anisometropia is present in all study cycles, registering a considerable increase from the beginning of school, that is, from the 1st cycle to the 3rd cycle. On the other hand, hyperopic anisometropia was manifested on a larger scale in children of the 1st cycle, with a lower occurrence in the following cycles. As for the simple MA, it is present in all study cycles and there is no specific pattern in its variation with the study cycle progress.\n\n\nDiscussion\n\nThe present study was carried out with students, including students from preschool education (three years old) to the 9th school year (~fifteen years old) and the value of the IOD considered was ≥1.25D, as it is the suggested value for the interpretation of the results obtained with the material used. An anisometropia rate of 6.1% was found, considering the spherical and meridional anisometropia. It was found that this rate varies with the cycle of studies, showing an increase as the level of education advances, ranging from 2.9% in preschool education to 9.4% in the 3rd cycle of basic education and no statistically significant differences were found in the distribution of anisometropia either between genders or between areas of residence. It was also found that myopic anisometropia was the most prevalent (46%), with a considerable increase in the 3rd cycle of studies.\n\nComparing with others studies, some authors point to a frequency similar to the one found on this research,4,7,8,11,21 others point to a lower frequency22 and others still refer to a higher frequency.23,24 Studies that included only children aged five and six years report rates of 1.3% and 1.6% (SA).5,25 The frequency of SA, found in the present study, in preschool education (children from three to six years old) was 1%, this value being closer to those studies. Others studies included participants from 15 to 19 years old and report rates of 11,2% for SA.24 For the 3rd cycle of studies (average between 12 and 15 years of age), the present study indicates a frequency of 8.6% (SA) and according to the observed variation pattern, at a more advanced age and school stage, a higher rate is expected.\n\nGeographical and methodological issues make it difficult to compare prevalence studies. There is a pattern of greater variability in studies on the Asian continent, where for an identical age group, there are records ranging from 2.5%22 to more than 10%;7 however this is the continent where more studies on the subject are found. In Europe, more similar results are found, 4,6% and 6,9%.4,11\n\nIn the literature, the pattern of variation of anisometropia as a function of age and during the school period is not clear, presenting discordant results. Although many studies focus on children, it is common to have relatively wide age ranges. Most authors conclude that anisometropia varies with age,4,5,7,26 although there are also studies where this relationship has not been found.10,13 Studies on the subject, at school age, which showed an increasing prevalence with age were carried out in populations with a high frequency of myopia, a condition whose prevalence increases in adolescence.26 On the other hand, longitudinal studies show that the prevalence of anisometropia increases after children start attending school.5,7,21 Given these two lines that justify the variation of anisometropia during school age, it appears that they are related to each other, since the progress in the school path is accompanied by increasing age. In the present study, an anisometropia frequency was also found to increase with advancement in the level of education, and consequently the age factor is also contributing to this situation, with myopic anisometropia being the one that most contributes to this variation pattern.\n\nRegarding the influence of gender on anisometropia, contradictory data are found in the scientific literature, while in one study it is reported that the prevalence found was higher in males26 in others it is reported that the prevalence rates are higher in females.10,24 The results of the present study reveal a higher frequency in females (7.1%) than in males (5.3%), however these differences are not statistically significant, and this finding is in line with the results of other authors.9,13,21,25\n\nThe influence of living in rural or urban areas has also been the object of study by several researchers, considering the development of myopia and, consequently, myopic anisometropia, which is more pronounced in urban areas.7,8,10 The present study did not prove whether the area of residence and the frequency of anisometropia are related. This parameter is highly dependent on the way in which each author classifies the area of residence, as rural or urban, and the limits of these regions are sometimes difficult to define. Also, living in a rural area and working in an urban area means that the daily experience of some populations turns out to be more urban, in both environments.\n\nThis study has several strengths. The study was carried out in children and adolescents in a school environment, which allows minimizing the potential bias that occurs in the sampling process and avoids overestimation of the problem when the investigation is carried out in a clinical environment. For this study, spherical anisometropia and astigmatic anisometropia were considered, the latter being disregarded in several studies and there is a record that this anisometropia is the one that most varies in terms of ethnicity.9\n\nCertain limitations can be pointed out in this study. Firstly, the use of autorefraction without cycloplegia is highlighted, which is not the gold standard method of refraction. This fact limits the analysis of the distribution of the different types of refractive errors found in the population studied, because despite the use of an open field autorefractometer, recognized as an instrument with good agreement with cycloplegic retinoscopy and which eliminates the need for cycloplegia in children17,18 tends to underestimate hyperopia.17,19 However, for the present study, this situation does not weaken the conclusions, as the refraction was evaluated in an open field and binocularly, both eyes are exposed to the same conditions, in addition to that studies by other authors with the same methodology, point out a sensitivity 100% for the diagnosis of anisometropia.19 Secondly, the choice of the cut-off point for the classification of anisometropia is pointed out, which on the one hand, the literature recommends considering an IOD of at least 1.00D, the sensitivity studies of the autorefractometer used, recommend considering 1.25D.16 Thirdly, the signalling of the area of residence of the participants as rural or urban is reported, since the limits of these regions were at times difficult to define, noting also that being a study carried out in an area of the inner country, whose territorial classification is of low density, it is expectable that habits and behaviours are more uniform between rural and urban areas, than if the same study had been carried out in an area of greater population density.\n\n\nConclusions\n\nThe present study estimates the frequency of anisometropia in Portuguese children from preschool to the 3rd cycle of basic education finding an occurrence rate of 6.1%. The results of this work also show that the level of the study cycle and the spherical anisometropia are related, verifying that it is low in preschool education and higher in the 3rd cycle of basic education. It was also found that, hyperopic anisometropia is more frequent in younger children and that with the progress of the school path, myopic anisometropia predominates. Taking into account the high frequency of anisometropia found in 3rd cycle students, we are of the opinion that the performance of visual screening at this age is essential for the timely detection and correction of possible eye problems and that, consequently, will lead to better development, learning and school outcomes at these ages, which is why it is important to extend screening actions beyond childhood.\n\n\nData availability\n\nDryad: Portuguese Children Refractive data - VER+ Project, https://doi.org/10.5061/dryad.h44j0zpm5.27\n\nThis project contains the following underlying data:\n\n‐ PortugueseChildrenRefractiveDataVERmaisProjectV2.xlsx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgments\n\nTo Rafaela Venâncio for the support and help in data collection. To the Vision Sciences Clinical and Experimental Centre and UBImedical for the availability of the equipment used and to the Beira Interior University Mission Group in Optometry and Vision Sciences for encouraging this study.\n\n\nReferences\n\nVincent SJ, Collins MJ, Read SA, et al.: Myopic anisometropia: Ocular characteristics and aetiological considerations. Clin. Exp. Optom. 2014; 97(4): 291–307. PubMed Abstract | Publisher Full Text\n\nSmith EL III, Hung LF, Arumugam B, et al.: Observations on the relationship between anisometropia, amblyopia and strabismus. Vis. Res. 2017; 134: 26–42. Publisher Full Text | Free Full Text PubMed Abstract |\n\nSouth J, Gao T, Collins A, et al.: Aniseikonia and anisometropia: implications for suppression and amblyopia. Clin. Exp. Optom. 2019; 102(6): 556–565. PubMed Abstract | Publisher Full Text\n\nHendricks TJ, De Brabander J, Vankan-Hendricks MH, et al.: Prevalence of habitual refractive errors and anisometropia among Dutch schoolchildren and hospital employees. Acta Ophthalmol. 2009; 87(5): 538–543. PubMed Abstract | Publisher Full Text\n\nDeng L, Gwiazda JE: Anisometropia in children from infancy to 15 years. Investig. Ophthalmol. Vis. Sci. 2012; 53(7): 3782–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYoo YC, Kim JM, Park KH, et al.: Refractive errors in a rural Korean adult population: the Namil Study. Eye. 2013; 27(12): 1368–1375. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHu YY, Wu JF, Lu TL, et al.: Prevalence and associations of anisometropia in Children. Investig. Ophthalmol. Vis. Sci. 2016; 57(3): 979–988. Publisher Full Text\n\nLee CW, Fang SY, Tsai DC, et al.: Prevalence and association of refractive anisometropia with near work habits among young schoolchildren: The evidence from a population-based study. PLoS One. 2017; 12(3): 1–15. Publisher Full Text\n\nAfsari S, Rose KA, Gole GA, et al.: Prevalence of anisometropia and its association with refractive error and amblyopia in preschool children. Br. J. Ophthalmol. 2013; 97(9): 1095–1099. Publisher Full Text PubMed Abstract |\n\nWei S, Sun Y, Li S, et al.: Refractive errors in university students in central China: the Anyang University Students Eye Study. Investig. Ophthalmol. Vis. Sci. 2018; 59(11): 4691–4700. Publisher Full Text\n\nFlitcroft I, Mccullough S, Saunders K: What can anisometropia tell us about eye growth?. Br. J. Ophthalmol. 2021; 105: bjophthalmol-2020-316406–bjophthalmol-2020-311215. Publisher Full Text\n\nJeon HS, Choi DG: Stereopsis and fusion in anisometropia according to the presence of amblyopia. Graefes Arch. Clin. Exp. Ophthalmol. 2017; 255(12): 2487–2492. PubMed Abstract | Publisher Full Text\n\nDobson V, Miller JM, Clifford-Donaldson CE, et al.: Associations between anisometropia, amblyopia, and reduced stereoacuity in a school-aged population with a high prevalence of astigmatism. Investig. Ophthalmol. Vis. Sci. 2008; 49(10): 4427–4436. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNunes AF, Monteiro PM, Ferreira FB, et al.: Convergence insufficiency and accommodative insufficiency in children. BMC Ophthalmol. 2019; 19(1): 1–8. Publisher Full Text\n\nNunes AF, Sena F, Calado R, et al.: Reduced visual acuity in children from 5 to 6 years old, with LEA chart. Graefes Arch. Clin. Exp. Ophthalmol. 2021; 259: 759–768. PubMed Abstract | Publisher Full Text\n\nSilbert D, Matta N, Tian J, et al.: Comparing the SureSight autorefractor and the plusoptiX photoscreener for pediatric vision screening. Strabismus. 2014; 22(2): 64–67. PubMed Abstract | Publisher Full Text\n\nDikkaya F, Erdur SK: Comparison of the PlusOptix S09 and Spot Vision photorefractor to cycloretinoscopy. Int. Ophthalmol. 2018; 2018: 3–10.\n\nYilmaz I, Ozkaya A, Alkin Z, et al.: Comparison of the Plusoptix A09 and Retinomax K-Plus 3 With Retinoscopy in Children. J Ped Ophthalmol Strab. 2015; 52(1): 37–42. 2015.\n\nFogel-Levin M, Doron R, Wygnanski-Jaffe T, et al.: A comparison of plusoptiX A12 measurements with cycloplegic refraction. J. AAPOS. 2016; 20(4): 310–4. PubMed Abstract | Publisher Full Text\n\nThibos LN, Wheeler W, Horner D: Power vectors: an application of Fourier analysis to the description and statistical analysis of refractive error. Optom. Vis. Sci. 1997; 74(6): 367–375. PubMed Abstract | Publisher Full Text\n\nAlrahili NHR, Jadidy ES, Alahmadi BSH, et al.: Prevalence of uncorrected refractive errors among children aged 3-10 years in western Saudi Arabia. Saudi Med. J. 2017; 38(8): 804–810. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYekta A, Fotouhi A, Hashemi H, et al.: Prevalence of refractive errors among schoolchildren in Shiraz, Iran. Clin. Exp. Ophthalmol. 2010; 38(3): 242–248. PubMed Abstract | Publisher Full Text\n\nOhlsson J, Villarreal G, Sjöström A, et al.: Visual acuity, amblyopia, and ocular pathology in 12-to 13-year-old children in Northern Mexico. J. AAPOS. 2003; 7(1): 47–53. PubMed Abstract | Publisher Full Text\n\nQuek TP, Chua CG, Chong CS, et al.: Prevalence of refractive errors in teenage high school students in Singapore. Ophthalmic Physiol. Opt. 2004; 24(1): 47–55. PubMed Abstract | Publisher Full Text\n\nHuynh SC, Wang XY, Ip J, et al.: Prevalence and associations of anisometropia and aniso-astigmatism in a population based sample of 6 year old children. Br. J. Ophthalmol. 2006; 90(5): 597–601. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWajuihian SO, Mashige KP: Gender and age distribution of refractive errors in an optometric clinical population. J Optom. 2021. Publisher Full Text\n\nNunes AF, Batista MJ, Monteiro PL: Portuguese Children Refractive data - VER+ Project.2021. Publisher Full Text"
}
|
[
{
"id": "98416",
"date": "12 Nov 2021",
"name": "Carla Lança",
"expertise": [
"Reviewer Expertise Refractive errors and strabismus"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study reports on the prevalence of anisometropia in a sample of Portuguese children and adolescents. The wording needs major revision. I have several comments as shown below.\nTitle\nI suggest replacing the word “frequency” by “prevalence”. This suggestion also applies throughout all sections of the manuscript.\nAbstract\nMethods - Please replace “cycloplegic” by \"cycloplegia”.\n\nResults - Please revise the wording of the following sentence “to state that the occurrence…”; The last sentence of the results it’s not clear and should be revised.\nIntroduction\nThe first sentence is too long, and the wording needs to be revised. I suggest splitting it into two sentences. I have a similar comment for the third paragraph of the introduction section.\n\nThere is no mention to previous studies on anisometropia prevalence. Also, there is the need to show more detailed results on the studies reporting risk factors and its association with anisometropia (e.g., sample size, age, p values, etc.).\nMethods\nThe methods section is incomplete. The methods section of a research paper provides the information by which a study's validity is judged. Therefore, it requires a clear and precise description of how an experiment was done, and the rationale for why specific experimental procedures were chosen. For example, more information is necessary on the sampling method and authors should describe their study design.\nResults\nThe first paragraph should be moved to the methods section.\n\nTable 2 – Replace “statistical test” by p value only (follow the same recommendation in the text results). Also, include a note referring to which comparisons are being made (for example, is it the distribution of children by cycles or the age by cycles?).\n\nAt the time you are writing your article, you have already completed your study, so you should use past tense in your methodology and results section to record what you did and found (for example, “this difference was statistically significant”).\n\nRefractive state and anisometropia sections need to be re-written, as it is confusing to present two percentages at the same time. Perhaps the authors can consider showing separate sentences for those results.\n\nInfluence of sociodemographic variables: the first sentence of this section should be moved to the statistical analysis; Delete “therefore this parameter is not in the table” and replace by the p value.\n\nTable 3 – delete the X2 value and only present p value. Non-significant p values may be presented with only 2 decimal places.\n\nFor risk factor analysis the multivariate adjusted analysis should be additionally shown.\n\nFigure 2. The colour of the legend is not clear, and it is difficult to distinguish the categories presented in the graph. The y axis wording needs revision.\nDiscussion\nPlease, delete the 1st sentence.\n\nThe differences between prevalence of anisometropia in Asia and Europe need a more careful explanation. Environmental factors play a major role in the development of refractive errors, especially myopia.\n\nAnother limitation of the study that was not referred is that factors such as reading habits or outdoor time were not collected and those may be risk factors for the development of refractive errors.\n\nIs this the first study in Portugal? Are your results comparable with other studies in Portugal?\nConclusions\nPlease revise the wording on the sentence that includes the following: “we are of the opinion”.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7520",
"date": "08 Dec 2021",
"name": "Amelia Nunes",
"role": "Author Response",
"response": "We would like to thank the reviewer for her valuable time and comments on our article; this will be very useful for us in future research and has allowed us to improve this document. We have made the required corrections. Title I suggest replacing the word “frequency” by “prevalence”. This suggestion also applies throughout all sections of the manuscript. R: The title was replaced Abstract Methods - Please replace “cycloplegic” by \"cycloplegia”. R: The word was replaced Results - Please revise the wording of the following sentence “to state that the occurrence…”; The last sentence of the results it’s not clear and should be revised. R: Sentence revised to “No statistical differences were found between genders or between areas of residence regarding the rate of anisometropia”; Last sentence revised to “Regarding spherical equivalent anisometropia, there is a pattern of variation that increases with the cycle of studies (��2(3)= 10.918; p = 0.012), with myopic anisometropia being the main contributor to this variation.” Introduction The first sentence is too long, and the wording needs to be revised. I suggest splitting it into two sentences. I have a similar comment for the third paragraph of the introduction section. R: The first sentence was split and wording revised to:” Anisometropia is an ocular disorder characterized by an interocular difference (IOD) in refractive error. It represents a specific refractive condition where the two eyes of an individual, with presumably similar sociodemographic, environmental and genetic influences, can have asymmetric eye growth.” The third paragraph split and wording revised to:” Although it is not clear what is the ideal age to perform the correction, in order to guarantee an ideal visual development and maturation, the early correction of anisometropia is important.11 This prevents the development of other changes such as aniseikonia, amblyopia and strabismus3,12,13 and even in small degrees (<1D) facilitates emmetropization.11 It also improves quality of life, reducing or eliminating symptoms of visual discomfort.” There is no mention to previous studies on anisometropia prevalence. Also, there is the need to show more detailed results on the studies reporting risk factors and its association with anisometropia (e.g., sample size, age, p values, etc.). R: These data were introduced in a new table, and the reference numbering was changed accordingly. Methods The methods section is incomplete. The methods section of a research paper provides the information by which a study's validity is judged. Therefore, it requires a clear and precise description of how an experiment was done, and the rationale for why specific experimental procedures were chosen. For example, more information is necessary on the sampling method and authors should describe their study design. R: The method section was completed including the following text “Data from the Portuguese Census 2011, shows a population of 319284 from 0 to 14 years old in the central region. For a confidence level of 95% and a 5% margin of error, taking into account that the prevalence of the studied condition is unknown, it was fixed at 50% to obtain a large enough sample size. The result was a minimum of 384 subjects. The data collection took place in 5 schools of the central region of Portugal, including all students that were authorized to participate by their legal guardians.” Results The first paragraph should be moved to the methods section. R: The paragraph was moved Table 2 – Replace “statistical test” by p value only (follow the same recommendation in the text results). Also, include a note referring to which comparisons are being made (for example, is it the distribution of children by cycles or the age by cycles?). R: Done. This table was moved to the methods section, and the statistical analysis was deleted since it did not provide significant information. At the time you are writing your article, you have already completed your study, so you should use past tense in your methodology and results section to record what you did and found (for example, “this difference was statistically significant”). R: Text rewritten to past tense. Refractive state and anisometropia sections need to be re-written, as it is confusing to present two percentages at the same time. Perhaps the authors can consider showing separate sentences for those results. R: Both sections were rewritten to avoid double percentages. Influence of sociodemographic variables: the first sentence of this section should be moved to the statistical analysis; Delete “therefore this parameter is not in the table” and replace by the p-value. R: The sentence was moved to the methods section. “Therefore..” was removed and the p-value information was added to the table. Table 3 – delete the X2 value and only present p-value. Non-significant p values may be presented with only 2 decimal places. R: X2 values deleted and p values with 2 decimal places For risk factor analysis the multivariate adjusted analysis should be additionally shown. R: The multivariate analysis was added to the table. Figure 2. The colour of the legend is not clear, and it is difficult to distinguish the categories presented in the graph. The y axis wording needs revision. R: Legend colour changed. Y-axis caption revised. Discussion Please, delete the 1st sentence. R: Sentence deleted The differences between prevalence of anisometropia in Asia and Europe need a more careful explanation. Environmental factors play a major role in the development of refractive errors, especially myopia. R: An extra sentence was added to explain to acknowledge the contribution of environmental factors “Some studies show that lifestyle parameters, such as reading and writing habits and time spent indoors, contribute to the prevalence of anisometropia variation. 7,8,10,11” Another limitation of the study that was not referred to is that factors such as reading habits or outdoor time were not collected and those may be risk factors for the development of refractive errors. R: We recognise the relevance of these factors, and they will be included in future studies. Accordingly to your suggestions, the following sentence was added to the end of the text “For future studies, data regarding reading habits and time spent outdoors will be collected, since these can be risk factors for the development of refractive errors.” Is this the first study in Portugal? Are your results comparable with other studies in Portugal? R: This is not the first study in Portugal, however in indexed research papers we couldn’t find any comparable studies for Portugal. We found an indexed research paper by Lança, Serra, and Prista in Portuguese children, which indirectly refers to the number of uncorrected anisometropic children, but the methodology is very different from ours, including the anisometropia classification criterium. However, the percentage of uncorrected anisometropia is similar. We considered this fact relevant and it was included in the discussion. Conclusions Please revise the wording on the sentence that includes the following: “we are of the opinion”. R: The sentence was revised and divided to: “Taking into account the high frequency of anisometropia found in 3rd cycle students, in our opinion the implementation of visual screening programs at this age is essential for the timely detection and correction of possible eye problems. This course of action will lead to better development, learning, and school outcomes at these ages.”"
}
]
},
{
"id": "98419",
"date": "19 Nov 2021",
"name": "Pedro M. Serra",
"expertise": [
"Reviewer Expertise Vision Sciences",
"Ophthalmic Optics."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral comment\nThank you for considering my name as a reviewer of the manuscript titled “Frequency of anisometropia in children and adolescents”. I would like to congratulate the authors for their work in this field of vision sciences which has a special interest in countries where is a shortage of epidemiologic data in the field of vision. Regarding the manuscript, my feeling is that it requires additional work before it is considered for indexing. In this report I will cover the technical issues that in my opinion would improve the quality of the manuscript, however, I would recommend the author's linguistic editing of the final manuscript. Examples of linguistic improvement are very long sentences with multiple ideas and some lack of concise writing.\nSpecific topics\nAbstract: Provide a statement defining the topic of research and a second sentence where you state the aim of the study (eg. This study aims to estimate the prevalence of anisometropia in the Portuguese population of children and adolescents.) I suggest changing the word frequency to prevalence throughout the text.\nMethods:\nIndicate the study design? (e.g. Observational Cross-sectional study)\n\nHow did you build the sample?\n\nDescribe the dependent and independent variables\n\nRemove any data from the methods\nResults\nUse direct messages (e.g. No association was found between the presence of anisometropia with gender or area of residence)\nConclusion\nThe first sentence should be deleted this is not a conclusion from the present study.\n\nIntroduction:\nI think the introduction requires some improvement\n1st paragraph – Provides a definition of the research topic\n\n“Anisometropia is an ocular disorder characterized by an interocular difference (IOD) in refractive error, representing a specific refractive condition insofar as the two eyes of an individual, with presumably similar sociodemographic, environmental and genetic influences, can have asymmetric eye growth.” Please reformulate this sentence, particularly remove the word presumably.\n\n2nd paragraph and 3rd paragraph – mention the risk factors for anisometropia and the importance of assessing it\n\n4th paragraph- describes the instrument used. I would suggest moving this information to the methods\n\n5th paragraph- states the aim of the study.\n\nMissing information- the authors should mention the prevalence studies published, especially in Portugal, and compare with other European countries.\n\nMethods:\n\nPlease include:\nType of study\n\nNature of the sample, how did you select the different groups? There are differences in the socioeconomic nature of the study sites? Please indicate how did you define Rural and Urban populations? (e.g. number of inhabitants covered by each school)?\n\nPlease indicate specifically the region where this study was conducted, this is important for instance in future meta-analysis studies.\n\nDuration of the study (e.g September 2021 – November 2021)\n\nCould you add information about the use of spectacles, you could try to see if the anisometropia had already been identified.\n\nInstrument description\nInclude PlusOptix manufacturer city and country\n\nProvide the repeatability of the instrument (published)\n\nThis is just a comment - “ Students' data for which it was not possible to obtain refraction were excluded, due to technical issues associated with the performance of the instrument (presence of strabismus, opacities, retinal anomalies or when the refractive error exceeded the instrument's measurement limit - spherical measurement range or cylindrical from −7.00 to +5.00D) or due to lack of cooperation from the participant.” This is probably one of the most valuable pieces of information from the data collection and it is a shame not being presented.\nData Analysis\nPlease indicate how the reader can interpret Thibos’ notation in regards to the J0 and J45.\n\nSay that the Cylinder component needs to be in negative form\n\nAnisometropia Classification\nI suggest writing the formulas used for calculating the SA, MA, and sMA.\n\nStatistical Analysis\nResults\nSample characterization – 1st paragraph move it to the methods section.\n\nRefractive State\nPlease provide a table or figure (Box plot) with the refractive error information, where is possible to see the mean, standard deviation and range\n\nFigure 1 has limited information, I suggest including the percentages in the table mentioned above\n\nAnisometropia\nPlease, use written numbers when placing them at the beginning of a sentence. (e.g Forty-six not 46)\n\nProvide information about the level of anisometropia per type. Describe the mean, standard deviation, and range\n\nSuggest creating a figure (bar plot with the percentages of anisometropia, total, young age group and older age group)\n\nDiscussion\nThe authors found a statistically significant association between the frequency of myopic anisometropia and age/ scholarly. Could the authors extend the discussion on the etiology of myopic anisometropia, which probably implies an asymmetric eye growth? Discussing this point could help the authors to suggest actions/mechanisms to prevent anisometropia.\n\nDiscuss the consequences of hyperopic anisometropia, use the values (mean and standard deviation) for arguing about the number of subjects in risk of developing amblyopia.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7521",
"date": "08 Dec 2021",
"name": "Amelia Nunes",
"role": "Author Response",
"response": "We thank the reviewer for his time and very constructive comments. We appreciate the reviewers' voluntary contributions in the form of helpful comments that allowed us to strengthen our article. We updated the article according to your comments. Specific topics Abstract: Provide a statement defining the topic of research and a second sentence where you state the aim of the study (eg. This study aims to estimate the prevalence of anisometropia in the Portuguese population of children and adolescents.) I suggest changing the word frequency to prevalence throughout the text. R: The abstract was modified to include the topic and the aims “This research was developed to study the epidemiology of anisometropia. It aims to estimate the prevalence of anisometropia in Portuguese children and adolescents at various educational stages, studying its association with sociodemographic variables” Methods: Indicate the study design? (e.g. Observational Cross-sectional study) How did you build the sample? Describe the dependent and independent variables Remove any data from the methods R: All information was included and data was removed. The sample was collected from several kindergartens and schools in the central region of Portugal. The central region was included in the abstract and more details were added to the methods section. Results Use direct messages (e.g. No association was found between the presence of anisometropia with gender or area of residence) R: Section changed Conclusion The first sentence should be deleted this is not a conclusion from the present study. R: Section changed Introduction: I think the introduction requires some improvement 1st paragraph – Provides a definition of the research topic “Anisometropia is an ocular disorder characterized by an interocular difference (IOD) in refractive error, representing a specific refractive condition insofar as the two eyes of an individual, with presumably similar sociodemographic, environmental and genetic influences, can have asymmetric eye growth.” Please reformulate this sentence, particularly remove the word presumably. 2nd paragraph and 3rd paragraph – mention the risk factors for anisometropia and the importance of assessing it 4th paragraph- describes the instrument used. I would suggest moving this information to the methods 5th paragraph- states the aim of the study. Missing information- the authors should mention the prevalence studies published, especially in Portugal, and compare with other European countries. R: All information was included. A new table (new table 1) was introduced containing prevalence studies. We did not find any studies regarding anisometropia prevalence in Portugal, in indexed research papers. We found an indexed research paper by Lança, Serra, and Prista in Portuguese children, which indirectly refers to the number of uncorrected anisometropic children, but the methodology is very different from ours, including the anisometropia classification criterium. However, the percentage of uncorrected anisometropia is similar. We considered this fact relevant and it was included in the discussion. Methods: Please include: Type of study Nature of the sample, how did you select the different groups? There are differences in the socioeconomic nature of the study sites? Please indicate how did you define Rural and Urban populations? (e.g. number of inhabitants covered by each school)? Please indicate specifically the region where this study was conducted, this is important for instance in future meta-analysis studies. Duration of the study (e.g September 2021 – November 2021) Could you add information about the use of spectacles, you could try to see if the anisometropia had already been identified. R: This information is important and was included to some extent in the methods section. Rural and Urban definitions were based on the information provided by the municipalities representative. Instrument description Include PlusOptix manufacturer city and country Provide the repeatability of the instrument (published) This is just a comment - “ Students' data for which it was not possible to obtain refraction were excluded, due to technical issues associated with the performance of the instrument (presence of strabismus, opacities, retinal anomalies or when the refractive error exceeded the instrument's measurement limit - spherical measurement range or cylindrical from −7.00 to +5.00D) or due to lack of cooperation from the participant.” This is probably one of the most valuable pieces of information from the data collection and it is a shame not being presented. R: Information included. Although a study reports repeatability of around 0,6D for MSE with the A09 model (Plusoptix Vision Screener: the accuracy and repeatability of refractive measurements using a new autorefractor) this and other studies are not focused on anisometropia, for which IOD MSE errors could be minimized. Another study with a different plus optix model, reports a sensitivity of 100% for anisometropia (A comparison of plusoptiX A12 measurements with cycloplegic refraction). We included this study in the introduction. Data Analysis Please indicate how the reader can interpret Thibos’ notation in regards to the J0 and J45. Say that the Cylinder component needs to be in negative form R: This information has been added Anisometropia Classification I suggest writing the formulas used for calculating the SA, MA, and sMA. R: The formulas were added Statistical Analysis Results Sample characterization – 1st paragraph move it to the methods section. R: Paragraph moved Refractive State Please provide a table or figure (Box plot) with the refractive error information, where is possible to see the mean, standard deviation, and range Figure 1 has limited information, I suggest including the percentages in the table mentioned above R: A new table (table 4) containing this data was added to this section Anisometropia Please, use written numbers when placing them at the beginning of a sentence. (e.g Forty-six not 46) Provide information about the level of anisometropia per type. Describe the mean, standard deviation, and range Suggest creating a figure (bar plot with the percentages of anisometropia, total, young age group and older age group) R: Sentence rewritten Mean, standard deviation, and range of anisometropia per type was added in table 4. An extra figure would duplicate the information. Information about the age group is already included in table 5, distributed by the study cycle which indirectly represents age groups. An extra figure would duplicate the information. Discussion The authors found a statistically significant association between the frequency of myopic anisometropia and age/ scholarly. Could the authors extend the discussion on the etiology of myopic anisometropia, which probably implies an asymmetric eye growth? Discussing this point could help the authors to suggest actions/mechanisms to prevent anisometropia. R: This is an excellent suggestion for future research. We can hypothesise that an excess of near-work activities, associated with incorrect posture, can lead to asymmetric eye growth. However, those factors were not controlled in the present study. Discuss the consequences of hyperopic anisometropia, use the values (mean and standard deviation) for arguing about the number of subjects at risk of developing amblyopia. R: Only 2 uncorrected anisometropes were hyperopic, and since no BCVA data was collected, we feel that there are no sufficient data to support this kind of analysis. However, we agree that it is an excellent suggestion for future work."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1101
|
https://f1000research.com/articles/10-539/v1
|
06 Jul 21
|
{
"type": "Brief Report",
"title": "Any neuron can perform linearly non-separable computations",
"authors": [
"Romain D. Cazé"
],
"abstract": "Multiple studies have shown how dendrites enable some neurons to perform linearly non-separable computations. These works focus on cells with an extended dendritic arbor where voltage can vary independently, turning dendritic branches into local non-linear subunits. However, these studies leave a large fraction of the nervous system unexplored. Many neurons, e.g. granule cells, have modest dendritic trees and are electrically compact. It is impossible to decompose them into multiple independent subunits. Here, we upgraded the integrate and fire neuron to account for saturating dendrites. This artificial neuron has a unique membrane voltage and can be seen as a single layer. We present a class of linearly non-separable computations and how our neuron can perform them. We thus demonstrate that even a single layer neuron with dendrites has more computational capacity than without. Because any neuron has one or more layer, and all dendrites do saturate, we show that any dendrited neuron can implement linearly non-separable computations.",
"keywords": [
"Dendrites",
"computation",
"linearly non-separable",
"neuroscience"
],
"content": "Introduction\n\nWe show here how dendrites can extend the computational capacity of all neurons, even the tiniest. We already knew that dendrites might extend the computational capacity of some pyramidal neurons. Their extended dendrites capable of dendritic spikes changed the way we saw them (see2 for one of the first articles presenting this idea). More recently a study suggested that we should model these neurons as a two layer neural networks.6 This theoretical model was further consolidated by experiments showing that we can see a pyramidal neuron as a collection of non-linear subunits.7 Certain non-linearities can even allow a dendrite to implement the exclusive or (XOR).9 Moreover, a similar kind of non-monotonic non-linearity was found in human pyramidal neurons.4 But what about other neurons with modest dendrites incapable of spiking?\n\nPyramidal neurons only represent a fraction of all neurons. For instance, the dendrites of cerebellar stellate cells cannot emit spikes, but they do saturate1 and they can be decomposed into multiple independent subunits - with independent membrane voltages - turning them into two-stage units like the pyramidal neuron.8 Previously we have shown that passive dendrites are sufficient to enable a neuron to perform linearly non-separable computations, for instance, the feature binding problem.3 We focus here on cells with a modest and passive dendritic tree. These cells form a single layer unit. In the present study, we demonstrate that these neurons can still implement a linearly non-separable computation. We use them as the simplest common denominator, as even spiking dendrites do saturate, and a 2 layer network can perform all the computation of a single layer architecture and more.\n\n\nMethods\n\nWe started from a leaky integrate and fire (LIF). This model has a membrane V modelled by the following equation:\n\nWith τ = 20 ms the neuron time constant, v(t) the membrane voltage at time t and vE = −65 mV which sets the resting membrane voltage. R = 20 mΩ is the value of the resistance and Is(t) models the time varying synaptic inputs conductance.\n\nThis current depends on the difference between v(t) the neuron voltage, equal everywhere, and Es the synaptic reversal potential (0 mV) while gdi is the synaptic conductance in dendrite i. Each gdi is bounded between 0 and 10pS. Each gdi jumps up instantaneously to its maximal value for each incoming input spike and decays exponentially with time constant τs = 1 ms. In a LIF all synaptic inputs are gathered into a single umbrella and i = 1. In the present study, we introduce the Dendrited Integrate and Fire (DIF) which includes at least two dendrites (i = 2). We cluster synaptic inputs into two groups, each targeting a dendrite (one green and one blue, see Figure 1). We used the Brian software version 2 to carry out our simulations, the code is freely available on the git repository attached with this report.10\n\n(A) A leaky integrate and fire (LIF) with two dendrites making it a dendrited integrate and fire (DIF), each half of the 4 synaptic inputs targets a distinct dendrite where g locally saturates at 10pS (B) Four stimulation scenarios, filled circles stand for a >50 Hz input spike train while empty circles stand for >50 Hz input spike train. Below, we plotted the response of the DIF (black) and a LIF (grey). We purposely removed the ticks label as the frequencies depend on the parameter of the model and input regularity. The parameters of the model can vary largely without affecting the observation.5\n\nFirst, let’s present Boolean functions:\n\nDefinition 1. A Boolean function of n variables is a function on {0,1}n into {0,1}, where n is a positive integer.\n\nImportantly, we commonly assume that neurons can only implement linearly separable computations:\n\nDefinition 2. f is a linearly separable computation of n variables if and only if there exists at least one vector w ∈ Rn and a threshold Θ ∈ R such that:\n\nwhere X ∈{0,1}n is the vector notation for the Boolean input variables.\n\n\nResults\n\nIn this section, we demonstrate a class of compact linearly inseparable (non-separable) computations that we are going to study. These computations are compact because they have four input/output lines.\n\nWe entirely specify an example in Table 1. This computation that we call the the compact feature binding problem (cFBP) is linearly inseparable.\n\nProposition 1. The cFBP is linearly inseparable (non-separable)\n\nProof. The output must be 0 for two disjoint couples (1,2) and (3,4) of active inputs. It means that w1 + w2 ≤ Θ, and w3 + w4 ≤ Θ, and we can add these two inequalities to obtain w1 + w2 + w3 + w4 ≤ 2Θ. However, the output must be 1 for two other couples made of the same active inputs (1,3) and (2,4). It means that w1 + w3 > Θ, and w2 + w4 > Θ, and we can add these two inequalities to obtain w1 + w2 + w3 + w4 > 2Θ. This yield a contradiction proving that no weights set exists solving this set of inequalities.\n\nThe cFBP is simple in two ways:\n\n• Four input/output relations define this computation - the same number as the famous XOR (exclusive or).\n\n• Contrary to the XOR it can be implemented with excitatory inputs and a monotone transfer function.3\n\nWe can extend the cFBP by increasing the number of inputs. In this case we deal with tuples instead of couples. As such, the cFBP corresponds to an entire family of linearly inseparable computations, and a dendrited neuron can implement them using the strategy that we will present in the next section.\n\nA LIF with its linear integration cannot implement such a computation. While a neuron with two saturating dendrites can easily implement it. We already proved how a ball-and-stick biophysical model can implement this computation in a previous study.3\n\nWe use two independently saturating conductances to implement the cFBP in a minimal extension of the LIF that we called the dendrited integrated and fire (DIF). The DIF has a single membrane voltage to account for its compactness so we might wonder how local saturation can arise in such a morphology. Saturation has two possible origins: (1) a reduction in driving force can cause saturation as in,1 but (2) it can also be due to the intrinsic limitations in conductance per unit of surface. This latter possibility makes saturation possible in an electrically compact neuron. Even in a neuron with a small dendritic tree, the conductance is going to reach an upper bound per unit of surface and the only possibility to increase excitation consists in stimulating a larger area. We are going to employ this local bounding of the conductance to implement the cFBP in a DIF.\n\nTo do that, we only need two dendrites as shown in Figure 1A. We can interpret the 0s and 1s in the truth table in at least two ways: (1) either the pre- or post-synaptic neurons activates (2) or they reach a given spike frequency. In the following section, we will use the latter interpretation. Consequently, we consider a pre-synaptic input active when it fires above 50 Hz regular spike-train and inactive if it fires below 50 Hz (this value is arbitrary and can largely vary to match a neuron working range). We stimulate our model in four different combinations of inputs to reproduce the truth table from the previous section. You can observe on Figure 1 that locally bounding g enables implemention of cFBP. When g has no bound, the membrane voltage always reaches the spiking threshold at the same speed (LIF case). When we locally bound conductances the membrane voltage takes more time to reach threshold in the clustered case (total g = 10pS) than in the scattered case (total g = 20pS). All in all, a DIF will respond differently for the clustered and scattered case while a LIF won’t. This enables a DIF to implement the cFBP while a LIF can’t.\n\n\nDiscussion/conclusion\n\nIn this brief report, we introduced a small extension to the leaky integrate and fire neuron: a dendrited integrate and fire neuron which can implement linearly non-separable computations. This single layer model applied to granule cells predicts that they can implement a linearly non-separable computation. These neurons have on average four dendrites, but we have shown here that two suffice. The DIF’s multiple distinctly bounded g underlie this ability. For example, we need a local saturation of gdi to implement the cFBP.\n\nThe experiment demonstrating this prediction seems straightforward. One would need to stimulate four distinct groups of mossy fibres following our different scenarios. We could then record how a group of granule cell respond using optogenetics reporting (i.e. calcium imaging). We predict that a significant part of granule cells might implement the cFBP. This prediction could reveal the true potential of single neurons. The next step consists of looking at the network level as already done with spiking dendrites.5\n\n\nData availability\n\nNo data are associated with this article.\n\n\nSoftware availability\n\n\n\n• Source code available from: https://github.com/rcaze/21_03Ca/tree/1.\n\n• Archived source code at time of publication: https://doi.org/10.5281/zenodo.4937792.10\n\n• License: MIT license.",
"appendix": "Competing interests\n\n\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThis work was supported by the Centre National de la Recherche Scientifique [ANR-UWAKE].\n\nThe funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\n\nAcknowledgements\n\nI used “we” as science is a collective endeavour. Discussions on this topic had begun as early as 2013 with my former PhD Advisor and collaborators from Institut Pasteur Paris. I also want to acknowledge M. Humphries, F Zeldenrust, A. Foust for their valuable comments on the early draft and Ms Marini-Audouard for the proof-reading before submission. An earlier version of this article can be found on bioRxiv (doi: https://doi.org/10.1101/2021.04.02.438177).\n\n\nReferences\n\nAbrahamsson T, Cathala L, Matsui K, et al.: Thin dendrites of cerebellar interneurons confer sublinear synaptic integration and a gradient of short-term plasticity. Neuron. 73(6): 1159–1172. PubMed Abstract | Publisher Full Text\n\nBartlett M: The clusteron: towards a simple abstraction to a complex neuron. Advances in Neural Information Processing Systems. 4.\n\nCazé RD, Humphries M, Gutkin B: Passive dendrites enable single neurons to compute linearly non-separable functions. PLoS Comput Biol. 9(2): e1002867. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGidon A, Zolnik TA, Fidzinski P, et al.: Dendritic action potentials and computation in human layer 2/3 cortical neurons. Science. 367(6473): 83–87. PubMed Abstract | Publisher Full Text\n\nMemmesheimer R-M, Timme M: Non-additive coupling enables propagation of synchronous spiking activity in purely random networks. PLoS Comput Biol. 8(4): e1002384. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPoirazi P, Brannon T, Mel BW: Pyramidal neuron as two-layer neural network. Neuron. 37(6): 989–999. PubMed Abstract | Publisher Full Text\n\nPolsky A, Mel BW, Schiller J: Computational subunits in thin dendrites of pyramidal cells. Nat Neurosci. 7(6): 621–627. PubMed Abstract | Publisher Full Text\n\nTzilivaki A, Kastellakis G, Poirazi P: Challenging the point neuron dogma: FS basket cells as 2-stage nonlinear integrators. Nat Commun. 10(1): 3664. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZador AM, Claiborne BJ, Brown TH: Nonlinear pattern separation in single hippocampal neurons with active dendritic membrane. Advances in Neural Information Processing Systems. page 8.\n\nDr Cazé RD : rcaze/21_03Ca: Relase F1000 (Version 1). Zenodo. 2021, June 12. Publisher Full Text"
}
|
[
{
"id": "89096",
"date": "13 Jul 2021",
"name": "Athanasia Papoutsi",
"expertise": [
"Reviewer Expertise computational neuroscience",
"dendritic computations"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis Brief Report shows at a conceptual level that electrically compact neurons can solve non-linearly separable computations of four or more inputs. This is a result of the saturating responses to ‘clustered’ input at the dendritic level (simulating mainly the reduction of the driving force in the dendrites), and increased response to ‘scattered’ input at the somatic level. This study expands on previous work of the author and others and adds on the range of computations neurons can perform with their dendrites.\nWe have two major concerns that limit the clarity of this work:\nFigure 1B and 3rd paragraph on page 5: The x-axis label states ‘Time’, and the relevant text states that “the membrane voltage takes more time to reach threshold in the clustered case (total g = 10pS) than in the scattered case (total g = 20pS)”. Given that this work is based on an arbitrary thresholding of the output frequency, it is not obvious where time is involved and its meaning in the x-axis.\n\nIn the provided code on GitHub (line 78 in the code), the ceiling of the second dendrite (i.e., syn2 in the code) is set to 0.5 and not to 0.1. Please clarify the value used. If those different saturating thresholds were indeed used, this should be explicitly stated and reasoned in the main text.\n\nMinor comments (not in order of importance nor appearance in the manuscript):\nFor clarity, specify that granule cells refer to the cerebellum (and not the hippocampus).\n\nCorrect R units to be MΩ (not mΩ).\n\nFigure 1 legend: “filled circles stand for a >50 Hz input spike train while empty circles stand for >50 Hz input spike train.” Change the second > to <.\n\nPage 4: “This computation that we call the the compact feature binding problem (cFBP) is linearly inseparable.” Delete the second ‘the’.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-539
|
https://f1000research.com/articles/11-625/v1
|
08 Jun 22
|
{
"type": "Research Article",
"title": "Grammatical awareness and language performance: examining gendered differences among Saudi EFL (English as a foreign language) learners",
"authors": [
"Ayed T Alharbi"
],
"abstract": "Background: Despite the many studies that have been conducted on the learners of English as a foreign language (EFL) regarding grammar ability in various contexts, some gaps are still unbridged and need researching. Therefore, this study addresses the research gap in the Saudi context concerning the grammatical competence of Saudi EFL (English as foreign language) learners. Methods: This study described the Saudi EFL learners’ level of awareness in developing grammatical forms. It also assessed Saudi EFL students' level of performance in grammar learning. Finally, it quantitatively explored what, if any, gendered differences exist in the grammar acquisition of Saudi EFL learners. The study employed descriptive and inferential statistics to analyze the data. The study sample comprised 50 Saudi EFL students out of the population of 120 students enrolled in EFL programs at Qassim University, Saudi Arabia with sample size being determined using online sampling calculator Raosoft. Results: The results of the present study show that the Saudi EFL learners manifest a favorable level of awareness in developing grammatical forms while they still not having attained mastery of English grammar. Results also indicate that grammatical competence and level of awareness are more advanced among the Saudi EFL female learners compared to their male counterparts. Conclusions: The outcomes of this research imply that Saudi EFL learners have sufficient performance in grammar learning but need further nurturance. Implications of this study will serve as a basis for English language learning development interventions in the benefit of the students.",
"keywords": [
"Acquisition",
"Gender difference",
"Grammatical Awareness",
"Language Teaching",
"Performance",
"Saudi EFL Learners."
],
"content": "Editorial note\n\nEditorial Note (26th July 2023): The F1000 Editorial Team is currently substantiating that this research was presented at an IIARP conference and should be included in the IIARP Gateway. The Editorial Team is currently requesting further information from the authors regarding this. This Editorial Note will be updated as new information is provided.\n\n\nIntroduction\n\nEnglish is a global language of communication as a majority of individuals use English on a daily basis though for various purposes. It is a vital language in current geopolitics since it is used to communicate with individuals from other nations. Proficiency in English also makes it possible for individuals to access almost unlimited information and knowledge, which in turn, play a key role in individual and national socio-economic growth. According to Oktaviani and Fauzan (2017), as English has risen to the status of the world’s lingua franca, countries all over the world have incorporated English language instruction into their educational curriculum. Many nations begin English education at the primary level, and pupils the world over are beginning to learn the language at a much younger age than ever before while there is common realization of its immense importance to stay connected not only with peoples form other nations, but also, with one’s compatriots. The scene is no different for learners of English as foreign language (EFL). The most visible manifestation of one’s language proficiency lies in speaking. However, students especially in Saudi Arabia, encounter problems in developing English conversation skills, which appear as anxiety and unwillingness to speak English, as well as an insufficient vocabulary, poor language formulation, and a general lack of grasp of grammatical structure. Also, as a result of limited exposure of instructors to the latest developments in the field of second language learning, funding restrictions, inadequate multimedia project teaching and learning system, and the absence of an English Language Club in many schools, many pupils do not obtain Standard Education of English (Hosain, 2018). Therefore, many researchers have consistently pointed out the need to develop skills such as grammatical competence and also, metalinguistic awareness to help students improve their English (Bessy & Knouse, 2020; Minasyan & Midova, 2016; Putri & Ngadiso, 2019; Roehr-Brackin, 2018).\n\nWhen words are placed together correctly, they make proper sentences. Grammar is the process by which words are put together coherently. It is a set of rules and norms that allows languages to function correctly (Hans & Hans, 2017). In an educational context, grammatical competence may be described as the skill that pupils must have in order to comprehend and communicate meaning in a variety of situations. He or she must have a firm grasp of the rules of the language code (lexicon, syntactic structure, semantic structure, phonetic structure, and pragmatic structure), which will allow them to employ these grammatical aspects to convey and comprehend the meaning of utterances (Pinto-Llorente et al., 2017). According to Crystal and McLachlan (2010), grammar is “the study of how sentences mean and how sentence elements signify” (p.29). The authors claim that grammar is the structural underpinning for understanding, expressing, and responding to meaning inside sentences. This knowledge enables language users to be more precise, recognize ambiguity, and use a larger range of expressions. Similarly, the Common European Framework of Reference (CEFR), released in 2001 by the Council of Europe, defines grammar as a set of principles that govern the construction of phrases and sentences in order to express meaning in a language.\n\nAs mentioned by Hans and Hans (2017), proper grammar is necessary for understanding English as a second language as well as for learning a new language because all languages follow grammatical patterns, regardless of the language. Grammatical abilities are beneficial in all elements of life, from schooling to leadership and from social interactions to work prospects. Their importance at home cannot be overstated since children learn their grammatical patterns from their caregivers and other members of their household. Furthermore, according to Minasyan and Midova (2016), grammar is inextricably linked to the meaning and effect of what we write and say; it provides individuals with the vocabulary necessary to discuss one’s choices, preferences, mood, and tone. Individuals employ a variety of phrase patterns, vocabulary levels, and structures in response to various conversation settings. As a result, a sufficient degree of grammatical competence enables individuals to use the 5Cs rule, which ensures that communication is clear, correct, concise, coherent, and cohesive.\n\nMetalinguistic awareness, on the other hand, is described as the recognition that an individual possesses the capacity to modify language in a number of ways, that he or she possesses the capacity to manipulate language. Metalinguistic awareness, as defined by the Oxford Dictionary, is the capacity to detach oneself from the substance of communication in order to reflect on and adjust the structure of language. According to Altman et al. (2018), metalinguistic awareness, which requires the speaker to pay attention to the structure and form of the language, develops in the late stages of language acquisition, around the age of 5–6, and builds on previously acquired linguistic knowledge. Possessing a strong sense of metalinguistic awareness is a necessary component of multilingual competency since it separates speakers of several languages from those who only speak one or two languages. Language awareness refers to a speaker’s capacity to approach and see language abstractly, as well as to examine and grasp the language as a system or entity capable of manipulation and control (Hofer & Jessner, 2019). Aside from those, metalinguistic development has been found to be associated with language usage and cognitive development as well as reading ability, academic accomplishment, environmental stimulation, intelligence quotient, and play (Chen, 2016).\n\nGenerally, this study aims to assess the grammatical competence of Saudi EFL learners. It specifically aims to: (1) describe the Saudi EFL level of awareness in developing grammatical forms, (2) assess Saudi EFL students’ level of performance in grammar learning, (3) test the difference in the level of student’s awareness and performance in grammar learning when grouped according to genders.\n\n\nMethods\n\nThis study employed a descriptive quantitative survey and comparative research design. It applied descriptive and inferential statistics to analyze the data. The participants of the study were 50 Saudi EFL students sampled from the population of 120 students of EFL at Qassim University, Saudi Arabia. Only students of English who enrolled in the grammar course were included in the study. Other students of English were excluded. Sample size was determined through the online sampling calculator Raosoft. Raosoft calculator was used to ensure the representativeness of the sample in variables like (various level of students, i.e., high, medium and low; motivation, i.e., high motivated and less motivated; and background rural and semi-rural) to the whole population of the study; this helped the researcher to generalize the findings.\n\nBefore undertaking the study, the researcher received a confirmation of ethical approval from the Scientific Committee in the Department of Curriculum and Instruction, College of Education, Qassim University, dated March 6, 2022. The study protocol including ethical consideration was submitted to and approved by the Scientific Committee of the English Department. Furthermore, the researcher explained to the students the purpose of the study and took an oral informed consent from them to take part in the study at hand. In most Saudi academic institutes in general and at Qassim University in particular, participants’ consent is usually expressed verbally. The researcher decoded the students’ agreement to take part in the study under the theme “we agree to participate in the study and share our attitudes/views with the researcher”. This study only used gender as a variable, considering that there are conflicting studies on the result of gender differences in language learning. Figure 1 presents the sampling characteristics as to gender variables.\n\nTo collect data for this study, research tools were developed, adopted, and updated. Students, professors, and administrators were provided with a cover letter via email that explained the description and function of the instruments in plain language. A confidentiality clause was also inserted to safeguard the gathered data. This study employed a self-made research tool to ascertain the Saudi EFL students’ level of awareness of grammatical forms. The tool was validated by a content expert to identify the grammar content learning focus of Saudi EFL students. Before the tool was used, it was subjected to pilot testing in a group not included in the study.\n\nIn like manner, the grammar learning performance test was prepared by the researcher. The tool consisted of 25 main items and each item has four sub-items under it. Thus, the total number of items of the test on grammar learning was 100. Students took the grammar test in paper copy. Before any data were collected, it was authorized by two Arabic-speaking professors who are EFL instructors in two public universities. As a result, they were checked to see whether they fit the underlying constructs and if their language level corresponds to the students’ proficiency. After surveying, they agreed that the test items were appropriate, although they suggested a few changes to make the text easier to comprehend. In gathering the data, proper scheduling and coordination were coordinated with the university authorities. The full test items administered online in the survey can be found in the Extended data (Alharbi, 2022b).\n\nThe setting of the study was the English department, College of Education, Qassim University, Saudi Arabia. Students appeared in the final grammar examination in, December, 2021, and their results from the exam were used by the researcher to report the students’ performance level in grammar. Moreover, all the variables, outcomes, and other diagnose criteria were explained and clarified along the study parts.\n\nData were analyzed through quantitative research data interpretation via SPSS, (version 23). For descriptive statistics, the frequency and parentages were used, while for inferential statistics, the use of independent sample t-test was used to assess the difference of students’ attributes when grouped according to their gender. It is common to use the independent samples t-test to determine the following: Disparities in the mean values between two groups in this study gender was taken. Before the use of the t-test, the following were the assumptions followed: (1) the measurement scale of the study, (2) the utilization of random sampling, (3) the normality of data distribution, and (4) the adequacy of the sampling size of the study.\n\n\nResults\n\nTable 1 and Figure 1 present the Saudi EFL learners’ level of awareness in the eight selected grammatical forms viz., article, preposition, number of noun, tense, concord, case, irregular verb (Alharbi, 2022a). Results revealed that students are aware of their level of grammatical forms. Looking intently at the data, they were very aware of learning the concept of singular/plural nouns and tenses as a component essential to developing their language skills. In like manner, they remarkably rate themselves aware of the concept of articles, prepositions, concord, possessive case, and irregular verbs. This indicates that the Saudi EFL learners manifest a favorable level of awareness in developing grammatical forms.\n\nLegend: 4.20-5.00 (Very Aware); 3.40-4.19 (Aware); 2.60-3.39 (Moderately Aware); 1.8-2.59 (Not aware); 1.0-1.79 (Not at all)\n\nTable 2 and Figure 2 present the Saudi EFL students’ level of performance in grammar learning taken from their academic performance during the conduct of the study. It is noteworthy to showcase that the students have a mean grade of 86.57 or satisfactory perforce in EFL learning as back up with a frequency of 93 and percentage of 35.77%. The least contributor of the study were those students who have outstanding performance in grammar learning. This finding showed that Saudi EFL learners are still on the level of moving towards mastery of grammar learning.\n\nTable 3 and Figures 3 and 4 present the test of difference on the level of awareness and grammatical competence when grouped according to gender. When taken individually, the level of awareness of students in developing grammatical forms showed that women have higher self-assessment compared to men. This showed that there is a significant difference in the awareness of the students when grouped according to gender, as evidenced with the p-value of 0.002. As to the level of grammatical competence of the students, it also showed that female students performed better than the male students, as shown with the computed p-value of 0.004. This finding generally implies that in this study, grammar competence and level of awareness are being favored by Saudi EFL female learners compared to their male counterparts.\n\n* =significant at 0.05 level; ns=not significant at 0.05 level.\n\n\nDiscussion\n\nThis study tried to uncover some queries including the Saudi EFL learners’ level of awareness in developing grammatical forms and level of performance in grammar learning. It also explored the gender difference so far as grammar learning in the Saudi context is concerned. The results of the study showed that the Saudi EFL learners manifest a favorable level of awareness in developing grammatical forms while they were still transitioning towards mastery of English grammar. Finally, grammatical competence and level of awareness are being favored by Saudi EFL female learners compared to their male counterparts. Some authors have added the necessity for cognitive control or purposeful control as a secondary ability to the concept of grammatical awareness. Grammatical awareness is the ability of a language user to analyze the grammatical structure of a sentence (Marzulina, 2019; Moore, 2021; Wyatt & Dikilitaş, 2021). When it comes to grammatical awareness, the capacity to generate grammatically correct phrases at an early age is not considered evidence. Tactical knowledge of language frequently leads to correct output without the need for conscious thought about it. As a consequence, generative grammar proficiency does not necessarily represent grammatical awareness in terms of tacit comprehension of the language grammar. The value of grammatical awareness research in language education cannot be overstated, even though it is not a new field of study. A study by Marzulina (2019) found that students in an English master’s teacher education program had improved grammatical skills. According to the findings of this research, raising students’ levels of awareness is beneficial in developing analytical mindsets that lead to more effective teaching approaches.\n\nTeachers’ understanding and knowledge of grammar rules and terminology are crucial in resolving students’ grammatical issues in class (Almakroob & Al-Ahdal, 2020; Alkhudiry & Al-Ahdal, 2020; Al-Ahdal & Hussein, 2020). This shows that language training should put stronger emphasis on grammatical exposure since participants in the study lacked fundamental grammar understanding. Further study on the grammatical awareness requirements of English language educators is also recommended by the author. Developing grammatical awareness in college can enable future English teachers better guide their students through a foreign language grammar system and help them write better.\n\nStudents’ beliefs and attitudes regarding grammar learning may impair their capacity to develop grammatical awareness (Amadi, 2018; Magulod Jr, 2018; Magulod, 2018; Qindah, 2018). According to Yurdagül and Öz (2018), learners’ beliefs not only affect their approaches to language learning but also affect the way they respond to instructional activities. As a result, it is safe to assume that teachers’ negative views about grammar education will have a similar effect in the future. On the other hand, future educators’ positive attitudes about grammar may help them become more grammatically aware. Schuman claims that emotions have an influence on pupils’ ability to learn. This is particularly true for students who are learning a second language. A positive attitude toward grammar increases the likelihood of learning a new language and improving grammatical awareness. This is true for both children and adults (Torres & Alieto, 2019).\n\nThis study confirmed the previous finding that Arabic language students have satisfactory grammar learning performance (Alharbi & Meccawy, 2020; Al-Hazzani & Altalhab, 2018; Ali et al., 2019; Almuhammadi, 2020; Khan et al., 2018). These studies were confident that students had learned enough morphological and syntactic information in grammar to be able to pronounce words, write sentences, and correct grammatical faults on their own. The result of the gender difference in grammar awareness and performance surfaced in this study in favor of female respondents. This finding is significant since studies on gender differences in students’ attitudes regarding language learning have been limited and reported mixed findings. For this reason, further investigation is needed to have a deeper understanding on the matter. Prior research on gender discrepancies in university students’ language attitudes (Chuang et al., 2018; Stanikzai, 2020) need be examined to determine whether they hold true in a Saudi context.\n\nConsequently, this study fills a major gap in the body of evidence on the linguistic beliefs of EFL learners in the local Saudi environment. Gender disparities in English as a foreign language grammar, listening, and writing proficiency have been linked to multiple intelligences, but the conclusions are contradictory, according to research. When it comes to language success and intellect types, no significant differences were found between male and female participants (Sun et al., 2019). This means that students can communicate with others because they naturally comprehend the grammatical system of that language while studying the phonological, structural, and semantic systems of language should be the focus of grammar learning (Yeh et al., 2018).\n\n\nConclusion\n\nThis study addresses the research gap in the Saudi context concerning the grammatical competence of Saudi EFL learners, and the outcomes of this research imply that Saudi EFL learners exhibit sufficient performance in grammar learning. The present study described the Saudi EFL level of awareness in developing grammatical forms. It also assessed Saudi EFL students’ level of performance in grammar learning. Finally, it quantitatively explored the gendered differences in the grammar learning of Saudi context. The results of the present study show that the Saudi EFL learners manifest a favorable level of awareness in developing grammatical forms while they manifest that the Saudi EFL learners were still on the level of progressing towards mastery of grammar learning. Finally, grammar competence and level of awareness are better favored by Saudi EFL female learners compared to their male counterparts.\n\nThe results will have an effect on both the teaching environment and the training environment for these individuals. There are various factors that might hinder future English language teachers’ ability to build grammatical awareness. It is necessary for teachers to take grammar classes in this setting, and this leaves them with a limited understanding of grammatical terms, particularly in the case of male students. In light of these conditions, it is possible that English language teachers are not developing their grammatical awareness to their maximum potential. Despite this, studies have revealed favorable links between students’ growing grammatical understanding and their future success. Saudi EFL students may have a better chance of developing grammatical awareness and completing academic writing assignments if they think grammar is crucial on the road to becoming communicative competent and have some good attitudes towards grammar. As to the limitation of this study, it considered only gender as a variable on language learning difference in grammar. Hence, other variables need to be researched in future investigations.\n\n\nData availability\n\nFigshare: Raw data. https://doi.org/10.6084/m9.figshare.19284767.v1 (Alharbi, 2022a).\n\nFigshare: Survey and Grammar Test. https://doi.org/10.6084/m9.figshare.19772059.v1 (Alharbi, 2022b).\n\nThis project contains the following extended data:\n\n- Level of awareness survey and grammar test\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAl-Ahdal AAMH, Hussein NMA: WhatsApp as a writing tool in EFL classroom: A study across two universities in Saudi Arabia. Asian EFL Journal. 2020; 27(3.1): 374–392.\n\nAlharbi AS, Meccawy Z: Introducing Socrative as a tool for formative assessment in Saudi EFL classrooms. Arab World English Journal. 2020; 11(3): 372–384. Publisher Full Text\n\nAlharbi A: Untitled Item. figshare. [Dataset]. 2022a. Publisher Full Text\n\nAlharbi A: Survey and Grammar Test. figshare. [Dataset]. 2022b. Publisher Full Text\n\nAl-Hazzani N, Altalhab S: Can explicit written corrective feedback develop grammatical and lexical accuracy of Saudi EFL learners?. International Journal of Education and Literacy Studies. 2018; 6(4): 16–24. Publisher Full Text\n\nAli JKM, Shamsan MA, Guduru R, et al.: Attitudes of Saudi EFL learners towards speaking skills. Arab World English Journal. 2019; 10(2): 353–364.\n\nAlkhudiry RI, Al-Ahdal AAMH: Analysing EFL discourse of Saudi EFL learners: Identifying mother tongue interference. The Asian ESP Journal. 2020; 16(2.1): 89–109.\n\nAlmakroob AY, Al-Ahdal AAMH: Culture-specific aspects of turn-taking: An analysis of conversations in a Saudi Context. Asian ESP Journal. 2020; 16(2.1): 50–69. Publisher Full Text\n\nAlmuhammadi A: Teaching grammar: Professional needs of Saudi EFL instructors. International Journal of English Linguistics. 2020; 10(3): 14–20. Publisher Full Text\n\nAltman C, Goldstein T, Armon-Lotem S: Vocabulary, metalinguistic awareness and language dominance among bilingual preschool children. Front. Psychol. 2018; 9: 1953. PubMed Abstract | Publisher Full Text\n\nAmadi SC: Learning the English passive voice: Difficulties, learning strategies of Igbo ESL learners and pedagogical implications. International Journal of English and Literature. 2018; 9(5): 50–62. Publisher Full Text\n\nBessy M, Knouse SM: Metacognition, metalinguistic awareness, and relevance in language learning: A Report on an intervention module project. International Journal for the Scholarship of Teaching and Learning. 2020; 14(9): 9. Publisher Full Text\n\nChen PJ: Learners’ metalinguistic and affective performance in blogging to write. Computer Assisted Language Learning. 2016; 29(4): 790–814. Publisher Full Text\n\nChuang HH, Weng CY, Chen CH: Which students benefit most from a flipped classroom approach to language learning?. British Journal of Educational Technology. 2018; 49(1): 56–68. Publisher Full Text\n\nCouncil of Europe. Council for Cultural Co-operation. Education Committee. Modern Languages Division: Common European Framework of Reference for Languages: learning, teaching, assessment. Cambridge University Press; 2001.\n\nCrystal D, McLachlan E: Rediscover grammar. Harlow (Reino Unido). Pearson Longman; 2010.\n\nDictionary, O. E: Oxford English dictionary. Simpson, Ja & Weiner, Esc; 1989.\n\nHans A, Hans E: Role of grammar in communication–writing skills. International Journal of English Language, Literature and Humanities. 2017; 5(1): 39–50.\n\nHofer B, Jessner U: Multilingualism at the primary level in South Tyrol: how does multilingual education affect young learners’ metalinguistic awareness and proficiency in L1, L2 and L3? Lang. Learn. J. 2019; 47(1): 76–87. Publisher Full Text\n\nHosain A: Difficulties of learning English language at the secondary level: A case study of Thakurgaon district. Journal of Education and Training. 2018; 5(2): 165–181. Publisher Full Text\n\nKhan RMI, Radzuan NRM, Shahbaz M, et al.: The role of vocabulary knowledge in speaking development of Saudi EFL learners. Arab World English Journal (AWEJ). 2018; 9(1). Publisher Full Text\n\nMagulod GC Jr: Innovative learning tasks in enhancing the literary appreciation skills of students. SAGE Open. 2018; 8(4): 215824401882038. Publisher Full Text\n\nMagulod GC: Literary appreciation skills and reading performance of university students. The Normal Lights. 2018; 12(2). Publisher Full Text\n\nMarzulina L: The grammatical awareness of student teachers. The Case of an English Education Study Program in Indonesia. 2019; 7(9). Reference Source\n\nMinasyan ET, Midova VO: Grammar as one of key competences of language acquisition. Russian Linguistic Bulletin. 2016; 3(7). Reference Source\n\nMoore M: Grammatical concepts and metalinguistic awareness in first-year college writers: A study of reading journals. Journal of College Reading and Learning. 2021; 51: 178–202. Publisher Full Text\n\nOktaviani A, Fauzan A: Teachers’ perceptions about the importance of English for young learners. Linguistic, English Education and Art (LEEA) Journal. 2017; 1(1): 1–15. Publisher Full Text\n\nPinto-Llorente AM, Sánchez-Gómez MC, García-Peñalvo FJ, et al.: Students’ perceptions and attitudes towards asynchronous technological tools in blended-learning training to improve grammatical competence in English as a second language. Computers in Human Behavior. 2017; 72: 632–643. Publisher Full Text\n\nPutri YK, Ngadiso N: Correlation between reading interest, grammatical competence and reading skill. Engl. Educ. 2019; 7(3): 373–382.\n\nQindah S: The effects of blended learning on EFL students’ usage of grammar in Context. The Eurasia Proceedings of Educational and Social Sciences. 2018; 10: 11–22.\n\nRoehr-Brackin K: Metalinguistic awareness and second language acquisition. Routledge; 2018.\n\nStanikzai M; Self-regulated learning: an exploratory study (level and gender difference).2020.Reference Source\n\nSun T, Gaut A, Tang S, et al.: Mitigating gender bias in natural language processing: Literature review. arXiv preprint arXiv:1906.08976. 2019.\n\nTorres JM, Alieto EO: Acceptability of Philippine English grammatical and lexical items among pre-service teachers. Online Submission. 2019; 21: 158–181.\n\nWyatt M, Dikilitaş K: English language teachers’ self-efficacy beliefs for grammar instruction: implications for teacher educators. The Language Learning Journal. 2021; 49(5): 541–553. Publisher Full Text\n\nYeh YL, Lan YJ, Lin YTR: Gender-related differences in collaborative learning in a 3D virtual reality environment by elementary school students. J. Educ. Technol. Soc. 2018; 21(4): 204–216.\n\nYurdagül C, Öz S: Attitude towards mobile learning in English language education. Education Sciences. 2018; 8(3): 142. Publisher Full Text"
}
|
[
{
"id": "139987",
"date": "25 Jul 2022",
"name": "Yasser Alrefaee",
"expertise": [
"Reviewer Expertise Pragmatics",
"Translation Studies",
"ELT"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGrammatical awareness and language performance: examining gendered differences among Saudi EFL (English as a foreign language) learners.\nThe paper is well-written and strongly organized supported by a strong argument which reflects the researcher' deep knowledge of the topic under study.\nThe literature review is well written with appropriacy of language and content that glides from one section to another according to the study variables, and is rich and vast with relevant up-to date references included to establish the theoretical background of the study.\n\nThe methodology is well presented describing the comparative research design used. Data analysis and statistical tests are clearly depicted.\n\nThe results section is organized according to the research questions. Tables and figures are used to present the findings. Clear explanations for each table and figure are written.\n\nSimilarly, the discussion summarizes the findings and shows points of similarities and differences with previous research findings.\n\nFinally, the conclusion presents the findings of the study in a clear and accurate manner with inclusion of implications of the study for EFL instructors. As is pertinent in research, the paper also highlights some of the limitations of the study.\n\nHowever, here are some suggestions for adding to the presentation of the study:\nThe study methodology as stated in the abstract can be edited to transpose the first two sentences to the section on purpose of the study. Similarly, it may be better to use the past tense to present the findings of the study rather than using present tense. Finally, it is recommended for the researcher to add pertinent recommendations for future research.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "139990",
"date": "01 Aug 2022",
"name": "Shaima Mahdi Saalh",
"expertise": [
"Reviewer Expertise I am specialist in methods of teaching English as foreign language",
"studied and have experience with statistics tools and the using of SPSS",
"and constructed scales some of them are in academic buoyancy",
"habits of mind",
"and flow. I have a study on the relationship between the EFL university students' awareness and their performance in spelling and pronunciation."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe tool of study should be presented in the abstract.\n\nThe introduction is not enough to present the literature review of the study.\n\nThe face and construct validity should be clarified in detail. Reliability of both tools have not mentioned.\n\nFurthermore, there is a suggestion for developing the research in that finding out the relationship between the students awareness and their performance to decide if they have or have not accurate self-assessment.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-625
|
https://f1000research.com/articles/11-488/v1
|
03 May 22
|
{
"type": "Research Article",
"title": "‘Comparison and correlation of the maxillary sinus dimensions in various craniofacial patterns: A CBCT Study’",
"authors": [
"Harshit Atul Kumar",
"U S Krishna Nayak",
"M N Kuttappa",
"U S Krishna Nayak",
"M N Kuttappa"
],
"abstract": "BACKGROUND To compare and correlate the maxillary sinus dimensions and basal bone height among various facial patterns using CBCT for advanced diagnosis and treatment planning in Orthodontics. METHODS 66 CBCT images within age group of 18-30 years were divided into horizontal (Group 1), average (Group 2) and vertical (Group 3) facial growth patterns. Maxillary sinus dimensions were compared and correlated in all three groups. The sinus height and basal bone height were recorded at 3 locations-between 1st premolar and 2nd premolar (PM1-PM2), between 2nd premolar and 1st Molar (PM2-M1) and between 1st and 2nd molar (M1-M2). RESULTS Overall reduction in sinus height and significantly reduced sinus volume was seen in Group-1. Longest maxillary sinus height in M1-M2 region and shortest in PM1-PM2 region was seen in Group-3. The basal bone height in PM1-PM2 region was significantly longer in Group-3 than in Group-1(p<.05).Shortest basal bone height in M1-M2 region was seen in Group-3. A significant negative correlation was seen between the maxillary sinus height and the basal bone height in Group-1 and Group-3(p<.05). CONCLUSION There is a correlation between the maxillary sinus height and basal bone height with that of facial pattern which needs to be considered during orthodontic treatment planning and while carrying out facial growth modification procedures in younger patients.",
"keywords": [
"Maxillary sinus dimensions",
"Basal bone height",
"Facial growth pattern",
"CBCT"
],
"content": "Introduction\n\nThe maxillary sinus is the largest of all paranasal air sinuses and its development begins at 3rd month of intrauterine life. It continues to expand at two different growth spurt periods after birth. Maxillary sinus growth occurs in the mid-face region and hence it affects the growth and development of facial contour and dentition to a great extent.1 In the maxillary bicuspid and molar regions we can see the maxillary sinus floor in proximity with the root apices and forming crests and troughs around the roots of teeth in the posterior region.2,3 This is an anatomic limitation that can adversely affect orthodontic tooth movement and may cause complications during the course of the treatment.4–6 Any alteration in the development of the maxillary sinus may consequently lead to the formation of skeletal or dental malocclusion.\n\nOktay used OPG to assess and correlate the variations of maxillary sinus dimensions in vrious skeletal malocclusion.7,8 However, panoramic radiography has its own limitation while evaluating the sinus, such as low resolution, vertical and horizontal image magnifications and superimpositions of anatomic structures are problems faced while evaluating the sinus. Cone-beam computed tomography (CBCT) solves the limitations of a panoramic radiograph. Outstandingly, CBCT technology has achieved a considerable reduction of absorbed radiation doses and low magnification when compared to medical CT imaging and a bit similar to dental panoramic radiography.8–11\n\nThere are hardly a few studies in the literature that have reported on the relationship between the dimensions of the maxillary sinus and skeletal malocclusions assessed using CBCT. We anticipate that individuals with vertical growth pattern will show larger sinus height and volume when compared to individuals with horizontal and average growth pattern as indicated in one of the previous studies.12 Keeping in view the existing literature, the goal of this study is to compare and correlate the maxillary sinus dimensions with various facial growth patterns using CBCT.\n\n\nMethods\n\nCone-beam computed tomography (CBCT) records of patients were obtained to meet the statistically calculated sample size from the archives of Department of Orthodontics and Dentofacial Orthopaedics at A.B. Shetty Memorial Institute of Dental Sciences, Mangalore. Clearance for the study was obtained from the Institutional Ethics Committee. (Certificate number - ABSM/EC/63/2018).\n\n• Inclusion criteria:\n\n1. Age - 18 years to 30 years\n\n• Exclusion criteria:\n\n1. History of Orthodontic treatment or Orthognathic surgery\n\n2. Severe craniofacial deformities like cleft lip or cleft palate/syndromic patients\n\n3. Pathological findings in maxillary sinus\n\n\nMethod\n\nA total of 66 full FOV CBCT scans of patients satisfying inclusion and exclusion criteria were collected from the department archives. The CBCT images were previously obtained with patients written consent for diagnostic purpose using Planmeca ProMax Machine (230-240 V, 50 Hz, 16 A) manufactured by Planmeca OY (Helsinki Finland). The images were in DICOM file format and were analysed using Planmeca Romexis Viewer (Version 5.1.0.4). All the records were analysed by a single observer. Three locations were chosen to measure sinus height and basal bone height: PM1-PM2(between premolars), PM2-M1(between 2nd premolar and 1st molar), M1-M2(between molars).\n\nLateral cephalogram obtained from CBCT images were used to further divide the records into 3 study groups based on Frankfurt mandibular plane angle (FMA). A total of 22 patients with equal number of males (11) and females (11) were included in each study group to avoid any possible gender related bias.\n\n1. Group 1-22 patients with low FMA (<21 degrees) - individuals with horizontal growth pattern.\n\n2. Group 2-22 patients with average FMA (22-28 degrees) - individuals with average growth pattern.\n\n3. Group 3-22 patients with high FMA (>29 degrees) - individuals with vertical growth pattern.\n\nFollowing measurements were recorded bilaterally and mean value was obtained; Figures: 1-3\n\n1. Height of the maxillary sinus\n\n2. Basal bone height\n\n3. Width of the maxillary sinus\n\n4. Depth of maxillary sinus\n\n5. Volume of the maxillary sinusz\n\nMean of the right and left maxillary sinus measurements was calculated for each parameter. SPSS version 2.0 software was used to compare and analyse relevant findings among the study groups. To compare maxillary sinus dimensions and basal bone height of maxilla between 3 groups, one way anova was used. p value less than 0.05 was considered to be significant. Tukey’s post hoc test was done for parameters with statistical significance. Pearson’s correlation test was also done to correlate 2 different parameters in same group.\n\n\nResults\n\nIn our study, maxillary sinus dimensions were compared to various facial skeletal patterns, and we found a difference in mean height of maxillary sinus at 3 different locations in all the study groups and are presented in Table 1.\n\n* p<0.05 Statistically Significant, p>0.05 Non Significant, NS.\n\nTable 2a shows comparison of the mean basal bone height in all the three study groups. The basal bone height in the PM1-PM2 region in Group-1 is significantly different from other groups with a p value of 0.02. Basal bone height in the PM2-M1 region and M1-M2 region were not statistically significant. Further in Table 2b, it is shown that when tukey’s post hoc test was done for pairwise comparison of mean basal bone height at PM1-PM2 region in between the three groups, Group-1 (13.78 mm) seems to have a significantly lesser when compared to the Group-3 (15.97 mm) with a p value of 0.02.\n\n* p<0.05 statistically significant, p>0.05 non significant, NS.\n\n* p<0.05 statistically significant, p>0.05 non significant, NS.\n\nResults obtained after comparison of mean sinus depth, mean sinus width, and total mean sinus volume in all the three study groups are shown in Table 3a with a significant statistical difference seen with respect to sinus volume in all the groups. Results of group wise comparison of maxillary sinus volume shows (Table 3b) statistically significant difference (p value-0.04) with least sinus volume seen in Group 1 and largest volume in Group 2.\n\n* p<0.05 statistically significant, p>0.05 non significant, NS.\n\n* p<0.05 statistically significant, p>0.05 non significant, NS.\n\nIn Group-1, a significant correlation was obtained with a p value of 0.003 (Table 4), showing a direct positive correlation of mean maxillary sinus height in between premolars (PM1-PM2) with that of basal bone height in the same region. In Group-3, a statistically positive correlation between the mean maxillary sinus height with that of mean basal bone height in between the premolars (PM1-PM2) and 2nd premolar and 1st molar (PM2-M1) region with a p value of 0.04 and 0.03 respectively.\n\n* p<0.05 statistically significant, p>0.05 non significant, NS.\n\n\nDiscussion\n\nMost of the previous studies have used OPG to analyse and assess the relationship of the maxillary sinus with malocclusions, which are more prone to error during sinus measurements due to overlap of anatomic structures and two-dimensional view whereas we used 3D CBCT technique to overcome those drawbacks.8 We maintained equal number of females and males in all three study groups to avoid the possible gender bias reported by previous authors.8,13 CBCT records of individuals above 18 years of age and below 30 years of age were chosen for our study to avoid bias related to age changes of the maxillary sinus, since the sinus growth is almost completed, and the size remains stable after 18 years of age till almost 30 years.14\n\nThe least sinus height was seen in Group-3 in the premolar region (PM1-PM2). Though statistically not significant, this difference can be clinically explained by the fact that Group-3 usually have an anti-clockwise rotation of maxilla leading to decreased anterior sinus height. As we speculated, in the molar region (M1-M2), Group-3 has the longest mean sinus height and shortest is seen in Group-1. Even though the results are not statistically significant, the values obtained positively indicate that in subjects with Group-3 had an anti-clockwise rotation of maxilla which may be attributed to elongated sinus height in the molar region.\n\nIn Group-1, there was a reduction in mid and lower facial height due to excessive muscle forces and tonicity, and it can be assumed that the horizontal growth pattern would tend to have a short overall sinus height as our study findings indicated the same clinically.15,16 In concordance with our findings, Endo et al. reported that there is no significant association between maxillary sinus height and skeletal jaw relationships in his cephalometric study.17 In contrast to our study results, Okasayan et al. reported a significant difference in sinus height among three vertical face growth patterns.13 However, the sinus height measured in previous studies was the longest possible distance between the roof and the floor of the sinus, unlike in our study where sinus height was measured at three predetermined locations. By doing this we could more accurately compare the variation of height throughout the sinus with various skeletal growth patterns.\n\nWe assessed the basal bone thickness at three different locations in our study groups which would help a clinician to accurately determine the safe locations for mini-screw placement. Group 1 showed statistically significant reduced length of basal bone when compared to other groups at the PM1-PM2 region. But interesting fact is that this region shows the longest basal bone height in all three study groups when compared to other locations. Similarly, a study to determine the precise safe placement position of mini screw in the maxilla concluded that about 6-8 mm deep from the alveolar crest in between the upper premolars was the safest position.18 This statistical difference could be because of anti-clockwise rotation of maxilla and decreased mean sinus height in vertical growth pattern resulting in a compensatory increase of basal bone deposition in the premolar region. In all the three study groups, a steady decrease in the mean basal bone height is seen from the most anterior location (PM1-PM2) to the posterior location (M1-M2) of the maxilla. Our results are in congruence with the results of a similar study done on patients with anterior open bite, which showed that basal bone height in such individuals was reduced in the maxillary posterior region. This particular study also reported that there was a greater degree of vertical pneumatization of sinus, indicating increased sinus height in between the posterior teeth in anterior open bite when compared to that of normal occlusion.19\n\nFew relevant studies emphasize on the bodily movement of the tooth through anatomic barriers such as the maxillary sinus. According to those studies, orthodontists must be cautious while moving the maxillary tooth root tips through the sinus floor as there are chances of root resorption or sinus floor perforation in case of heavy force application.2,6,20,21\n\nTo help us understand better about the relationship of sinus height and facial patterns, we should also consider the possibility of frequent nasal obstruction and enlarged lymphoid tissue (adenoids, tonsils) seen in mouth breathing habit which is often strongly associated with vertical growth pattern. Due to reduced nasal air circulation seen in young vertical growers, there is decreased vertical pneumatization in the anterior sinus region. Supplementary to this, the peak lymphoid tissue growth regresses after 10–12 years of age and the maxillary dentition development moves posteriorly with the eruption of first and second molars.22 All these synergistic functions result in greater pneumatization in the posterior region as compared to anterior region, leading to downward elongation of posterior maxillary sinus. This is in line with Moss’s view of functional matrix theory where function precedes the form of skeletal development.23\n\nWe found a statistically significant correlation between sinus height and basal bone height in premolar region (PM1-PM2) in Group-1 and Group-3 individually, and a correlation in PM2-M1 region in Group-3. It confirms the view that with a decrease in sinus height, there might be a complementary increase in basal bone thickness in these locations. Our study results will be the first of its kind to aid in establishing this possible inverse relationship among various facial growth patterns. Interestingly, in Group-2 these parameters are not correlated. Ryu et al. also reported on the similar inverse relationship that was seen between sinus height and basal bone thickness in open bite cases. In concordance to our study results, Nimigean et al. had first reported about such a relationship while studying the maxillary sinus floor for oral implantology.19\n\nThe importance of basal bone thickness and its relation to maxillary sinus has critical implications during orthodontic treatment planning. Our study data may aid in the placement of mini-screw in basal bone more safely keeping in mind the type of growth pattern of an individual. In confirmation with our study results, previously only one study has been reported in literature stating hypodivergent growth pattern shows reduced basal bone width and needs more horizontal insertion or reduced length of the implant due to proximity to the sinus floor.24\n\nFurther in our study, when the mean A-P depth and mean M-D width was compared among the 3 study groups, Group-2 had the longest mean A-P depth and longest mean M-D width of the maxillary sinus, whereas Group-1 had the shortest mean A-P depth and mean M-D width. Mean maxillary sinus volume was statistically significantly less in Group-1 when compared to other groups. In horizontal growth pattern due to increased muscle forces and tonicity, it is expected there will be a general decrease in maxillary sinus dimensions and sinus volume as seen in our study as well, indicating close link between facial growth pattern and sinus volume.15,16 Contrary to our results Okasayan reported that sinus width was greater in horizontal growth pattern when compared to vertical and average growth patterns.13 There are no other previous studies that have measured the width and depth of maxillary sinus correlating with skeletal facial growth patterns using CBCT.\n\nPrevious studies have reported about the maxillary sinus dimensions varying in mouth breathers, cleft lip/palate and Orthognathic surgery patients but none among average normal individuals.19,25,26 In future, studies conducted on larger sample size would be helpful to extrapolate the results of our study to a bigger community.\n\n\nConclusion\n\nMaxillary sinus height has a correlation with the basal bone height in vertical facial growth pattern. In vertical growth pattern, shortest sinus height is seen in anterior region and longest is seen in the posterior region indicating anti-clockwise rotation of the maxilla and horizontal growth pattern has the least sinus volume. Maxillary sinus dimensions should be considered while planning orthodontic treatment.",
"appendix": "References\n\nBasdra EK, Stellzig A, Komposch G: The importance of the maxillary sinuses in facial development: a case report. Eur. J. Orthod. 1998 Feb 1; 20(1): 1–4. PubMed Abstract | Publisher Full Text\n\nPark JH, Tai K, Kanao A, et al.: Space closure in the maxillary posterior area through the maxillary sinus. Am. J. Orthod. Dentofac. Orthop. 2014 Jan 1; 145(1): 95–102. PubMed Abstract | Publisher Full Text\n\nSharan A, Madjar D: Correlation between maxillary sinus floor topography and related root position of posterior teeth using panoramic and cross-sectional computed tomography imaging. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2006 Sep 1; 102(3): 375–381. PubMed Abstract | Publisher Full Text\n\nOh H, Herchold K, Hannon S, et al.: Orthodontic tooth movement through the maxillary sinus in an adult with multiple missing teeth. Am. J. Orthod. Dentofac. Orthop. 2014 Oct 1; 146(4): 493–505. PubMed Abstract | Publisher Full Text\n\nDaimaruya T, Takahashi I, Nagasaka H, et al.: Effects of maxillary molar intrusion on the nasal floor and tooth root using the skeletal anchorage system in dogs. Angle Orthod. 2003 Apr; 73(2): 158–166. PubMed Abstract\n\nWehrbein H, Bauer W, Wessing G, et al.: The effect of the maxillary sinus floor on orthodontic tooth movement. Fortschritte der Kieferorthopadie. 1990 Dec; 51(6): 345–351. PubMed Abstract | Publisher Full Text\n\nVan Den Bergh JP, Ten Bruggenkate CM, Disch FJ, et al.: Anatomical aspects of sinus floor elevations. Clinical Oral Implants Research: Treatment Rationale. 2000 Jun; 11(3): 256–265. PubMed Abstract | Publisher Full Text\n\nOktay H: The study of the maxillary sinus areas in different orthodontic malocclusions. Am. J. Orthod. Dentofac. Orthop. 1992 Aug 1; 102(2): 143–145. PubMed Abstract | Publisher Full Text\n\nLoubele M, Bogaerts R, Van Dijck E, et al.: Comparison between effective radiation dose of CBCT and MSCT scanners for dentomaxillofacial applications. Eur. J. Radiol. 2009 Sep 1; 71(3): 461–468. PubMed Abstract | Publisher Full Text\n\nLudlow JB, Ivanovic M: Comparative dosimetry of dental CBCT devices and 64-slice CT for oral and maxillofacial radiology. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology. 2008 Jul 1; 106(1): 106–114. PubMed Abstract | Publisher Full Text\n\nBarghouth G, Prior J, Lepori D, et al.: Paranasal sinuses in children: size evaluation of maxillary, sphenoid, and frontal sinuses by magnetic resonance imaging and proposal of volume index percentile curves. Eur. Radiol. 2002 Jun 1; 12(6): 1451–1458. PubMed Abstract | Publisher Full Text\n\nTikku T, Khanna R, Sachan K, et al.: Dimensional changes in maxillary sinus of mouth breathers. J. Oral. Biol. Craniofac. Res. 2013 Jan 1; 3(1): 9–14. PubMed Abstract | Publisher Full Text\n\nOkşayan R, Sökücü O, Yeşildal S: Evaluation of maxillary sinus volume and dimensions in different vertical face growth patterns: a study of cone-beam computed tomography. Acta Odontol. Scand. 2017 Jul 4; 75(5): 345–349. PubMed Abstract | Publisher Full Text\n\nJun BC, Song SW, Park CS, et al.: The analysis of maxillary sinus aeration according to aging process; volume assessment by 3-dimensional reconstruction by high-resolutional CT scanning. Otolaryngology—Head and Neck. Surgery. 2005 Mar; 132(3): 429–434. Publisher Full Text\n\nIngervall B, Thilander B: Relation between facial morphology and activity of the masticatory muscles: An electromyographic and radiographic cephalometric investigation. J. Oral Rehabil. 1974 Apr; 1(2): 131–147. PubMed Abstract | Publisher Full Text\n\nOzdemir F, Tozlu M, Germec-Cakan D: Cortical bone thickness of the alveolar process measured with cone-beam computed tomography in patients with different facial types. Am. J. Orthod. Dentofac. Orthop. 2013 Feb 1; 143(2): 190–196. PubMed Abstract | Publisher Full Text\n\nEndo T, Abe R, Kuroki H, et al.: Cephalometric evaluation of maxillary sinus sizes in different malocclusion classes. Odontology. 2010 Feb 1; 98(1): 65–72. PubMed Abstract | Publisher Full Text\n\nIshii T, Nojima K, Nishii Y, et al.: Evaluation of the implantation position of mini-screws for orthodontic treatment in the maxillary molar area by a micro CT. The Bulletin of Tokyo Dental College.\n\nRyu J, Choi SH, Cha JY, et al.: Retrospective study of maxillary sinus dimensions and pneumatization in adult patients with an anterior open bite. Am. J. Orthod. Dentofac. Orthop. 2016 Nov 1; 150(5): 796–801. PubMed Abstract | Publisher Full Text\n\nCostea MC, Bondor CI, Muntean A, et al.: Proximity of the roots of posterior teeth to the maxillary sinus in different facial biotypes. Am. J. Orthod. Dentofac. Orthop. 2018 Sep 1; 154(3): 346–355. PubMed Abstract | Publisher Full Text\n\nRe S, Cardaropoli D, Corrente G, et al.: Bodily tooth movement through the maxillary sinus with implant anchorage for single tooth replacement. Clin. Orthod. Res. 2001 Aug; 4(3): 177–181. PubMed Abstract | Publisher Full Text\n\nSubtelny JD: The significance of adenoid tissue in orthodontia. Angle Orthod. 1954 Apr; 24(2): 59–69.\n\nMoss ML: The functional matrix hypothesis revisited. 1. The role of mechanotransduction. Am. J. Orthod. Dentofac. Orthop. 1997 Jul 1; 112(1): 8–11. PubMed Abstract | Publisher Full Text\n\nVibhute PJ, Patil PA: Inferior Level of Maxillary Sinus and Cortical Bone Thickness at Maxillary Posterior Quadrant, in Three Different Growth Patterns: 3D-Computed Tomographic Study. Journal of Oral Implants. 2014; 2014: 1–9. Publisher Full Text\n\nKoppe T, Weigel C, Baerenklau M, et al.: Maxillary sinus pneumatization of an adult skull with an untreated bilateral cleft palate. J. Cranio-Maxillofac. Surg. 2006 Sep 1; 34(34): 91–95. PubMed Abstract | Publisher Full Text\n\nPanou E, Motro M, Ateş M, et al.: Dimensional changes of maxillary sinuses and pharyngeal airway in Class III patients undergoing bimaxillary orthognathic surgery. Angle Orthod. 2013 Sep; 83(5): 824–831. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "137160",
"date": "23 May 2022",
"name": "Rohan Mascarenhas",
"expertise": [
"Reviewer Expertise Dentistry",
"Orthodontics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript is well structured and the topic is relevant to the current scenario specially with the increased use of CBCT. However, there are a few abstractions, clarifications and minor corrections which I have noted.\nThe terminology used in the title ‘Craniofacial patterns’ should be used consistently throughout instead of 'Facial Growth Patterns'.\n\nThe spelling of 'Orthopedics' should be consistent throughout instead of 'Orthopaedics' in some places.\n\nIn the author details, the place 'Mangalore' is spelt as 'Managlore' in one place.\n\nIn abstract, results section Maxillary sinus height is described as longest and shortest. But it should actually be maximum or minimum.\n\nThe conclusion in the manuscript and in the abstract should be the same. The words ‘longest’ and ‘shortest’ should be substituted with 'maximum' and 'minimum' when describing maxillary sinus measurements.\n\nIn the introduction, in the last paragraph which states the need for the study, dimensions of maxillary sinus and ‘skeletal malocclusion' are mentioned whereas it should be ‘Craniofacial patterns’.\n\n‘We anticipate’ can be substituted with ‘Hypothesis’.\n\n‘The goal’ of the study should be ‘The aim’ of the study is to compare and correlate the maxillary sinus dimensions with various Craniofacial patterns.\n\nIn the methods, the word ‘CBCT scan’ should be used with consistency instead of ‘CBCT images’. Were the scans used anonymised when obtained from the repository?\n\nThe institute name and place has been disclosed. Ideally this should be blinded to avoid bias.\n\nIn the methods section, 'Frankfort' has been misspelt as 'Frankfurt'. Also ‘years’ is mentioned twice in inclusion criteria which can be changed to ‘18-30 years’. Under the ‘measurements of Sinus’ section, the spelling of sinus needs to be corrected in point 5. Under the results section, a word “basal bone height” is missing in the last line of the 2nd paragraph. Avoid the word ‘direct’ in the 4th paragraph while mentioning the ‘positive correlation’. Add ‘is seen’ following ‘statistically positive correlation’ in the same paragraph.\n\nThe height of maxillary sinus should be correlated only to craniofacial pattern, rather than growth rotation as mentioned in the discussion.\n\nUnder the discussion section, references can be added for previous studies done using OPG.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8299",
"date": "07 Jun 2022",
"name": "Harshit Atul Kumar",
"role": "Author Response",
"response": "I thank the reviewer for carefully going my article and approving it. Keeping in mind the suggested minor changes which are listed in points , I would like to inform you that I am happy to make those changes and I have already submitted an updated version with the corrections as suggested by you."
}
]
},
{
"id": "139129",
"date": "31 May 2022",
"name": "Shahistha Parveen Dasnadi",
"expertise": [
"Reviewer Expertise CBCT",
"Orthodontics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nBe consistent with the word \"Craniofacial pattern, Growth pattern, or Facial pattern\". In some places, it is mentioned Craniofacial pattern, in other places Growth pattern, or Facial pattern.\n\nFor the reader's interest, can you elaborate on the standardization of parameters used?\n\nCan you recheck the version of SPSS used?\n\nCan you bring out a discussion of the use of maxillary sinus volume in Orthodontic treatment planning?\n\nMatch your conclusions with the aim of the study.\n\nThe word 'Goal' may be substituted with 'Aim'.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8329",
"date": "07 Jun 2022",
"name": "Harshit Atul Kumar",
"role": "Author Response",
"response": "Thank you for your valuable review and inputs for my article. I shall make the corrections in the article as you suggested."
}
]
}
] | 1
|
https://f1000research.com/articles/11-488
|
https://f1000research.com/articles/10-365/v1
|
10 May 21
|
{
"type": "Research Article",
"title": "Closing the communication gap in neonatal inter-hospital transfer: a neonatal referral form for resource-limited settings - a modified e-Delphi-consensus study",
"authors": [
"Oscar Mwizerwa",
"Christian Umuhoza",
"Mark H. Corden",
"Tom Lissauer",
"Peter Thomas Cartledge",
"Oscar Mwizerwa",
"Christian Umuhoza",
"Mark H. Corden",
"Tom Lissauer"
],
"abstract": "Background: Standardised neonatal referral forms (NRFs) facilitate effective communication between healthcare providers and ensure continuity of care between facilities, which are essential for patient safety. We sought to determine the essential data items, or core clinical information (CCI), that should be conveyed for neonatal inter-hospital transfer in resource-limited settings (Rounds 1 to 3) and to create an NRF suitable for our setting (Round 4). Methods: We conducted an international, four-round, modified Delphi-consensus study. Round-1 was a literature and internet search to identify existing NRFs. In Round-2 and -3, participants were Rwandan clinicians and international paediatric healthcare practitioners who had worked in Rwanda in the five years before the study. These participants evaluated the draft items and proposed additional items to be included in an NRF. Round-4 focused on creating the NRF and used five focus groups of Rwandan general practitioners at district hospitals. Results: We identified 16 pre-existing NRFs containing 125 individual items. Of these, 91 items met the pre-defined consensus criteria for inclusion in Round-2. Only 33 items were present in more than 50% of the 16 NRFs, confirming the need for this consensus study. In Round-2, participants proposed 12 new items, six of which met the pre-defined consensus criteria. In Round-3, participants scored items for importance, and 57 items met the final consensus criteria. In Round-4, 29 general practitioners took part in five focus groups; a total of 16 modifications were utilised to finalise the NRF. Conclusions: We generated a novel, robust, NRF that may be readily employed in resource-limited settings to communicate the essential clinical information to accompany a neonate requiring inter-hospital transfer.",
"keywords": [
"Infant",
"Newborn",
"Referral and consultation",
"Patient transfer",
"Communication",
"Developing countries",
"Rwanda"
],
"content": "Introduction\n\nGlobally, neonatal mortality fell to 19 per 1000 live births in 2015 with the aim to reduce neonatal mortality to less than 12 per 1000 live births by 2030.1 In Rwanda, the neonatal mortality rate has fallen from 37 to 19 per 1000 live births over 15 years (2005-2020).2,3 The reason for this decline is multifactorial, but the centralisation of specialist care has contributed to an increase in the number of neonatal transfers between low-level units and more specialised hospitals. Transport of neonates carries a range of risks, and adverse outcomes in up to 40% of transported neonates have been reported, with higher mortality associated with long-distance and duration of transport.4–6\n\nA specialised transport system for neonates can mitigate against these risks.7 In most resource-limited settings, such systems do not yet exist.8 For example, in Rwanda, a general patient-referral transport system is in place, but specialised neonatal transfer is lacking.9 To optimise the transfer of care when transferring a newborn, it is paramount that the essential demographic and clinical information is shared between the referring and receiving sites. Neonatal referral forms (NRFs) are standardised instruments that aid in ensuring high-quality handover of medical history, which include demographics, pre-transfer care, and, potentially, the transport course of the neonate.10–18 The quality of the shared clinical information has the potential to improve the outcome for the neonate and also reduce the repetition of investigations and treatments, thus decreasing the cost to families and facilities.17 In the resource-limited setting, there is a lack of evidence about which clinical information should be communicated between hospital sites and included in NRFs.19\n\nWe sought to determine the essential data items (core clinical information, CCI) that should be conveyed for neonatal inter-hospital transfer in a resource-limited setting and to create an NRF suitable for our setting.\n\n\nMethods\n\nWe employed a four-round, modified Delphi technique to identify the CCI that would be essential to communicate during neonatal transfer. Reporting of the study is in accordance with the Sinha and Williamson checklists for creating a “Core Outcome Set” using Delphi techniques.20,21 The Delphi methodology was chosen as a consensus tool as it allows large numbers of individuals across diverse locations and areas of expertise to be included anonymously, thus avoiding the domination of the consensus process by one or a few experts. It also can be undertaken remotely, removing the need for participants to travel. We modified the Delphi technique in two respects. In Rounds-1 to -3, we sought to meet the first objective of the study, namely to gain consensus on the CCI that should be conveyed for neonatal inter-hospital transfer in a resource-limited setting. In Round-4, we sought to meet the second objective to create an NRF suitable for our setting and employed focus-groups of clinicians who work in the setting to gain consensus.\n\nA comprehensive literature and internet search was undertaken to identify pre-existing NRFs and research articles describing NRFs and/or CCI required for inter-hospital transfer of a neonate in the resource-limited setting. In Round-1 we used a Medline/PubMed literature search (rather than participants) in order to help improve response rates in the subsequent rounds, as well as to provide an initial sound CCI set to participants.22 The search strings included MeSH terms and synonyms for “neonates”, “transportation of patients,” and “resource-limited settings” (Supplementary Table 1, Extended data34). Using informal networking of contacts known to the authors, we then contacted local (Rwandan) healthcare facilities as well as experienced paediatricians in the region (Malawi, Uganda, and Kenya), by email, to identify any NRFs relevant to our setting. We aimed for a minimum of 10 NRFs. Due to the low number of NRFs identified from resource-limited settings, the Medline/PubMed search was then repeated for NRFs, and articles containing NRFs, from outside of the resource-limited setting (Supplementary Table 1, Extended data34), by removing the “developing countries” search string. The individual items found in each NRF were then coded by two authors (OM and PC). During the coding process, items were intentionally removed if they were judged not to be relevant to resource-limited settings where there is no dedicated transport team (e.g., therapeutic hypothermia). Consensus in this round was pre-defined as any item that was used in two or more of the identified NRFs. These items were then used to create the first draft of our CCI list in preparation for Rounds-2 and -3 of the Delphi process.\n\nParticipants from four groups of clinicians were eligible to be included: (i) Rwandan clinicians working in clinical paediatric practice, including all paediatric specialists and senior paediatric residents practising in Rwanda, identified via the Rwanda paediatric email group; (ii) members of the Rwandan Neonatal Working Group (NWG) including paediatricians, public health specialists and policymakers, identified through the chair of the NWG; (iii) general practitioners (GPs; clinicians working in Rwandan district hospitals) identified through the NWG; (iv) non-Rwandan paediatricians with paediatric clinical experience in Rwanda through the Human Resources for Health (HRH) project identified from the Ministry of Health (MoH) database of HRH faculty.23\n\nIn Round-2, the draft CCI list from Round-1 was divided into eight themes/sections. Participants were informed about the process involved in gaining the first draft CCI in Round-1. Each section contained a list of the included items in the first draft of the CCI. The list of items was then presented to participants with an open question using a \"free text\" option at the end of each section.\n\nParticipants were presented with a scenario: \"We want you to imagine that you are either transferring or receiving a sick neonate who is being transferred between facilities in a resource-limited setting (e.g. Rwanda).\" They were then asked what additional clinical items they would add to that section/theme. Consensus was pre-defined as any additional item suggested independently by two or more participants; these were then added to the second draft CCI for Round-3. Non-participation in Round-2 did not exclude participation in Round-3, but no additional participants were invited to Round-3.\n\nAll items from the second draft of the CCI were listed in their themes/sections. Each item was presented with feedback from Round-1 in the form of the percentage of articles/NRFs that contained the item, or if it was a new addition from Round-2. After piloting the Round-3 Delphi questionnaire, several items that described similar clinical information were combined to minimise bias from questionnaire fatigue (e.g., stimulation, bag-mask ventilation, etc. were combined into \"resuscitation\") (Table 1). The participants were provided with the same clinical scenario as in Round-2 and were then asked to rank the importance of each CCI item on a nine-point Likert scale. Consensus for inclusion in the final CCI was pre-defined as greater than 70% of participants scoring 7–9 (important) AND less than 15% of participants scoring 1-3 (not important) as per GRADE/COMET criteria.24,25 Participants were informed of the pre-defined consensus to engage them in the process. Participants gave their year of birth and initials in Round-2 and -3 to assess attrition rate.\n\nThe Round-2 and Round-3 questionnaires were hosted and completed using Google Forms® and distributed to participants via email (see Extended data for Round-2 and Round-3 questionnaires34). Participants were given two weeks to answer each questionnaire from Round-2 and Round-3 with email reminders sent after one week. We aimed for a minimum of 15 respondents in each round.26 Google Forms® provides data in a downloadable Microsoft Excel® spreadsheet (V16 for Macintosh) which was used to code and describe statistics (i.e., median, mean, standard deviation, attrition rate) where appropriate.\n\nRounds 1-3 provided consensus from the participants on the CCI that should be conveyed for neonatal inter-hospital transfer in a resource-limited setting and met the first objective of the study. The second objective of the study sought to use this CCI list to create an NRF for clinical use. The CCI items were therefore employed to create a draft NRF. This draft NRF was produced on two pages to enable double-sided printing on a single sheet of A4 paper to keep costs low and facilitate use. The draft NRF was then reviewed at a face-to-face meeting of the Rwandan MoH Neonatal Technical Working Group (NTWG). At this point, amendments were made to the structure and format of the NRF. The member of the NTWG then agreed that a fourth round of the Delphi process was required to ensure that the NRF was ready to be utilised in the clinical setting.\n\nEligible participants for Round-4 (focus groups)\n\nIn Rwanda, and many similar settings, referrals between the district and regional/tertiary hospitals are almost universally made by GPs. GPs are medically qualified doctors who have not undertaken specialist training. Eligible participants for the Round-4 focus groups, were, therefore, GPs who had referred neonates to regional and tertiary hospitals. Focus group participants were selected opportunistically as those GPs that were available, and consenting, at the hospital sites on the dates the Principle Investigator visited each hospital.\n\nFocus groups\n\nFocus groups were undertaken in a quiet room, with no patients or other professionals present. The participants were given hard paper copies of the NRF and an explanation of the purpose of the process and the objective of producing an NRF for clinical use in Rwanda. They were then asked to review the NRF and collectively make suggestions to improve and amend the NRF. No interview guide was used. Focus groups were undertaken in a mix of Kinyarwanda, English and French (official national languages of Rwanda). Recordings were not taken, with the Principal Investigator (OM) taking field notes.\n\nCoding and analysis\n\nField notes were coded by two coders (OM and PC) using Microsoft Excel, and consensus identified if a code was introduced in two or more separate focus groups. These themes were used to amend the NRF further.\n\nApproval\n\nFinally, the NRF was re-reviewed by the MoH NTWG and the MoH National Health Referral System committee, with no further amendments to the content of the form made.\n\nEthics approval\n\nThe study protocol was reviewed and approved by the University of Rwanda College of Medicine and Health Sciences Institutional Review Board (IRB) (Ref: 002/CMHS IRB/2018). There were no significant physical, emotional, social, financial or legal risks to participants identified.\n\nConsent:\n\nFor Rounds-2 and -3 information regarding the study was provided to participants at the same time as the online google questionnaire and completion of the questionnaires implied informed consent of participation. For Round-4 verbal information was given to participants and participation was deemed as implied consent.\n\nConfidentiality\n\nThe questionnaire was fully anonymised, and email invitations were sent individually to maintain confidentiality. Participant demographics and response data were obtained via Google forms®, which is password-protected and accessed only by the principal investigator and both supervisors of this project.\n\n\nResults\n\nWe identified a total of 16 NRFs. Initial searches related to resource-limited settings identified two NRFs from Rwandan Provincial hospitals (Rwamagana and Ruhengeri). Fourteen NRFs were identified from upper-middle and high-income countries: eight from the United Kingdom, five from the United States and one from South Africa. These 16 NRFs contained a total of 125 individual items, of which ten items were immediately removed as being not relevant to the CCI in a resource-limited setting (e.g., therapeutic hypothermia). Ninety-one of the remaining 115 items (79%) met the pre-defined criteria for consensus to be included in the first draft of the CCI. These items were listed individually, grouped under eight relevant sections to aid interpretation by participants (Table 1). Each NRF contained a mean of 34 items (min = 11, max = 52). Only 33 of the 91 identified items (36%) were present in more than half of the 16 NRFs, confirming the need for this consensus study.\n\n124 participants were contacted. The response rate was 32 (25%) and 33 (27%) participants for Round-2 and Round-3, respectively. This response rate exceeded our desired sample size of 15, required for consensus, in each round. Eleven of the 32 (33%) participants from Round-2 also completed Round-3; thus, 22 of 33 (67%) participants in Round-3 were new responders. Participants in Round-2 and -3 had a mean of 14 years and 13 years of paediatric experience, respectively (Table 2).\n\nAll sections/themes had additional items suggested by participants, with 20 participants suggesting new additions to the “Patient Identification” section. Fifty-two items were suggested that were already present in the Round-1 CCI and were therefore excluded. Thirty-three new items were suggested. Twelve (36%) of these were independently suggested by two or more participants and therefore met the pre-defined consensus criteria and were added to the existing 91 items from Round-1 to form the draft CCI list of 103 items for Round-3 (Table 1).\n\nPiloting of the Delphi questionnaire between Round-2 and Round-3 revealed that 21 items could be merged with existing items (Figure 1). For example, in Round-2, seven different types of birth resuscitation were described (e.g., bag-valve-mask, stimulation, etc.); these were merged with the item of \"resuscitation at birth.\" This was to reduce questionnaire fatigue, which was reported by the piloting participants. Therefore, after merging these items, the list reduced from 103 to 82 items.\n\nMoH NTWG, Ministry of Health Neonatal Technical Working Group; NRF, neonatal referral form.\n\nThe questionnaire was again divided into the same eight sections/domains, to form a second draft CCI list. Eighty-two items were presented individually for scoring of “importance” in Round-3 (Supplementary Table 2, Extended data34). Of these, 57 items (70%) met the pre-defined consensus criteria to be included in the final CCI list (Supplementary Table 3, Extended data34). Seven of the 12 items (58%) suggested in Round-2 met the inclusion criteria for the final CCI list. This list was then used to generate the first draft of the NRF (Supplementary File 3, Extended data34).\n\nThe draft NRF was then reviewed at the Rwandan MoH Neonatal Technical Working Group (NTWG), and eight amendments were made (Supplementary Table 4, Extended data34). Twenty-nine general practitioners then took part in five focus groups to review the NRF, with each focus group lasting between 60 and 90 minutes. The five focus groups were undertaken at three rural district hospitals [Gahini (n = 5), Nemba (n = 9) and Ruli (n = 4)] and two urban provincial (secondary) hospitals [Ruhengeri (n = 8), Rwamagana (n = 3)]. The focus-groups created a total of 37 new suggestions for modifying the NRF (Supplementary Table 4, Extended data34). Nineteen of these suggestions were made in two or more of the focus groups. Sixteen of these changes were incorporated into the final NRF (Supplementary File 4, Extended data34); three were not feasible, namely, creating a French version, adapting a version specific for health centres and reducing the size of the NRF.\n\n\nDiscussion\n\nWe sought to determine the essential data items that should be conveyed for neonatal inter-hospital transfer in a resource-limited setting. By employing Delphi consensus techniques, we have generated a neonatal referral form in order to close the communication gap in inter-hospital transfer in Rwanda. Additionally, given the breadth of experience of our participants, we anticipate that the form is readily adaptable to other similar resource-limited settings.\n\nPrecise records are an essential component of neonatal inter-hospital transfer.27 However, there is limited evidence for how such data should be communicated. For example, the NRFs we identified in Round-1 were heterogeneous in nature, with only 33 (36%) of the 91 items identified being present in more than half of the 16 NRFs. Therefore, many NRFs may be excluding important data points because robust methods were not employed to develop them. We found that these existing NRFs contained a mean of 34 items, which is less than the 57 items we identified in Rounds -1 to -3 and therefore these NRFs may not be comprehensive. Despite having more items, our NRF fits on two pages as practicalities such as printing costs are important in our setting. Items in the NRF that are unique to resource-limited settings include modes of transport (e.g. motorcycle, walking), conditions in pregnancy (e.g. tuberculosis), and perinatal infant care (e.g. tetracycline eye ointment).\n\nCommunication errors have been established as a potential cause of significant adverse events during transport.28 By encouraging strict adherence to data collection and sharing, NRFs can also assist with providing a standardised patient handoff, which has been identified as a quality metric for neonatal transport.29,30 Also, NRFs allow for tracking data to assist with clinical benchmarking for transport outcomes, a much-needed measure in neonatal inter-hospital transfer and neonatal registries.31–33\n\nBy utilising a modified Delphi consensus process, we have incorporated core items that previous NRFs included while tailoring the form for use specifically in a resource-limited setting. The participants contributing to the consensus process had a broad length of experience and diverse backgrounds and training. Their broad expertise helped contribute extensive and informed feedback in Round-2 and -3 of the Delphi. Given that two-thirds of these participants were from East African countries, we feel that the consensus process produced CCI items that are generalisable to other resource-limited settings. Using focus groups of general practitioners in Round-4 of the study has made the NRF relevant and practical to the professionals working in the health facilities that are required to transfer neonates for more specialist care.\n\nWe identified several possible limitations to our study. First, only two of the 16 NRFs obtained in Round-1 were from resource-limited settings. The content validity of the 14 other NRFs may, therefore, be decreased for our setting. There may be other NRFs from a similar setting, but despite internet/literature searches and contacting local networks, these were not identifiable. However, we feel that this is minimised by the participant contributions in Rounds-2, -3 and -4. Second, the participants involved were all physicians. Parents and nursing staff were not included. It was felt that parents were unlikely to understand the terminology or the nature of the clinical information being presented. However, adding nursing staff could have affected our results by eliminating certain items or introducing additional novel items in our NRF. Only four board-certified neonatologists participated in our study. In practice, many of the general paediatricians who participated in our study, particularly from resource-limited settings, care primarily for neonates but simply do not have official certification as subspecialists. Hence, we feel that the expertise of our participants remains highly relevant to the setting and scope of our study. Regarding potential biases, there are 91 items in the first draft of the CCI list. Asking participants to score the importance of all of these items could result in questionnaire fatigue and bias the results of the later outcomes. To mitigate against this possibility, the questionnaire was split into eight themes/sections, and some items were combined in the final round.\n\nDespite these limitations, we anticipate that our NRF can be used in its current form at any centre that refers neonates to institutions that provide a higher level of care in resource-limited settings. The first page also has the potential to be used for intra-hospital transfer. If employed in other settings, the language and terminology would need to be modified where appropriate and the items assessed for local suitability. How the use of this NRF affects the outcomes of neonatal transfer between health facilities in Rwanda is an area for future research. Furthermore, this NRF represents an important first step in standardising data collection in our own clinical setting in Rwanda, and may do the same for other resource-limited settings. These data can form the foundation for future quality improvement initiatives in neonatal inter-hospital transfers or centres establishing neonatal registries.33\n\nAdverse outcomes occur in up to 40% of neonates transported between hospitals, and there are currently no standardised, robustly designed, communication tools for the transport of neonates in resource-limited settings. We have used Delphi consensus methods to generate a novel NRF to close the communication gap in inter-hospital transfer in the resource-limited setting, such as Rwanda, where it is now in national clinical use. The NRF is freely available on Harvard Dataverse34 with a CC0 licence, allowing other settings to use and adapt the NRF to their own setting needs.\n\n\nData availability\n\nHarvard Dataverse: A Neonatal Referral Form For Resource-Limited Settings - A Modified Delphi-Consensus Study. https://doi.org/10.7910/DVN/Q0ZGDZ.34\n\nThis project contains the following underlying data:\n\n- Round-1 - NRF e-Delphi.tab (Round-1 dataset)\n\n- Round-2 - NRF e-Delphi.xlsx (Round-2 dataset)\n\n- Round-3 - NRF e-Delphi.tab (Round-3 dataset)\n\n- Round-4 - NRF e-Delphi.tab (Round-4 dataset)\n\nHarvard Dataverse: A Neonatal Referral Form For Resource-Limited Settings - A Modified Delphi-Consensus Study. https://doi.org/10.7910/DVN/Q0ZGDZ.34\n\nThis project contains the following extended data:\n\n- e-Delphi consent form.docx (Consent description for Round-2 and Round-3)\n\n- Google Forms - Questionnaire for Round-2.pdf (Round 2 Questionnaire)\n\n- Google Forms - Questionnaire for Round-3.pdf (Round 3 Questionnaire)\n\n- Supplementary_File_3_RaNRF_Round3.docx (Draft neonatal referral form generated in Round-3)\n\n- Supplementary_File_2_FINAL_NRF_after_Round_4.docx (Final neonatal referral form for resource-limited settings - for public use)\n\n- Supplementary_Table_1_Search_terms.docx (Search terms used in Round-1)\n\n- Supplementary_Table_2_Round_3.docx (Round-3 responses and consensus application)\n\n- Supplementary_Table_3_Final_CCI_list.docx (Final CCI list at end of Round-3)\n\n- Supplementary_Table_4_Round_4_coding.docx (Coding used in Round-4)\n\nData are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nWorld Health Statistics 2017: Monitoring health for the SDGs.Switzerland; 2017. Reference Source\n\nRwanda National Institute of Statistics: Demographic and Health Survey, 2014-15, final Report.Kigali; 2016 [cited 2018 Aug 1]. p. 1–615. Reference Source\n\nNational Institute of Statistics of Rwanda, Ministry of Health (MOH): Rwanda demographic and health survey 2019-2020: Key indicators report.2020. Reference Source\n\nRathod D, Adhisivam B, Bhat BV: Transport of sick neonates to a tertiary care hospital, South India: condition at arrival and outcome. Trop Doct. 2015; 45(2): 96–9. PubMed Abstract | Publisher Full Text\n\nAbdulraheem MA, Tongo OO, Orimadegun AE, et al.: Neonatal transport practices in ibadan, Nigeria. Pan Afr Med J. 2016; 24(216): 1–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMori R, Fujimura M, Shiraishi J, et al.: Duration of inter-facility neonatal transport and neonatal mortality: Systematic review and cohort study. Pediatr Int. 2007; 49(4): 452–8. PubMed Abstract | Publisher Full Text\n\nKumar PP, Kumar CD, Shaik F, et al.: Transported neonates by a specialist team- How STABLE are they. Indian J Pediatr. 2011; 78(7): 860–2. PubMed Abstract | Publisher Full Text\n\nKumar PP, Kumar CD, Shaik FAR, et al.: Prolonged neonatal interhospital transport on road: Relevance for developing countries. Indian J Pediatr. 2010; 77(2): 151–4. PubMed Abstract | Publisher Full Text\n\nMinistry of Health; Republic of Rwanda: Health Sector Policy.2015 [cited 2018 Aug 1]. p. 1–33. Reference Source\n\nKwaZulu-Natal: Monitoring & handover sheet for neonatal transfers (NRF).2016 [cited 2017 Dec 7]. Reference Source\n\nNeonatal Health System: Embrace acute call medical control form (NRF).2016 [cited 2017 Dec 7]. Reference Source\n\nUtah Women and Newborns Quality Collaborative: Utah Neonatal Transfer Form (NRF).[cited 2017 Dec 7]. Reference Source\n\nCalfornia Perinatal Transport System (CPETS): Acute Inter-facility Neonatal Transport form (NRF).2017 [cited 2017 Dec 7]. p. 1–2. Reference Source\n\nMcConnell D, Butow PN, Tattersall MHN: Improving the letters we write: An exploration of doctor-doctor communication in cancer care. Br J Cancer. 1999; 80(3–4): 427–37. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCouper ID, Henbest RJ: The quality and relationship of referral and reply letters. S Afr Med J. 1996; 86(12): 1540–2. PubMed Abstract\n\nUnited Nations Children’s Fund (UNICEF), World Health Organization: Model Chapter for IMCI Textbooks. 2001.\n\nOrimadegun AE, Akinbami FO, Akinsola AK, et al.: Contents of referral letters to the children emergency unit of a teaching hospital, southwest of Nigeria. Pediatr Emerg Care. 2008; 24(3): 153–6. PubMed Abstract | Publisher Full Text\n\nVincent-Lambert C, Wade G: Challenges relating to the inter-facility transport of high acuity paediatric cases. Afr J Emerg Med. 2018; 8(1): 29–33. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMwizerwa O, Umuhoza C, Corden MH, et al.: What is the key medical information required to care for a transferred neonate appropriately? – A Best Evidence Topic (BET). Rwanda Med J. 2018; 75(4): 1–5. Publisher Full Text\n\nSinha IP, Smyth RL, Williamson PR: Using the Delphi Technique to Determine Which Outcomes to Measure in Clinical Trials: Recommendations for the Future Based on a Systematic Review of Existing Studies. PLoS Med. 2011 Jan 25 [cited 2016 Nov 17]; 8(1): e1000393. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilliamson PR, Altman DG, Blazeby JM, et al.: Developing core outcome sets for clinical trials: Issues to consider. Trials. 2012; 13(132): 1–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCuster RL, Scarcella JA, Stewart BR: The Modified Delphi Technique - A Rotational Modification. J Career Tech Educ. 1999; 15(2): 1–9. Publisher Full Text\n\nBinagwaho A, Kyamanywa P, Farmer PE, et al.: The Human Resources for Health Program in Rwanda — A New Partnership. NEJM. 2010; 369(21): 2054–9. PubMed Abstract | Publisher Full Text\n\nGuyatt GH, Oxman AD, Kunz R, et al.: GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol 2011; 64(4): 395–400. PubMed Abstract | Publisher Full Text\n\nWilliamson PR, Altman DG, Bagley H, et al.: The COMET Handbook: Version 1.0. Trials. 2017; 18(Suppl 3): 1–50. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHsu C, Sandford B: The delphi technique: making sense of consensus. Pract Assessment, Res Eval. 2007; 12(10): 1–8. Publisher Full Text\n\nPan P: Inter Hospital Transfer of Critically Ill Neonates-Challenges Faced. J Pediatr Neonatal Care. 2017; 6(2): 235. Publisher Full Text\n\nGunz AC, Dhanani S, Whyte H, et al.: Identifying Significant and Relevant Events During Pediatric Transport: A Modified Delphi Study. Pediatr Crit Care Med. 2014; 15(7): 653–9. PubMed Abstract | Publisher Full Text\n\nBigham MT, Schwartz HP: Quality Metrics in Neonatal and Pediatric Critical Care Transport: A Consensus Statement. Pediatr Crit Care Med. 2013; 14(5): 518–23. PubMed Abstract | Publisher Full Text\n\nSchwartz HP, Bigham MT, Schoettker PJ, et al.: Quality Metrics in Neonatal and Pediatric Critical Care Transport: A National Delphi Project*. Pediatr Crit Care Med. 2015; 16(8): 711–7. PubMed Abstract | Publisher Full Text\n\nRatnavel N: Early Human Development Evaluating and improving neonatal transport services. Early Hum Dev. 2013; 89(11): 851–3. Publisher Full Text\n\nStroud MH, Trautman MS, Meyer K, et al.: Pediatric and neonatal interfacility transport: Results from a national consensus conference. Pediatrics. 2013; 132(2): 359–66. PubMed Abstract | Publisher Full Text\n\nChoi J, Urubuto F, Dusabimana R, et al.: Establishing a neonatal database in a tertiary hospital in Rwanda – an observational study. Paediatr Int Child Health. 2019; 39(4): 265–74. PubMed Abstract | Publisher Full Text\n\nCartledge P: A Neonatal Referral Form For Resource-Limited Settings - A Modified Delphi-Consensus Study. Harvard Dataverse, V2, UNF:6:vhUBB3u7tvovHWLUGWJYwQ== [fileUNF]. 2020. Publisher Full Text"
}
|
[
{
"id": "85767",
"date": "14 Jun 2021",
"name": "Pradyumna Pan",
"expertise": [
"Reviewer Expertise Surgical outcome of opertion"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nWell researched and clearly written article. Very informative. In this paper, the authors explored the nature and use of the Delphi research method, explored how and why it may be applied. The authors established the Delphi method being used principally to explore issues and risks as a result of previous research and to forecast future technology application and best practices.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "125910",
"date": "28 Mar 2022",
"name": "Peter Lachman",
"expertise": [
"Reviewer Expertise Patient Safety",
"Quality Improvement and implementation",
"Paediatrics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper provides a report on the development of a neonatal referral form for use in a low resource setting. This is an important development to improve reliability of communication thereby improving reliability of care and neonatal outcomes.\nThe rationale for the study is well explained i.e. the lack of a standardized referral process in the context of high neonatal mortality and the need for improved communication on referral.\n\nThe context is relevant and important.\n\nThe rationale for the study is clear.\n\nThe study methodology is described well.\n\nThe literature search for similar tools appears to be good – though there may be grey literature i.e unpublished referral forms not available for review.\n\nThe modified Delphi appears to be well run and addresses possible bias.\n\nThe results are described in sufficient detail.\n\nThe supplementary data provides the important background to the paper as well as the final version of the form.\n\nAs a paper reporting the development of a tool to improve the reliability of information transfer, the authors have met the aim of the study i.e. developing a form co-designed by referrers and receivers of the referral using a Delphi approach.\n\nI would have expected the theory of standardization of communication to be discussed in the context of patient safety theory, in particular human factors and reliability .\nThe layout of the form could also be designed more ergonomically.\n\nWas the layout tested in the field to see how best to set out the required information?\n\nThe paper does not address the following though the authors note that the form “is now in national clinical use in Rwanda\"\nDoes the form work i.e. do clinicians use it reliably where reliability is defined as completion of all required information accurately 100% of the time?\n\nAre any modifications required especially in design of form?\n\nAre all the items necessary in real life outside the research environment where it was developed.\n\nWhat training is required to have the form used? Is there a training manual?\n\nWho fills out the form – nurses or doctors?\n\nOn case by case basis has the form improved the outcome for babies when filled out correctly?\n\nI note that that these questions are for future research. However a comment on this and on how the implementation of the form is carried out and scaled up would be a good follow up study. A neonatal collaborative across the country may be the way to ensure the form is used on a reliable basis.\nA note on the above would add value to the findings of the paper.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8273",
"date": "24 May 2022",
"name": "Peter Cartledge",
"role": "Author Response",
"response": "We would like to thank the reviewer for their comments and input into the article, which we feel contribute to the article. Here we respond to each comment, point by point: The literature search for similar tools appears to be good – though there may be grey literature i.e unpublished referral forms not available for review Response: This is a very valid point. During the study design phase, we did undertake a “grey search” using both an internet search and through networking of contacts known to us. We have amended the text in “Methods” > ”Round-1” to hopefully make this a bit more clear to readers. I would have expected the theory of standardization of communication to be discussed in the context of patient safety theory, in particular human factors and reliability. Response: We have added some new text to the background putting the study in context of human factors. We can see that much of what we did employed Human Factors/Ergonomics (HFE) theory, but we feel it would be disingenuous to imply that we used this approach formally in our methodology. The layout of the form could also be designed more ergonomically. Response: Yes, we would agree with this. Printing costs and practicalities had to be a major consideration and this has certainly come at the cost of ergonomics. We have added a comment into the Discussion to discuss this; “The practicality of ensuring printing on a single A4 double-sided sheet of paper does that mean that font size may be challenging for persons with reduced eye-sight, and that the ergonomics of the form may not be optimal.” Was the layout tested in the field to see how best to set out the required information? The paper does not address the following though the authors note that the form “is now in national clinical use in Rwanda\" Response: The layout was not formally field-tested. But its use has adapted since we have submitted the article for publication. We have therefore added the following text into the clinical implications section “The NRF was not initially field-tested in its double-sided A4 format but has now been subsequently adapted by the Ministry of Health. It has been adapted to fit onto a double-spread pad of carbon-copied paper so that the form can be sent to the receiving hospital, with the sending facility being able to keep a copy of the information being shared.” Does the form work i.e. do clinicians use it reliably where reliability is defined as completion of all required information accurately 100% of the time? Response: The form has now been implemented in Rwanda, and its use will make an interesting piece of research work. We have added an additional comment into “Clinical application” to make this a bit clearer. Are any modifications required especially in design of form? Response: The initial NRF design was evaluated by Round-4 participants for face validity with modifications applied. Beyond the scope of the “methodology” of this study, the form has now been adapted by the Ministry of Health (as discussed in the point above). Are all the items necessary in real life outside the research environment where it was developed. Response: The aimed output was for a NRF suitable for “day-to-day” clinical use, rather than research. We have added this comment into the Objectives and the “Clinical Application” section. What training is required to have the form used? Is there a training manual? Response: We have added the following text to the Clinical Implications section – “There is currently no formal training delivered for use of the NRF.” Who fills out the form – nurses or doctors? Response: We have added the following text to the Clinical Implications section “In its current use in Rwanda, the NRF is being used at all levels of referral by different professionals. Normal practice is that doctors complete the form in hospitals and nurses and/or midwives complete it at the health center level.” On case by case basis has the form improved the outcome for babies when filled out correctly? Response: We aren’t able to comment on this at this point in time in the article. Anecdotally professionals have commented to the authors that the form is helpful in their clinical practice. But this information hasn’t been collected in any formal setting. I note that that these questions are for future research. However a comment on this and on how the implementation of the form is carried out and scaled up would be a good follow up study. A neonatal collaborative across the country may be the way to ensure the form is used on a reliable basis. Response: As the Clinical Implications section was getting large we have added a new heading “future research”. We have added the following statement to this section “The design and use of the form have now been taken over by the Neonatal Working Group of the Ministry of Health, which includes multi-disciplinary professionals, who are best placed to evaluate its use.” Additional comments from the authors: Clinical implications section: “The first page also has the potential to be used for intra-hospital transfer.” In the previous version we made this comment. There is a potential for this to be undertaken in Rwanda, but it hasn’t been implemented yet, and we are aware that the section of text is becoming long, therefore we have removed this comment."
}
]
}
] | 1
|
https://f1000research.com/articles/10-365
|
https://f1000research.com/articles/11-264/v1
|
02 Mar 22
|
{
"type": "Research Article",
"title": "The Impact of Green Practices in Value Chain on Firm Performance in the Context of a Developing Country",
"authors": [
"Jeen Wei Ong",
"Gerald Guan Gan Goh",
"Sally Hui Siang Yong",
"Gerald Guan Gan Goh",
"Sally Hui Siang Yong"
],
"abstract": "Background: Companies need to go green to remain relevant. Previous studies have confirmed that going green leads to superior performance for companies. However, research of green practices in a value chain requires further attention, especially in identifying the green value chain activities that lead to superior performance. A value chain analysis focuses on identifying competitive advantages of firms through five primary and four support activities. Methods: This study extends from Ong et al. (2019), who developed and validated the instrument for the nine green value chain activities, to also examine their effect on firm performance. The 207 valid responses in this study are collected through a questionnaire survey of the sampling frame consisting of companies in Bursa Malaysia and the Federation of Malaysian Manufacturers Directory. Results: The findings reveal that the companies’ green practices in primary value chain activities are higher than in the supporting value chain activities. Technological development is the activity with the lowest green attention among the nine value chain activities. Our multiple regression analysis shows that 25% of the variation in firm performance can be significantly explained by the nine green value chain activities. In terms of the individual green value chain activities, green technology development is the only activity that can positively and significantly explain firm performance. Conclusions: The findings of the study suggest that companies intending to build their green core competence need to engage in green technology development. Companies that go green for the purpose of complying to regulations and fulfilling minimum customers’ demands can still embed green practices into their green value chain without compromising their performance.",
"keywords": [
"Green Practices",
"Value Chain",
"Firm Performance",
"Malaysian Corporations",
"Multilinear Regression Analysis"
],
"content": "Introduction\n\nIt is no longer a choice, but it is instead becoming necessary for companies to be environmentally friendly or greener in their business operations. Consumers, especially millennials, show a preference for environmentally friendly companies and products.1 Companies need to embed an environmentally friendly approach completely into multiple dimensions of their business operations in order capture the value created in the form of performance.1 Various research findings have confirmed that green practices in businesses lead to greater performance (e.g., Refs. 2–4). However, there is still an opportunity to further study green practices from the value chain perspective. The value chain, introduced by Porter,5 provides a comprehensive analysis of the value creation activities within a company. Anchoring green research to businesses from the value chain perspective can provide further detail on the actual value creation activities that lead to superior performance.\n\nIn analysing the competitive advantage of a firm, Porter5 introduced value chain analysis to distill the value creation activities within a company into five primary and four support activities. The five primary activities are the inbound logistics, operations, outbound logistics, marketing, and sales and services, denoting the complete value creation process from materials to after-sales services to the customers.5 The procurement, firm infrastructure, technology development, and human resources management support the primary activities as the support activities in the value creation process.5 Studies by Handfield, Walton, Seegar, et al.6 and Hartman and Stafford7 are among the early researches that explore the idea of a green value chain. Subsequently, Ndubisi and Nair,8 Yong, Goh and Ong,9 Anthony Jnr10 and Ong et al.11 are among the studies that consider the full value chain in the context of Porter (1985). Both Anthony Jnr10 and Ong et al.11 have operationalized the value chain activities but neither of these studies examined the impact of the green value chain activities on firm performance. Anthony Jnr10 studies the impact of green value chain activities on the sustainable value chain practices while Ong et al.11 focus on validating the instrument.\n\n\nMethods\n\nThe survey instrument for the nine activities of the green value chain was developed using responses from semi-structured interviews with 35 companies across different business sectors. The interviewees from these companies were in managerial positions and were asked to list the important green activities under each of the nine value chain activities suggested by Porter.5 Findings from these interviews were compiled and formulated into the survey instrument. There are a total of 99 items for the nine green value chain activities. On the other hand, the instrument to measure the firm performance is adopted from Ong12 and consists of seven items. All the items are measured using the seven-point itemized rating scale with one indicating strongly disagree and seven indicating strongly agree.\n\nThe survey form also consisted of a cover letter and an informed consent statement. These documents communicated the purpose of the study, and detailed the research sponsor and researchers, the research procedure, the voluntary nature of zthe study, the possible risks and benefits of participating in the research, and the confidentiality of the respondents’ identity. The respondents were informed that by returning the survey form, they indicated their consent to participate in the research but that they could withdraw their participation by informing the researchers.\n\nA census method was used to contact all 1,150 companies listed in the main market and ACE market of Bursa Malaysia and the Federation of Malaysian Manufacturers Directory with complete mailing information. Letters were sent out to all. Fourteen letters were returned due to inaccurate mailing information. By the end of the survey, 207 valid responses were received. The assurance of confidentiality of the identity of respondents and the absence of fixed or expected responses in the survey aimed to ease the possible issue of common method variance.13\n\nThe data collected was analysed using SPSS version 26 (IBM SPSS Statistics, RRID:SCR_019096). Alternatively, GNU PSPP is a free open-source software that can be used to perform similar functions. The results are presented in the next section, starting with the presentation of a brief profile of the responding companies, followed by the reliability and validity analysis and mean analysis for all the variables. Lastly, the impact of the nine green value chain activities on firm performance is tested using multiple linear regression analysis.\n\n\nResults\n\nThe demographic profile of the companies, in terms of the company size, years of operation, and status of ownership, are presented in Table 1. The statistical results show that more than half of the companies have 1,000 or fewer employees. In terms of years of operation, close to half of them have operated for 10 years and lesser. A vast majority of them are locally owned.\n\nWe performed exploratory factor analysis on the all the items for the nine green value chain activities and the firm performance. Results show that the Kaiser-Meyer-Olkin (KMO) is higher than 0.80 and the Bartlett’s test of sphericity is significant at the 95% confidence level. Two items, one each for Operations and Services were removed due to cross loading. The rule of thumb used was that the loading must be above 0.40 in one factor only.14 The inter-item consistency for all individual variables was tested using Cronbach’s Alpha, with results indicating a satisfactory level of inter-item consistency for all variables. The details are presented in Table 2.\n\nIn addition, Table 2 presents the mean and standard deviation for each variable. The mean for the nine green value chain activities ranged from 3.68 to 5.66 on the seven-point scale. The activity with the highest mean score was services, with a mean of 5.66 and a standard deviation of 1.03. On the other hand, technology development had the lowest mean with a score of 3.68 and a standard deviation of 1.44. Firm performance had a mean score of 4.91 and standard deviation of 0.96 on the seven-point scale.\n\nTable 3 shows the results of the multiple linear regression analysis. This analysis was used to test the effect of the nine green value chain activities on firm performance. The correlation coefficient, R, was 0.500 and the R-squared was 0.250 (F = 7.282; p < 0.05). This shows that 25% of variation in the firm performance is explained by the nine green value chain activities. Among the nine green value chain activities, only technology development was found to have a significant impact on firm performance (Beta = 0.257; t-value = 2.815; p < 0.05).\n\n\nDiscussion\n\nThe general profile of the sample companies in the study is relatively small and young with more than half of them having employee numbers below 1,000 and near to half of them having been established for less than 10 years. In terms of the value chain activities, these companies embed green practices into the primary value chain better than the support activities, except for the inbound logistics. The smaller size of suppliers could contribute to lesser enforcement of green practices in this primary value chain activity. A worrying observation is that the green practices in the four support activities are low. Without the right technology, infrastructure, procurement processes, and human resources, the effectiveness and sustainability of the green practices in the primary activities remain questionable. Our findings suggest that the companies need to strengthen their green practices in technology development to achieve better performance. Unfortunately, technology development has the fewest elements of green practices among the nine value chain activities.\n\nOur findings suggest that the involvement of companies in the research and development of green technologies is crucial for companies to gain superior performance. This signifies the importance of proprietary green technology to firm performance. The visibility of a companies’ involvement in green technology development could be a contributor, especially for those involved in the business-to-business sector. The capability and experience in green proprietary technology development is vital to gain superior performance from going green. In the case of Malaysia, based on this study, the worrying situation is the lack of involvement of the companies in green technology development. On the other hand, there is no evidence to show that involvement in green practices inversely affects firm performance.\n\nCompanies have to make a strategic decision in going green. They could decide to take a strategic move to create core competency by developing the green technology to gain superior performance. On the other hand, companies can decide to use the compliance model by fulfilling the minimum regulatory or customer requirements in going green. They can build their core competency elsewhere. There is no evidence from this study that the latter model could cost their performance. The findings from the green practices in primary and support value chain activities, show that most of the companies could be using the latter model.\n\n\nConclusions\n\nThe study extends from Ong et al.11 to further analyse the impact of green value chain activities on firm performance. Our findings support the notion that companies involved in green activities can gain superior performance. There is no evidence suggesting that embedding green practices in the value chain can have a negative impact on firm performance. Companies need to have the correct business model and strategy in approaching the trend of increasing demand to be environmentally friendly. Nonetheless, future research could further validate the instruments used in this study. Future research could also study the existence of mediators or moderators that cause the insignificance of all the primary green value chain activities in explaining the superior firm performance.\n\n\nData availability\n\nFigshare: https://doi.org/10.6084/m9.figshare.14883240.v115\n\nThis project contains the following underlying data:\n\n• GVC_Dataset_Share.sav (The dataset was collected through a questionnaire)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nEthical approval and consent\n\nThe consent form was attached to the survey form and sent to the respondents as a letter. The form included the research purpose, research sponsor, research procedures, a statement of voluntary participation, confidentiality of the respondents and the company's identity, risks and benefits of participating in the study and a statement on consent agreement. The consent agreement clearly spelled out that completing and returning the completed survey form indicated the respondent's consent to participate in the research.\n\nEthical approval was granted by the Research Ethics Committee (REC) of Multimedia University. The committee granted the approval after reviewing the self-declared form submitted by the researchers.\n\nThe approval number is EA2312021.\n\n\nAuthor contributions\n\nOng, J. W. involves in data collection and data analysis and completing the first draft of write-up for this article.\n\nGoh, G. G. G. contributes in the items development and editing the final version of this article.\n\nYong, H. S. S. involves in early stage interviews that subsequently leads to the measurement items development. She assists also in data collection.",
"appendix": "Acknowledgements\n\nThe authors would like to thanks all the individuals and organisations that participated in contributing to this research.\n\n\nReferences\n\nButler: Do Customers Really Care about your Environmental Impact?. Forbes New York Business Council; 2018, November 21. Reference Source\n\nRaharjo K: The role of green management in creating sustainability performance on the small and medium enterprises. Manag. Environ. Qual. 2019; 30(3): 557–577. Publisher Full Text\n\nChege SM, Wang D: The influence of technology innovation on SME performance through environmental sustainability practices in Kenya. Technol. Soc. 2020; 60: 101210. Publisher Full Text\n\nZhang Y, Ouyang Z: Doing well by doing good: How Corporate Environmental Responsibility influences Corporate Financial Performance. Corp. Soc. Responsib. Environ. Manag. 2021; 28(1): 54–63. Publisher Full Text\n\nPorter ME: Competitive Advantage: Creating and Sustaining Superior Performance. New York: The Free Press; 1985.\n\nHandfield RB, Walton SV, Seegers LK, et al.: ‘Green’ value chain practices in the furniture industry. J. Oper. Manag. 1997; 15(4): 293–315. Publisher Full Text\n\nHartman CL, Stafford ER: Crafting' enviropreneurial' value chain strategies through green alliances. Bus. Horiz. 1998; 41(2): 62–72. Publisher Full Text\n\nNdubisi NO, Nair SR: Green entrepreneurship (GE) and green value added (GVA): A conceptual framework. Int. J. Entrepreneurship. 2009; 13: 21.\n\nYong SHS, Goh GGG, Ong JW: Do Green Value Chains Contribute To Competitive Advantage?. Proceedings of USM-AUT International Conference 2012 Sustainable Economic Development: Policies and Strategies. 2012; (Vol. 167, p. 343).\n\nAnthony Jnr B: Sustainable value chain practice adoption to improve strategic environmentalism in ICT-based industries. J. Glob. Oper. Strateg. Sourc. 2019; 12(3): 380–409. Publisher Full Text\n\nOng JW, Goh GGG, Goh CY, et al.: The green value chain construct: instrument validation and green practices among Malaysian corporations. World Rev. Entrepreneurship, Manag. Sustain. Dev. 2019; 15(4): 494–512. Publisher Full Text\n\nOng JW: Market Orientation and Industrial Organisation View of Factors Contributing towards Firm Performance: A Study of Malaysian Small Medium Enterprises. PhD thesis, Multimedia University. 2017.\n\nPodsakoff PM, MacKenzie SB, Lee JY, et al.: Common method biases in behavioral research: a critical review of the literature and recommended remedies. J. Appl. Psychol. 2003; 88(5): 879–903. PubMed Abstract | Publisher Full Text\n\nHair JF Jr, Black WC, Babin BJ, et al.: Multivariate Data Analysis: A Global Perspective. 7th ed.Upper Saddle River: Pearson Education; 2010.\n\nOng JW, Goh G: GVC_Dataset_Share.sav. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "126018",
"date": "24 Mar 2022",
"name": "Uchenna Cyril Eze",
"expertise": [
"Reviewer Expertise Mindful consumption",
"e-business",
"knowledge management",
"sustainability in business",
"green marketing",
"strategy"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript titled \"The impact of green practices in the value chain on firm performance in the context of a developing country\" appears well-written and provides insights in the domain of study, which although extremely important for industry operation, is rarely researched in the context presented. The objectives were clearly outlined and the findings appear valid. This manuscript, however, could have benefited from more clarity in the research method, more context in how the findings were presented, and some editing to remove obvious writing errors.\nThere should be more details on how the semi-structured interview was conducted. For example, what were the positions of these managers for this reader to get a sense of the capability of the participants to provide reliable information? How much time elapsed between the interview and the survey, and how did this time affect the design of the survey questionnaire, if any?\nProvide more context in the discussion of the findings. How do the findings in this manuscript compare to the findings of prior studies in related area?\nPlease check the overall manuscript to remove obvious grammar and typographical errors.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8291",
"date": "07 Jun 2022",
"name": "Jeen Wei Ong",
"role": "Author Response",
"response": "Dear Reviewer, Thank you very much for your constructive review of this article. We have made the amendments as the following based on your suggestions. 1. For your suggestion about the respondents, we added the description that the respondents are holding managerial positions in different business functions. We verify their capability to provide a reliable response by asking them to describe the company and their experience with the company. 2. We also compare our results with the available results from previous studies. In general, our finding is consistent with the previous studies that green practices lead to greater performance. However, compared to the previous study that uses a dependent variable that comprises the triple bottom line, a discrepancy in the results is observed. 3. We also recheck the article for obvious grammatical and typographical errors."
}
]
},
{
"id": "126017",
"date": "11 Apr 2022",
"name": "Sumesh Nair",
"expertise": [
"Reviewer Expertise Green/environmental marketing and Ethical Marketing."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n\"The Impact of Green Practices in Value Chain on Firm Performance in the Context of a Developing Country\" is an interesting read. The introduction portrays the literature gap rather briefly. A brief literature review section would have benefited the paper in terms of elaborating the extant literature's contributions and identifying the gaps in the literature.\n\nThe methods section would have been a little more detailed with some discussion around the semi-structured interviews. What questions were asked, and how did these responses contribute to the construction of the survey instrument? I am wondering why no hypotheses were used in the study.\n\nIn a few instances of the discussion section, the researchers used the word 'worrying', it is not clear why some findings worry the researchers. The use of a more neutral language would be ideal in these instances. It would have been great to discuss the implications of the study findings in a separate section of the paper.\n\nOverall, the paper presents a very interesting analysis and findings but minimally. I am not sure this is due to any word count requirements of the journal.\n\nI wish the authors good luck with this publication.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8292",
"date": "07 Jun 2022",
"name": "Jeen Wei Ong",
"role": "Author Response",
"response": "Dear reviewer, Thank you very much for your reviews and suggestions to improve the article. We have revised the article based on your suggestions. The amendments are summarised below. 1. The literature review is part of the introduction section. More literature review is added to strengthen the argument on the existence of the research gap in terms of insufficient empirical evidence linking the green value chain to the firm performance. 2. More information on the semi-structured interviews is provided, including verifying the capacity of the respondents to provide a valid response, the questions asked during the interviews and the process of converting the findings into the questionnaire item. 3. The research framework and hypotheses are added to the article. 4. We take not on the inappropriate use of the term \"worrying\" in the article and have replaced the term with a neutral word. 5. The implications of the study are moved to a separate paragraph and implications for policymakers are added. To comply with the format of the article, a separate section is not created. 6. More discussion of the findings is added, especially in comparing the findings of our study with the previous studies and the suggestion to the policymakers."
}
]
}
] | 1
|
https://f1000research.com/articles/11-264
|
https://f1000research.com/articles/11-125/v1
|
31 Jan 22
|
{
"type": "Review",
"title": "The genetic causes of male infertility: a Middle East and North Africa perspective",
"authors": [
"Ruthwik Duvuru",
"Mouhammad Halabi",
"Temidayo S. Omolaoye",
"Stefan S. Du Plessis",
"Ruthwik Duvuru",
"Mouhammad Halabi",
"Stefan S. Du Plessis"
],
"abstract": "Male infertility is attributable to 50% of total infertility cases and about 30% of these cases remain idiopathic. In the Middle East and North Africa region (MENA), male infertility affects about 22.6% of men of reproductive age. Male infertility is caused by a variety of factors, including endocrine disruption, exposure to toxins, lifestyle, genetic and epigenetic modifications. Genetic modifications, including chromosomal abnormalities, chromosomal rearrangements, Y chromosome microdeletions and single-gene mutations, explain for about 10-15% of infertility cases. Since genetic aberration is a key player in the pathogenesis of male infertility, it is important to explore the impact in the MENA region due to the high incidence of male infertility. Therefore, the current study aims to systematically analyse the literature regarding the impact and common causes of male infertility in the MENA region. To achieve this aim, a comprehensive literature search was performed on PubMed, Google Scholar, and Science Direct databases. Following the search, a total of 126 articles was retrieved, of which 12 were duplicates and another 69 articles did not meet the inclusion criteria, totaling the exclusion of 81 articles. Studies excluded were those that had patient populations originating outside the MENA region, review articles, non-English written articles, or studies where the patient population was under 18 years of age. Findings showed that the frequent genetic aberration leading to male infertility in these regions include Y chromosome microdeletions, gene polymorphisms or copy number variations, mitochondrial microdeletions and other genetic deletions or mutations. In lieu of this, diverse clinical genetic tests should be made available for the proper diagnosis of male infertility.",
"keywords": [
"male infertility",
"chromosomal abnormalities",
"MENA",
"gene deletion",
"gene mutation",
"Y chromosome microdeletion."
],
"content": "Introduction\n\nInfertility represents the inability to achieve pregnancy after twelve or more months of regular unprotected sexual intercourse, and it affects about 15% of couples of reproductive age. Of the total cases, 50% are attributable to the male factor (Vander Borght and Wyns 2018). Not until recently, infertility represented a reproductive health disorder that was neglected, especially in the MENA region. In 2012, Mascarenhas et al. reported that infertility prevalence was highest in South Asia, Sub-Saharan Africa, North Africa and the Middle East, Central/Eastern Europe and Central Asia (Mascarenhas et al. 2012). Six years later, Eldib and Tashan (2018) showed that the incidence of primary infertility (inability to conceive after 12 or more months of regular unprotected sexual intercourse) in the Middle East and North Africa region (MENA) region is estimated at 3.8%, and secondary infertility (incapacity to conceive after 5 years of previous live birth) at 17.2%, while demographic infertility (failure to achieve conception with live birth within 5 years of exposure, based on a consistent union status, lack of contraceptive use, non-lactating and maintaining a desire for a child (Mascarenhas et al. 2012)) is estimated at 22.6% (Eldib and Tashani 2018). Recently, Sun et al. reported that the global age-standardized prevalence of infertility has increased by 23.184%, with the prevalence of male infertility estimated at 8.224%. The variations in the prevalence of male infertility across different populations were also noted (Sun et al. 2019). The Western Sub-Saharan African population have the highest rates of age-standardized male infertility at 1800 infertile men per 100,000, whereas Australasia has the lowest rates, approximately 200 infertile men per 100,000 (Sun et al. 2019). According to the same study, infertility rates in the MENA region are well above Central Europe, Western Europe, South-East Asia amongst several others at 800 infertile men per 100,000. Out of the three countries that presented with an increase in the trend of male infertility, two are from the MENA region. One is from the Middle East (Turkey; 1.498%) and the other is from North Africa (1.676%) (Sun et al. 2019). Since demographic infertility in the MENA region is on the high side (Eldib and Tashani 2018), and as well as the trend in male infertility (Sun et al. 2019), it is of utmost importance to investigate the causes.\n\nUtilizing the World Health Organization diagnostic classification for male infertility (Organization 2018), studies have elucidated azoospermia, oligozoospermia, asthenozoospermia, teratozoospermia, or combinations thereof, as part of the causes of male infertility (Ikechebelu et al. 2003, Punab et al. 2017). A study conducted in Turkey revealed that 32% of the infertility cases was due to the male factor, who were either azoospermic or oligozoospermic (Karabulut et al. 2018). Even with the discovery of different causes of male infertility using semen analysis, diagnosing male infertility is complex due to a wide variety of genetic aberrations associated with the condition.\n\nDuring the past decade, genetic studies have made great progress in elucidating the causes of male infertility, which include chromosomal translocations, azoospermia factor (AZF) deletions, Klinefelter syndrome, cystic fibrosis, and Noonan syndrome (Elsawi et al. 1994, Okada et al. 1999, Sokol and Shapiro 2001, Dhanoa et al. 2016, Kuroda et al. 2020). Some studies have identified chromosomal translocations as the most common structural genetic aberration seen in men, with nearly 1.23 per 1000 (Chen 2007, Kuroda et al. 2020). Until recently, genetic testing for chromosomal aberrations and AZF deletions are the only ways to come to a conclusive diagnosis of genetic abnormality induced male infertility. The optimal treatment plans for treating idiopathic male infertility have remained unclear unlike for established conditions such as hypogonadotropic hypogonadism and retrograde ejaculation. In order to get more informed about the genetic causes of male infertility, especially in the MENA region, the current study aimed to analyse the literature extensively regarding the effect, and the common genetic aberrations leading to male infertility from the MENA region perspectives. The epidemiological relevance of genetic anomalies induced male infertility was also discussed.\n\n\nLiterature search\n\nTo explore the common genetic aberrations in the MENA region, a thorough literature search was performed following the methodology of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. Since the MENA countries include Algeria, Bahrain, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Palestine, Qatar, Saudi Arabia, Syria, Tunisia, Turkey, United Arab Emirates, and Yemen, the search terms integrated each country with other parameters, such as “male infertility”, and “genetic alteration”. The literature search was performed on PubMed, Google Scholar, and Science Direct databases, retrieving articles that included male patients above the age of 18 from the MENA region, and research articles published between 1999 and 2020.\n\nFollowing the search, a total of 126 articles was retrieved, of which 12 were duplicates and another 69 articles did not meet the inclusion criteria. Studies excluded were those that had patient populations originating outside the MENA region, review articles, non-English written articles, or studies where the patient population was under 18 years of age (Figure 1).\n\nFollowing the search from different databases, a total of 126 articles was retrieved, of which 12 were duplicates and another 69 articles did not meet the inclusion criteria. Studies excluded were those that had patient populations originating outside the MENA region, review articles, non-English written articles, or studies where the patient population was under 18 years of age.\n\nForty-five studies met the inclusion criteria and are reported in the current study (Table 1). After analysing the 45 studies, 24 were performed in Iran, 14 in Turkey, 4 in Saudi Arabia, 2 from Tunisia and 1 in Iraq. Represented in Figure 2 is the distribution of MENA studies according to the genetic abnormalities. From our findings, the following are the common genetic abnormalities found in the MENA region: (i) Y chromosome microdeletion, (ii) deletion or gene mutation, (iii) gene polymorphism or copy number variations, (iv) chromosomal disorders, and (v) mitochondrial mutation. The findings will be discussed under these headings.\n\nFrom our findings, the following are the common genetic abnormalities found in the MENA region: (i) Y chromosome microdeletion, (ii) deletion or gene mutation, (iii) gene polymorphism or copy number variations, (iv) chromosomal disorders, and (v) mitochondrial mutation.\n\n\nY chromone microdeletion\n\nOne of the most common genetic aberrations contributing to infertility is Y chromosome microdeletion. The Y chromosome is one of two sex chromosomes available within the human genome. Structurally, the Y chromosome is composed of a short arm (Yp) and a long arm (Yq) (Ferlin et al. 2006, Gurkan et al. 2013). The long arm of the Y chromosome is made of repetitive elements that leave individuals at a high risk of internal recombination and segmental deletions. The function of the Y chromosome is to drive gonadal differentiation and develop the male phenotype (Gurkan et al. 2013).\n\nY chromosomal microdeletions can arise in the P or Q arm of the chromosome. If it arises in the p arm, it directly disturbs the differentiation of the testis. Y chromosome microdeletions in the AZF region of the q arm may lead to infertility. The AZF region is made up of multiple genomic loci, including AZFa, AZFb, AZFc, AZFd. These regions are believed to be responsible for spermatogenesis (Gurkan et al. 2013).\n\nLocated in the AZFa region is Ubiquitin specific peptidase 9 Y linked (USP9Y), which plays an important role in male reproductive development and spermatogenesis (Colaco and Modi 2018), as studies have shown its absence in infertile men whilst also noting its lack even in normal sperm count fertile men (Colaco and Modi 2018). Dead Box RNA Helicases, Box 3, Y linked (DBY), another functional gene in the AZFa region, encodes an ATP-dependent DEAD-box RNA helicase that is only expressed in germ cells. It has a homologue on the X chromosome (DBX) with 95% similarity, with the former playing a role limited to pre-meiotic male germ cells and the latter on post-meiotic spermatids. Males who did not have the DBY gene exhibited either Sertoli Cell only Syndrome (SCOS) or severe hypospermatogenesis, suggesting the gene’s importance in spermatogenesis (Foresta et al. 2000, Stanton et al. 2012). The functional genes seen in AZFb include Ribosomal protein S4, Y linked (RPS4Y2), which is expressed in the testis and prostate (Stahl et al. 2012). It plays a vital role in post-transcriptional regulation of the spermatogenic process. The Heat Shock Transcription Factor, Y linked (HSFY), exists as two coding copies in AZFb, HSFY1 and HSFY2. HSFY is predominantly present in the nuclei of round spermatids and is also associated with spermatogenesis (Stahl et al. 2012). One of the most important genes located in the AZFb region with 6 copies is the Ribonucleic Acid Binding Motif, Y linked (RBMY) and it is responsible for the regulation of alternating splicing during spermatogenesis (Poongothai et al. 2009). Deleted in Azoospermia (DAZ) genes are located in the AZFc region and have autosomal homologues. There are palindromic duplications of DAZ. These sequences together encode an RNA-binding protein vital for spermatogenesis. Infertile males with loss of DAZ seem to be highly predisposed to azoospermia and oligozoospermia (Al-Janabi et al. 2020). Albeit that the presence of DAZ deletions in both fertile and infertile men question its importance, the former although fertile have lower sperm counts and reduced sperm motility. Basic protein Y linked 2 (BSY2) is expressed in the testis and it is implicated in the process of male germ cell development. This gene is hypothesized to be involved in the cytoskeletal regulation of spermatogenesis. Testis specific protein is a multicopy gene that is only expressed in the testis and is possibly responsible for germ cell proliferation (Ceylan et al. 2009, Dhanoa et al. 2016).\n\nAcross the different populations of the MENA region, studies have elucidated the role of Y chromosome microdeletion in male infertility (Madgar et al. 2002, Vicdan et al. 2004, Hellani et al. 2005, Ceylan et al. 2009, Mirfakhraie et al. 2010, Ghorbian et al. 2012, Saliminejad et al. 2012, Totonchi et al. 2012, Mohammad-Hasani et al. 2019, Akbarzadeh Khiavi et al. 2020, Al-Janabi et al. 2020). The summary of these findings is presented in Table 1. A study carried out in Turkey by Vicdan et al. (2004) reported that of 208 infertile male patients, 119 had obstructive azoospermia (OA), and 89 had severe oligoasthenoteratozoospermia (OAT). Seventeen out of 119 OA patients and two out of 89 patients with OAT had Y chromosome microdeletion (Vicdan et al. 2004), with the DAZ gene of the AZFc locus being the most frequently deleted. In total, 19 cases of Y chromosome microdeletion were detected in 208 infertile men, and chromosomal abnormalities were observed in another 5 non-obstructive azoospermia (NOA) (4.2%), and 2 OAT cases (2.2%). Of which these genetic abnormalities were not seen in the fertile men. It was also added that Y chromosome microdeletion and chromosomal abnormalities are associated with various histological alterations in the testes, such as SCOS and maturation arrest, while hypospermatogenesis occurred often in genetically normal patients.\n\nThe study conducted by Saliminejad et al. (2012) in Iran examined a total of 115 infertile male patients, 94 had azoospermia and 21 had severe oligozoospermia. Both patient groups were examined for Y chromosome microdeletions. Of the 94 patients with azoospermia, none had Y chromosome microdeletions, and of the 21 patients with severe oligospermia two patients were reported to have Y chromosome microdeletions. One of the patients had a deletion in the AZFc locus and the other had a deletion in the AZFb and AZFc loci (Saliminejad et al. 2012). The frequency of Y chromosome microdeletion occurrence in this study is relatively low compared to other reports from the MENA region (Vicdan et al. 2004, Al-Janabi et al. 2020).\n\nAnother study carried out in Turkey by Ceylan et al. (2009) reported that of the 90 infertile male patients with severe male infertility, 30 patients had NOA, 30 had oligozoospermia, and 30 were normozoospermic. Y chromosome microdeletions were present in five of the 30 patients with NOA, four of the thirty with oligospermia, and two of the normozoospermic patients. They also reported that among these patient groups the most commonly deleted Y chromosome region was the AZFc locus (Ceylan et al. 2009). Chromosomal abnormalities were also seen in another 10 NOA, four oligozoospermic patients and four normozoospermic infertile men, while the 75 recruited fertile men had no deletions or chromosomal abnormalities. This shows that genetic aberration, especially Y chromosome microdeletion may be involved in idiopathic male infertility.\n\nHormonal aspects of Y chromosome microdeletion were reported by Mostafa et al. (2020) in the Iranian population. Levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were evaluated in fertile and infertile patients. They noted that the levels of FSH and LH were higher in Infertile men than that of their fertile counterparts, this may also serve as a reliable marker for epithelial damage, azoospermia, and Oligospermia. Additionally, high levels of testosterone and thyroid-stimulating hormone may serve as primary markers for primary testicular failure (Akbarzadeh Khiavi et al. 2020).\n\nAl-Janabi et al. (2020) reported that the most common region that microdeletion occurred in the sampled Iraqi population is the AZFb region, where the incidence of microdeletion was found at 33.3%. The next most common region that microdeletion occurred was the AZFc region, with a frequency of 23%. No microdeletion was reported in the AZFa region (Al-Janabi et al. 2020).\n\nDeducing from these findings, it is evident that Y chromosome microdeletion can cause several testicular dysfunctions, such as SCOS, and maturation arrest (pre- and post-meiotic), which can lead to hypospermatogenesis, NOA or OAT. Hence, the importance of testing for Y chromosome microdeletion in men experiencing idiopathic infertility should be promoted in the MENA region.\n\n\nGenetic mutations\n\nGenes control a variety of physiological processes, including reproductive developments. Spermatogonial stem cells must undergo a variety of processes before becoming fully matured spermatozoa; these phases are controlled by genes. Any variation in genes that contribute to sperm maturation may lead to infertility.\n\nGenetic abnormalities account for 15-30% of infertility cases worldwide (Kovac and Alexander W. Pastuszak 2014), hence, identifying and understanding the various genetic mutations is vital. It is important to recognize the genetic basis of infertility to provide better care, as well as an improved prognosis to infertile couples. Several studies have shown how the variation in essential spermatogenesis specific genes led to the impairment of this process and ultimately male infertility (Avenarius et al. 2009, Shahid et al. 2010, Etem et al. 2010, Asadpor et al. 2013, Jamshidi et al. 2014, Alazami et al. 2014, Shaveisi-Zadeh et al. 2017, Al-Agha et al. 2018, Monsef et al. 2018, Akbari et al. 2019, Askari, Karamzadeh, et al. 2019, Askari, Kordi-Tamandani, et al. 2019, Hojati et al. 2019, Alimohammadi et al. 2020). This section will briefly describe some genes that the deletion or mutation thereof led to impaired male fertility.\n\nGlutamine-Fructose-6-Phosphate Transaminase 2\n\nA study done in Iran by Askari et al. (2019) discussed the effects of variation in Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) on fertility. GFPT2 is a rate-limiting enzyme that is responsible for hexosamine biosynthesis. They found that a homozygous missense mutation in the gene led to azoospermia. They also noted that GFPT2 may protect against reactive oxygen species (ROS); ROS may induce the peroxidation of unsaturated fatty acids or phosphorylate axoneme proteins. Both mechanisms eventually lead to decreased sperm motility (Askari, Kordi-Tamandani, et al. 2019).\n\nLysine demethylase 3A pathway\n\nA study carried out by Hojati et al. (2019) examined the relationship between variation in lysine demethylase 3A (KDM3A) and male Infertility. KDM3A is a gene that is believed to be responsible for sperm chromosome condensation. The study reported that various mutations in the KDM3A gene led to infertility in five Iranian males (Hojati et al. 2019). To rule out the common causes of infertility, they also examined Y chromosome microdeletion and partial AZF deletions. Surprisingly, the five patients with variation in KDM3A had no Y chromosome microdeletion or AZF microdeletion. This study proves that a variations in KDM3A could lead to spermatogenic failure. They also pointed out that the KDM3A gene is located on chromosome 2, which can be transferred to the offspring via the genetic pool. This means that the offspring, regardless of gender, could be susceptible to inheriting this type of mutation.\n\nCATSPER channel protein\n\nAvenarius et al. (2009) carried out a study to report the relationship between variation in the CATSPER1 channel and infertility amongst Iranian men. The study showed that the CATSPER1 channel protein is responsible for the calcium influx during the hyperactivity phase of sperm after ejaculation. Thus, any variation in this protein channel can disrupt the hyperactivity phase, evidently leading to infertility (Avenarius et al. 2009).\n\nSpermatogenesis associated 33 mutation (SPATA33)\n\nThis study performed by Monsef et al. (2018) examined the relationship between variations in SPATA33 and infertility in men with NOA. SPATA33 is highly expressed in the testis, and so it was reasonable to assume that a variation of this gene might lead to infertility. However, it was reported that there is no direct association between SPATA33 mutation and infertility in men with NOA. The authors discuss that the study population was limited to men with NOA, and encouraged that the same study be done in men with oligospermia and teratozoospermia (Monsef et al. 2018).\n\nPiwi interacting RNA pathway\n\nA study carried out by Kamaliyan et al. (2018) investigated the PiRNAs, which are amongst the non-coding regions of RNA and male germline development. PIWI and TDRD proteins are essential for PiRNAs to function appropriately, hence they are necessary for proper spermatogenesis. The study examined the association between polymorphisms in the HIWI genes and the risk of idiopathic non-obstructive azoospermia in Iranian males. Variations may cause RNA instability. Evidently, any variants in the PiRNA pathway genes may predispose spermatogenesis defects (Kamaliyan et al. 2018).\n\nExtrapolating from the results, it can be suggested that the mutation or deletion of genes necessary for normal development of germ cells, even without the presence of Y chromosome microdeletion may impair male fertility by triggering altered spermatogenesis, reduced sperm function, and some may even cause the offspring to be prone to inheriting the variation. Hence, it is important to identify if male infertility is caused by a gene mutation. This will help to develop treatment strategies that would prevent the offspring from having the same mutation.\n\nX-ray repair cross complementing group 1 genetic polymorphism\n\nDNA is under constant threat and damage from various sources. The X-ray Cross Complementing Group 1 (XRCC1) gene is responsible for repairing single strand breaks in the DNA. Mutations in the XRCC1 are detected by using polymerase chain reaction reaction-restriction fragment length polymorphism (Bi et al. 2013). A study by Akbas et al. examined polymorphisms within the XRCC1 gene and their effect on male fertility. A control group was compared to a group with men that suffered from idiopathic non-obstructive azoospermia. No significant differences were reported in XRCC1 polymorphisms between the control and experimental group, suggesting that XRCC1 polymorphisms do not influence male fertility (Akbas et al. 2019).\n\nProtamine (PRM) and Y-box binding protein 2 (YBX2)\n\nProtamine (PRM) genes produce protamine, which are small arginine rich proteins and are believed to be essential for DNA stabilization and function to condense spermatid genome (Domenjoud et al. 1991). Y-box binding protein 2 (YBX2) is essential in the transcription, translation, and splicing of mRNA. A study by Aydos et al. aimed to demonstrate the effects of polymorphism in such genes, and whether they can potentially affect male fertility. It was reported that PRM1 polymorphism was associated with sperm DNA fragmentation, while a polymorphism in PRM2 and YBX2 were not associated with male fertility (Aydos et al. 2018).\n\n\nSingle nucleotide polymorphisms (SNPs)\n\nSingle nucleotide polymorphisms (SNPs) are the replacement of a nucleotide at a single position within the genome, giving rise to a new allele. A SNP may occur anywhere along the genome, affecting genetic integrity. If it occurs on the sex chromosomes it may hinder the maturation of sperm, leading to infertility (Ben khelifa et al. 2011, Gurkan et al. 2013, Haji Ebrahim Zargar et al. 2015, Yousefi et al. 2015, Najafipour et al. 2016, Kamaliyan et al. 2018, Nasirshalal et al. 2020, Pashaei et al. 2020). Understanding the specifics of where the gene is mutated, and how it can lead to male infertility is vital in the treatment and management plan of the patient.\n\nA study conducted by Zargar et al. (2015) discussed the relationship between variation in the X-linked gene and a specific pattern of male infertility. They reported that a gene on the x chromosome, known as H2B.W, is linked to male infertility (Haji Ebrahim Zargar et al. 2015). The study discovered two SNPs (-9C>T and 368A>G) in the H2B.W gene in a population of infertile Iranian men.\n\nThe study showed that the -9T frequency at the -9C>T position was higher in the complete maturation arrest group than in the SCOS group. This suggests that the variation of allele C to T might influence the mRNA stability affecting the maturation of the spermatids. However, there was no significant association between SNP 368A>G and the risk of infertility in the Iranian male population (Haji Ebrahim Zargar et al. 2015).\n\nAnother study analysed the whole blood samples of 180 idiopathic infertile males and 120 fertile controls to investigate the association between the occurrence of gene polymorphism (-656T>G and 1349>G variants in the ApE1 promoter and coding region) and the susceptibility to idiopathic male infertility (Yousefi et al. 2015). ApE1 is responsible for maintaining genomic integrity, a polymorphism in this gene might lead to infertility as it may cause damage to the DNA leading to reproductive disorders. The study revealed that -656T>G polymorphism is related to infertility, while a variation in the 1349T>G region was unrelated to idiopathic male infertility (Yousefi et al. 2015).\n\n\nChromosomal disorders\n\nThe implication of chromosomal disorders on male infertility including numerical, structural, replacement, inversion, insertion and translocational chromosomal abnormalities have been explored and documented (Balkan et al. 2008, Akgul et al. 2009, Alhalabi et al. 2013), especially for the numerical and structural chromosome disorders (Balkan et al. 2008, Alhalabi et al. 2013).\n\nComing to the MENA region, Mehdi et al. (2012) reported a significantly increased frequency of chromosome 1818XY, XX, and YY disomies in the spermatozoa of men with severe teratozoospermia from Tunisia (Mehdi et al. 2012). The rate of total diploidy was also increased. Another study from Turkey showed that out of 179 infertile men that were evaluated, a total of 21 cases (11.74%) showed chromosomal alteration. This include 13 (7.26%) that were 47,XXY; three (1.68%) were pericentric inversion of chromosome 9, one (0.56%) 46,XY/45,XO, one (0.56%) 46,XY/47,XXY/48,XXXY, one (0.56%) 46,XY,t(X;1), one (0.56%) 46,XY/46,XY,del(Y)(q11.2), and one (0.56%) 46,XX (Akgul et al. 2009). The occurrence of diploidy originating from either meiotic maturation or by a compromised testicular environment may impair male fertility. A case report by Balasar et al. demonstrates that not all chromosomal mutations will result in variation in the AZF and SRY regions (Balasar et al. 2017), which demonstrates the importance of understanding the differences in variation to properly treat infertility.\n\n\nMitochondrial mutation\n\nThe mitochondrion is a double-membrane organelle that generates about 90% of cell energy in the form of adenosine triphosphate by oxidative phosphorylation reaction in mammalian cells. Mitochondria play a crucial role in a series of signal pathways, including tricarboxylic acid cycle, the β-oxidation of fatty acids, regulation of intrinsic apoptosis, and participating in the cell cycle (Arakaki et al. 2006, Finkel and Hwang 2009, Yan et al. 2019). In contrast to the other organelles in a mammalian cell, mitochondria have DNA, known as mitochondrial DNA (mtDNA), which encodes a series of crucial proteins for mitochondrial respiration. The mtDNA is particularly susceptible to certain stress-induced damages due to a lack of histones in the structure and effective repair mechanisms (Kujoth et al. 2005) mtDNA mutation caused by stress-induced damage is highly associated with various human diseases, including male infertility (Venkatesh et al. 2009).\n\nAbnormal sperm function has been identified as one of the leading causes of male infertility. Defective sperm motility has been recognized as one of the primary causes of abnormal sperm function. Gashti et al. (2013) reported that variations in mtDNA in ATP generating genes may cause infertility, as mtDNA deletion was observed in 81.66% of infertile men with varicocele. This means that varicocele may induce mtDNA deletion in spermatozoa and cause infertility (Gashti et al. 2014). Many factors can contribute to mtDNA damage, such as infection, lifestyle, diet, and the environment. These factors promote the production of ROS, at a high level of oxidative damage, spermatozoa may be damaged, promoting infertility. Sperm plasma membranes are rich in poly-unsaturated fatty acids, which makes the membrane prone to oxidative damage. Nasrin also reported that ROS in testicular tissue and semen may lead to mtDNA microdeletions, which affects the electron transport chain, which is consequently a direct cause of male infertility.\n\n\nClinical implications\n\nIn vitro fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI) have allowed couples with fertility problems to achieve success. The success of these procedures varies from couple to couple, due to the fact that different couples present with diverse causes of male infertility. A study by Ocak et al. explored the causes of reproductive failure in a cohort of 500 patients. They found that the causes of infertility ranged from no chromosomal variations to Y-chromosomal variation. Thus, demonstrating the importance of genetic testing before commencing assisted reproductive techniques (ART) (Ocak et al. 2014). With that being said, most patients are still willing to attempt such procedures, as these procedures present as a last hope option.\n\nY chromosome microdeletion is one of the most common causes of male infertility; many males who suffer from Y chromosome microdeletion undergo IVF and ICSI. Screening for Y chromosome microdeletion has become a standard practice before partaking in either IVF or ICSI, as they may offer a prognostic value, predicting the potential success for ART (Sadeghi-Nejad and Farrokhi 2007). Knowing the type of Y chromosome microdeletion may help offer some prognostic value, as not all types of microdeletions yield the same results with ART. It has been demonstrated that sperm retrieval through testicular sperm extraction was possible in patients with AZFC microdeletion but not possible in AZFA and AZFB (Krausz et al. 2000, Hopps et al. 2003). A more recent study by Abur et al. also demonstrated that ART was possible with AZFC deletion (Abur et al. 2019), marking the importance of differentiating between types of Y-chromosome microdeletion before commencing ART. Other chromosomal abnormalities may affect the success rate of ART; such an example would be 46 XX chromosomal abnormalities. Akar et al. reported that other than the clinical and laboratory findings of 46 XX chromosomal translocation, patients with such a condition may have to resort to a sperm donor as sperm retrieval is not a viable option in such a patient population (Akar et al. 2020). Furthermore, this patient population should opt for testosterone replacement therapy to be protected against the negative effects of testosterone deficiency (Akinsal et al. 2017).\n\nAdditionally, high levels of aneuploidy are positively associated with an increased level of male factor infertility (Schulte et al. 2010). As such, sperm with aneuploidy is associated with a higher rate of failure with ART (Harton and Tempest 2012). Sperm relies on energy from the mitochondria for its motility, therefore, any variation in mtDNA leads to altered motility, negatively impacting fertility outcomes. A proposed solution for such infertility is ICSI. Studies now show that although mitochondrial DNA variation has a negative impact on ICSI outcomes, it is still possible (Al Smadi et al. 2021). Sperm DNA integrity is one of the vital prognostic factors of male fertility. Anything that compromises sperm DNA can lead to infertile outcomes. The findings on IVF outcomes in patients with abnormal sperm DNA have been conflicting. Some studies state that variation in the DNA of sperm have no effect on fertility outcomes (Collins et al. 2008), while others state otherwise (Simon et al. 2017). The controversy may be due to the diversity methodological approaches. Hence, it is suggested that a standardized protocol be developed.\n\nUpon achieving success with ART, the main concern shifts to the possible vertical transmission to the offspring. Reports have shown that microdeletions have the capability of transmitting to the offspring by ICSI (Jiang et al. 1999, Zhu et al. 2010). Unfortunately, vertical transmission of Y chromosome microdeletion have been reported to cause infertility in offspring (Kim et al. 2003, Dai et al. 2012). Studies have also shown that males with aneuploidy have a higher chance of giving birth to children with aneuploidy which can translate to a variety of health conditions (Harton and Tempest 2012). This dilemma requires the design of further prospective clinical cohort studies that will assess whether the deleted regions on the Y chromosome are amplified and whether they can cause any significant new health consequences. Investigations on the possible transmission of damaged DNA should also be developed.\n\n\nConclusion\n\nIn comparison to the data available on the global investigation of infertility, particularly male infertility, findings about this subject in the MENA region is lacking. This may be due to the poorly funded niche-specific research, or social stigmatization. Accessibility to the few studies has revealed that the prevalence of demographic male infertility in the MENA region is on the increase, which makes the investigation of the causes of male infertility important.\n\nIn addition to semen analysis derived diagnosis, studies have indicated the role of genetic abnormalities as part of the cause of male infertility. Findings from the current study showed that the prevalent genetic aberration leading to male infertility in the MENA region include Y chromosome microdeletion, the occurrence of gene polymorphism, mitochondrial microdeletion and other genetic deletions or mutations.\n\nThe study of male infertility in the MENA region should encompass the investigation of various genetic variations. Diverse clinical genetic tests should also be made available for the proper diagnosis of male infertility. This would furthermore help researchers and clinicians to develop informed treatment strategies. Additionally, before providing couples with ART options, a thorough screening should be performed, and the scope of interest of reproductive medicine physicians should as well include understanding the root cause of infertility rather than just establishing pregnancy.\n\n\nData availability\n\nNo data is associated with this article.",
"appendix": "References\n\nAbur U, Gunes S, Ascı R, et al.: Chromosomal and Y-chromosome microdeletion analysis in 1,300 infertile males and the fertility outcome of patients with AZFc microdeletions. Andrologia. 2019; 51: e13402. PubMed Abstract | Publisher Full Text\n\nAkar OS, Gunes S, Abur U, et al.: Multiscale analysis of SRY-positive 46,XX testicular disorder of sex development: Presentation of nine cases. Andrologia. 2020; 52(11): 1–10. Publisher Full Text\n\nAkbari A, Pipitone GB, Anvar Z, et al.: ADCY10 frameshift variant leading to severe recessive asthenozoospermia and segregating with absorptive hypercalciuria. Hum. Reprod. 2019; 34(6): 1155–1164. PubMed Abstract | Publisher Full Text\n\nAkbarzadeh Khiavi M, Jalili A, Safary A, et al.: Karyotypic abnormalities and molecular analysis of Y chromosome microdeletion in Iranian Azeri Turkish population infertile men. Syst. Biol. Reprod. Med. 2020; 66(2): 140–146. PubMed Abstract | Publisher Full Text\n\nAkbas H, Balkan M, Binici M, et al.: The Possible Role of XRCC1 Gene Polymorphisms with Idiopathic Non-obstructive Azoospermia in Southeast Turkey. Urol. J. 2019; 16(4): 380–385. PubMed Abstract | Publisher Full Text\n\nAkgul M, Ozkinay F, Ercal D, et al.: Cytogenetic abnormalities in 179 cases with male infertility in Western Region of Turkey: Report and review. J. Assist. Reprod. Genet. 2009; 26(2–3): 119–122. PubMed Abstract | Publisher Full Text\n\nAkinsal EC, Baydilli N, Demirtas A, et al.: Ten cases with 46,XX testicular disorder of sex development: single center experience. International Brazilian Journal of Urology: Official Journal of the Brazilian Society of Urology. 2017; 43(4): 770–775. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAl-Agha AE, Ahmed IA, Nuebel E, et al.: Primary ovarian insufficiency and azoospermia in carriers of a homozygous PSMC3IP stop gain mutation. J. Clin. Endocrinol. Metab. 2018; 103(2): 555–563. PubMed Abstract | Publisher Full Text\n\nAl-Janabi AM, Rahim AI, Faris SA, et al.: Prevalence of Y chromosome microdeletion in azoospermic infertile males of Iraqi population. J. Genet. 2020; 99(1): 1–5. Publisher Full Text\n\nAlazami AM, Alshammari MJ, Baig M, et al.: NPHP4 mutation is linked to cerebello-oculo-renal syndrome and male infertility. Clin. Genet. 2014; 85(4): 371–375. PubMed Abstract | Publisher Full Text\n\nAlhalabi M, Kenj M, Monem F, et al.: High prevalence of genetic abnormalities in Middle Eastern patients with idiopathic non-obstructive azoospermia. J. Assist. Reprod. Genet. 2013; 30(6): 799–805. PubMed Abstract | Publisher Full Text\n\nAlimohammadi F, Ebrahimi Nasab M, Rafaee A, et al.: Deletion of dpy-19 like 2 (DPY19L2) gene is associated with total but not partial globozoospermia. Reprod. Fertil. Dev. 2020; 32: 727. Publisher Full Text\n\nArakaki N, Nishihama T, Owaki H, et al.: Dynamics of mitochondria during the cell cycle. Biol. Pharm. Bull. 2006; 29(9): 1962–1965. Publisher Full Text\n\nAsadpor U, Totonchi M, Sabbaghian M, et al.: Ubiquitin-specific protease (USP26) gene alterations associated with male infertility and recurrent pregnancy loss (RPL) in Iranian infertile patients. J. Assist. Reprod. Genet. 2013; 30(7): 923–931. PubMed Abstract | Publisher Full Text\n\nAskari M, Karamzadeh R, Ansari-Pour N, et al.: Identification of a missense variant in CLDN2 in obstructive azoospermia. J. Hum. Genet. 2019; 64(10): 1023–1032. PubMed Abstract | Publisher Full Text\n\nAskari M, Kordi-Tamandani DM, Almadani N, et al.: Identification of a homozygous GFPT2 variant in a family with asthenozoospermia. Gene. 2019; 699: 16–23. PubMed Abstract | Publisher Full Text\n\nAvenarius MR, Hildebrand MS, Zhang Y, et al.: Human Male Infertility Caused by Mutations in the CATSPER1 Channel Protein. Am. J. Hum. Genet. 2009; 84(4): 505–510. PubMed Abstract | Publisher Full Text\n\nAydos OSE, Hekmatshoar Y, Altlnok B, et al.: Genetic Polymorphisms in PRM1, PRM2, and YBX2 Genes are Associated with Male Factor Infertility.2018; 22(1): 55–61. Publisher Full Text Reference Source\n\nBalasar Ö, Zamani AG, Balasar M, et al.: Male infertility associated with de novo pericentric inversion of chromosome 1. Turk. J. Urol. 2017; 43(4): 560–562. PubMed Abstract | Publisher Full Text\n\nBalkan M, Tekes S, Gedik A: Cytogenetic and Y chromosome microdeletion screening studies in infertile males with Oligozoospermia and Azoospermia in Southeast Turkey. J. Assist. Reprod. Genet. 2008; 25(11–12): 559–565. PubMed Abstract | Publisher Full Text\n\nBeyaz CC, Gunes S, Onem K, et al.: Partial Deletions of Y-Chromosome in Infertile Men with Non-obstructive Azoospermia and Oligoasthenoteratozoospermia in a Turkish Population. In Vivo. 2017; 31(3): 365–371. PubMed Abstract | Publisher Full Text\n\nBi J, Zhong C, Li K, et al.: Association study of single nucleotide polymorphisms in XRCC1 gene with risk of hepatocellular carcinoma in Chinese Han population. Biomed. Res. Int. 2013; 2013: 1–6. PubMed Abstract | Publisher Full Text\n\nVander Borght M, Wyns C: Fertility and infertility: Definition and epidemiology. Clin. Biochem. 2018; 62: 2–10. PubMed Abstract | Publisher Full Text\n\nCeylan GG, Ceylan C, Elyas H: Genetic anomalies in patients with severe oligozoospermia and azoospermia in eastern Turkey: A prospective study. Genet. Mol. Res. 2009; 8(3): 915–922. PubMed Abstract | Publisher Full Text\n\nChen CP: Chromosomal abnormalities associated with omphalocele. Taiwan. J. Obstet. Gynecol. 2007; 46: 1–8. Publisher Full Text\n\nColaco S, Modi D: Genetics of the human Y chromosome and its association with male infertility. Reprod. Biol. Endocrinol. 2018; 16: 14. PubMed Abstract | Publisher Full Text\n\nCollins JA, Barnhart KT, Schlegel PN: Do sperm DNA integrity tests predict pregnancy with in vitro fertilization?. Fertil. Steril. 2008; 89(4): 823–831. PubMed Abstract | Publisher Full Text\n\nDai RL, Sun LK, Yang X, et al.: Expansion and de novo occurrence of Y chromosome microdeletions occurring via natural vertical transmission in Northeastern China. J. Int. Med. Res. 2012; 40(3): 1182–1191. Publisher Full Text\n\nDhanoa JK, Mukhopadhyay CS, Arora JS: Y-chromosomal genes affecting male fertility: A review. Veterinary World. 2016; 9(7): 783–791. PubMed Abstract | Publisher Full Text\n\nDomenjoud L, Kremling H, Burfeind P, et al.: On the expression of protamine genes in the testis of man and other mammals. Andrologia. 1991; 23(5): 333–337. PubMed Abstract | Publisher Full Text\n\nEldib A, Tashani O: Infertility in the Middle East and North Africa Region: A systematic review with meta-Analysis of prevalence surveys. Libyan Journal of Medical Sciences. 2018; 2(2): 37. Publisher Full Text\n\nElsawi MM, Pryor JP, Klufio G, et al.: Genital tract function in men with Noonan syndrome. J. Med. Genet. 1994; 31(6): 468–470. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEtem EO, Erol D, Huseyin Y, et al.: Mediterranean fever gene mutation analysis in infertile Turkish males. Genet. Mol. Res. 2010; 9(2): 611–619. PubMed Abstract | Publisher Full Text\n\nFerlin A, Arredi B, Foresta C: Genetic causes of male infertility. Reprod. Toxicol. 2006; 22(2): 133–141. Publisher Full Text\n\nFinkel T, Hwang PM: The Krebs cycle meets the cell cycle: Mitochondria and the G1-S transition. Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 11825–11826. PubMed Abstract | Publisher Full Text\n\nForesta C, Ferlin A, Moro E: Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum. Mol. Genet. 2000; 9(8): 1161–1169. PubMed Abstract | Publisher Full Text\n\nGashti NG, Salehi Z, Madani AH, et al.: 4977-bp mitochondrial DNA deletion in infertile patients with varicocele. Andrologia. 2014; 46(3): 258–262. PubMed Abstract | Publisher Full Text\n\nGhorbian S, Saliminejad K, Sadeghi MR, et al.: The association between Y chromosome microdeletion and recurrent pregnancy loss. Iran Red. Crescent Med. J. 2012; 14(6): 358–362. PubMed Abstract\n\nGurkan H, Aydin F, Kadioglu A, et al.: Investigation of mutations in the synaptonemal complex protein 3 (SYCP3) gene among azoospermic infertile male patients in the Turkish population. Andrologia. 2013; 45(2): 92–100. PubMed Abstract | Publisher Full Text\n\nHaji Ebrahim Zargar H, Mohseni Meybodi A, Sabbaghian M, et al.: Association of two polymorphisms in H2B.W gene with azoospermia and severe oligozoospermia in an Iranian population. Int. J. Fertil. Steril. 2015; 9(2): 205–214. PubMed Abstract\n\nHarton GL, Tempest HG: Chromosomal disorders and male infertility. Asian J. Androl. 2012; 14: 32–39. PubMed Abstract | Publisher Full Text\n\nHellani A, Al-Hassan S, Al-Duraihim A, et al.: Y chromosome microdeletions: Are they implicated in teratozoospermia?. Hum. Reprod. 2005; 20(12): 3505–3509. PubMed Abstract | Publisher Full Text\n\nHojati Z, Soleimanpour E, Javadirad SM, et al.: Identification of two novel mutations in KDM3A regulatory gene in iranian infertile males. Iran. Biomed. J. 2019; 23(3): 220–227. PubMed Abstract | Publisher Full Text\n\nHopps CV, Mielnik A, Goldstein M, et al.: Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb, and AZFc regions. Hum. Reprod. 2003; 18(8): 1660–1665. PubMed Abstract | Publisher Full Text\n\nIkechebelu JI, Adinma JIB, Orie EF, et al.: High prevalence of male infertility in southeastern Nigeria. J. Obstet. Gynaecol. 2003; 23(6): 657–659. PubMed Abstract | Publisher Full Text\n\nJamshidi J, Pouresmaeili F, Darvish H, et al.: FABP9 mutations are not detected in cases of infertility due to sperm morphological defects in Iranian Men. Int. J. Fertil. Steril. 2014; 7(4): 275–280. PubMed Abstract\n\nJiang MC, Lien YR, Chen SU, et al.: Transmission of de novo mutations of the deleted in azoospermia genes from a severely oligozoospermic male to a son via intracytoplasmic sperm injection. Fertil. Steril. 1999; 71(6): 1029–1032. Publisher Full Text\n\nKamaliyan Z, Pouriamanesh S, Soosanabadi M, et al.: Investigation of piwi-interacting RNA pathway genes role in idiopathic non-obstructive azoospermia. Sci. Rep. 2018; 8(1): 142. PubMed Abstract | Publisher Full Text\n\nKarabulut S, Keskin İ, Kutlu P, et al.: Male infertility, azoozpermia and cryptozoospermia incidence among three infertility clinics in Turkey. Turk. J. Urol. 2018; 44(2): 109–113. Publisher Full Text\n\nBen Khelifa M, Zouari R, Harbuz R, et al.: A new AURKC mutation causing macrozoospermia: Implications for human spermatogenesis and clinical diagnosis. Mol. Hum. Reprod. 2011; 17(12): 762–768. PubMed Abstract | Publisher Full Text\n\nKim HA, Lee SH, Cho SW, et al.: Vertical transmission, de novo, and expansion of Y chromosome microdeletion in male fetuses pregnant after intracytoplasmic sperm injection (ICSI). Fertil. Steril. 2003; 80: 113. Publisher Full Text\n\nKoc G, Ozdemir AA, Girgin G, et al.: Male infertility in Sertoli cell-only syndrome: An investigation of autosomal gene defects. Int. J. Urol. 2019; 26(2): 292–298. PubMed Abstract | Publisher Full Text\n\nKovac JR, Pastuszak AW, Lamb DJ: The use of genomics, proteomics and metabolomics in identifying biomarkers of male infertility. Bone. 2014; 23(1): 1–7.\n\nKrausz C, Quintana-Murci L, McElreavey K: Prognostic value of Y deletion analysis: What it the clinical prognostic value of Y chromosome microdeletion analysis?. Hum. Reprod. 2000; 15: 1431–1434. PubMed Abstract | Publisher Full Text\n\nKujoth CC, Hiona A, Pugh TD, et al.: Medicine: Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005; 309(5733): 481–484. Publisher Full Text\n\nKuroda S, Usui K, Sanjo H, et al.: Genetic disorders and male infertility. Reprod. Med. Biol. 2020; 19: 314–322. PubMed Abstract | Publisher Full Text\n\nMadgar I, Green L, Kent-First M, et al.: Genotyping of Israeli infertile men with idiopathic oligozoospermia. Clin. Genet. 2002; 62(3): 203–207. Publisher Full Text\n\nMascarenhas MN, Flaxman SR, Boerma T, et al.: National, Regional, and Global Trends in Infertility Prevalence Since 1990: A Systematic Analysis of 277 Health Surveys. PLoS Med. 2012; 9(12): 1–12. Publisher Full Text\n\nMehdi M, Gmidène A, Brahem S, et al.: Aneuploidy rate in spermatozoa of selected men with severe teratozoospermia. Andrologia. 2012; 44(SUPPL.1): 139–143. PubMed Abstract | Publisher Full Text\n\nMirfakhraie R, Mirzajani F, Kalantar SM, et al.: High prevalence of AZFb microdeletion in Iranian patients with idiopathic non-obstructive azoospermia. Indian J. Med. Res. 2010; 132(9): 265–270.\n\nMohammad-Hasani A, Hosseinzadeh Colagar A, Fallah A: Association of the human aryl hydrocarbon receptor repressor (AhRR)-c.565C>G transversion with male infertility: A case-control study from Iran. J. Cell. Biochem. 2019; 120(6): 8999–9005. PubMed Abstract | Publisher Full Text\n\nMonsef L, Borjian Boroujeni P, Totonchi M, et al.: Gene alterations and expression spectrum of SPATA33 in nonobstructive azoospermic Iranian men. Mol. Reprod. Dev. 2018; 85(10): 760–767. PubMed Abstract | Publisher Full Text\n\nNajafipour R, Rashvand Z, Alizadeh A, et al.: Association of G/T (rs222859) polymorphism in Exon 1 of YBX2 gene with azoospermia, among Iranian infertile males. Andrologia. 2016; 48(9): 1044–1048. PubMed Abstract | Publisher Full Text\n\nNasirshalal M, Tahmasebi-Birgani M, Dadfar M, et al.: Identification of the PRM1 gene mutations in oligoasthenoteratozoospermic men. Andrologia. 2020; 52(11): e13872. PubMed Abstract | Publisher Full Text\n\nOcak Z, Üyetürk U, Dinçer MM: Clinical and prognostic importance of chromosomal abnormalities, Y chromosome microdeletions, and CFTR gene mutations in individuals with azoospermia or severe oligospermia. Turk. J. Med. Sci. 2014; 44(2): 347–351. Publisher Full Text\n\nOkada H, Fujioka H, Tatsumi N, et al.: Klinefelter’s syndrome in the male infertility clinic. Hum. Reprod. 1999; 14(4): 946–952. Publisher Full Text\n\nOrganization, W.H. (WHO): International Classification of Diseases. WHO; 2018.\n\nPashaei M, Rahimi Bidgoli MM, Zare-Abdollahi D, et al.: The second mutation of SYCE1 gene associated with autosomal recessive nonobstructive azoospermia. J. Assist. Reprod. Genet. 2020; 37(2): 451–458. PubMed Abstract | Publisher Full Text\n\nPoongothai J, Gopenath TS, Manonayaki S, et al.: Genetics of human male infertility. Singap. Med. J. 2009; 50(4): 336–347. PubMed Abstract\n\nPunab M, Poolamets O, Paju P, et al.: Causes of male infertility: A 9-year prospective monocentre study on 1737 patients with reduced total sperm counts. Hum. Reprod. 2017; 32(1): 18–31. PubMed Abstract | Publisher Full Text\n\nSadeghi-Nejad H, Farrokhi F: Genetics of azoospermia: current knowledge, clinical implications, and future directions. Part II: Y chromosome microdeletions. Urol. J. 2007; 4: 192–206. PubMed Abstract\n\nSaliminejad K, Sadeghi MR, Kamali K, et al.: Discrepancy in the frequency of y chromosome microdeletions among iranian infertile men with azoospermia and severe oligozoospermia. Genet. Test. Mol. Biomarkers. 2012; 16(8): 931–934. PubMed Abstract | Publisher Full Text\n\nSchulte RT, Ohl DA, Sigman M, et al.: Sperm DNA damage in male infertility: Etiologies, assays, and outcomes. J. Assist. Reprod. Genet. 2010; 27: 3–12. PubMed Abstract | Publisher Full Text\n\nShahid M, Dhillon VS, Khalil HS, et al.: A SRY-HMG box frame shift mutation inherited from a mosaic father with a mild form of testicular dysgenesis syndrome in Turner syndrome patient. BMC Med. Genet. 2010; 11(1). PubMed Abstract | Publisher Full Text\n\nShaveisi-Zadeh F, Alibakhshi R, Asgari R, et al.: TTY2 genes deletions as genetic risk factor of male infertility. Cell. Mol. Biol. 2017; 63(2): 57–61. PubMed Abstract | Publisher Full Text\n\nSimon L, Zini A, Dyachenko A, et al.: A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome. Asian J. Androl. 2017; 0: 0. Publisher Full Text\n\nAl Smadi MA, Hammadeh ME, Solomayer E, et al.: Impact of Mitochondrial Genetic Variants in ND1, ND2, ND5, and ND6 Genes on Sperm Motility and Intracytoplasmic Sperm Injection (ICSI) Outcomes. Reprod. Sci. 2021; 28(5): 1540–1555. PubMed Abstract | Publisher Full Text\n\nSokol RZ, Shapiro BJ: Infertility in men with cystic fibrosis. Curr. Opin. Pulm. Med. 2001; 7: 421–426. Publisher Full Text\n\nStahl PJ, Mielnik AN, Barbieri CE, et al.: Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia. Asian J. Androl. 2012; 14(5): 676–682. PubMed Abstract | Publisher Full Text\n\nStanton PG, Sluka P, Foo CFH, et al.: Proteomic changes in rat spermatogenesis in response to in vivo androgen manipulation; Impact on meiotic cells. PLoS One. 2012; 7(7): e41718. PubMed Abstract | Publisher Full Text\n\nSun H, Gong TT, Jiang YT, et al.: Global, Regional, and National Prevalence and Disability-Adjusted Life-Years for Infertility in 195 Countries and Territories, 1990-2017: Results from a Global Burden of Disease Study, 2017. Aging. 2019; 11(23): 10952–10991. PubMed Abstract | Publisher Full Text\n\nTotonchi M, Mohseni Meybodi A, Borjian Boroujeni P, et al.: Clinical data for 185 infertile Iranian men with Y-chromosome microdeletion. J. Assist. Reprod. Genet. 2012; 29(8): 847–853. Publisher Full Text\n\nVenkatesh S, Deecaraman M, Kumar R, et al.: Role of reactive oxygen species in the pathogenesis of mitochondrial DNA (mtDNA) mutations in male infertility. Indian J. Med. Res. 2009; 129(2): 127–137. PubMed Abstract\n\nVicdan A, Vicdan K, Günalp S, et al.: Genetic aspects of human male infertility: The frequency of chromosomal abnormalities and Y chromosome microdeletions in severe male factor infertility. Eur. J. Obstet. Gynecol. Reprod. Biol. 2004; 117(1): 49–54. PubMed Abstract | Publisher Full Text\n\nYan C, Duanmu X, Zeng L, et al.: Mitochondrial DNA: Distribution, Mutations, and Elimination. Cell. 2019; 8(379): 1–15. Publisher Full Text\n\nYousefi M, Salehi Z, Mashayekhi F, et al.: The association of ApE1 −656T>G and 1349T>G polymorphisms and idiopathic male infertility risk. Int. Urol. Nephrol. 2015; 47(6): 921–926. PubMed Abstract | Publisher Full Text\n\nZhu XB, Liu YL, Zhang W, et al.: Vertical transmission of the Yq AZFc microdeletion from father to son over two or three generations in infertile Han Chinese families. Asian J. Androl. 2010; 12(2): 240–246. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "126419",
"date": "30 Mar 2022",
"name": "Małgorzata Piasecka",
"expertise": [
"Reviewer Expertise Basic and non-conventional seminological studies",
"genetic aspects of male infertility",
"sperm biology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript presented to me for review concerns the genetic causes of male infertility in the Middle East and North Africa (MENA) region. The topic discussed is important and still relevant due to its clinical significance and implications. Based on a literature review (different electronic databases were searched), the authors showed that genetic aberrations (Y chromosome microdeletion, deletion or gene mutation, gene polymorphism or copy number variation, chromosomal disorders, mitochondrial mutation) are a common cause of male infertility in the MENA region. The obtained research results are comprehensively presented in Table 1 and described in the text. Taking into account the obtained data, the authors rightly suggest that genetic tests should be part of the diagnosis of male infertility. Undoubtedly, such diagnostics will allow for proper therapeutic management, especially in the case of using ART. Generally, the text is written correctly in terms of its content. However, the manuscript requires revision prior to indexing.\nThe most important remarks are listed below:\nAbstract: “…30% of these cases remain idiopathic.” This data should be updated. Idiopathic infertility accounts for 30-50% of male infertility (Agarwal et al., 2019,2021).\n\nThere is no information in the Introduction about idiopathic failure.\n\n“Y chromone (?) microdeletion”; “…P or Q arm of…” should be p arm or q arm\n\nThe content on the molecular structure of the Y chromosome should also be presented in the form of a diagram (structure of the Y chromosome with regions and genes marked).\n\nThe caption under figure 2 should be corrected: ”…the genetic alteration the genetic alteration.”\n\nInformation on ROS is contained in two sections: “Evidence of genetic mutations in the MENA region” and “Evidence of mitochondria mutation in the MENA region”. I suggest that they be written exhaustively only in the section: “Evidence of mitochondria mutation in the MENA region”. They should be expanded and superseded with the latest literature. The text includes many mental abbreviations.\n\nSection: “CATSPER channel protein”. “Avenarius et al. (2009) carried out a study to report the relationship between variation in the CATSPER1 channel and infertility amongst (???) Iranian men. The study showed that the CATSPER1 channel protein is responsible for the calcium influx during the hyperactivity phase of sperm after ejaculation. Thus, any variation in this protein channel can disrupt the hyperactivity phase, evidently leading to infertility (Avenarius et al. 2009).” This fragment of text should be corrected. Hyperactivation of ejaculated sperm cells (the spermatozoa movement is changed) is the result of their capacitation in the female reproductive system and enables the fertilization process. The authors used too much shortcut. References should be updated.\n\nNo development of the abbreviation PiRNAs, TDRD; “PIWI (comment of reviewer: gene or protein, italics means gene) and TDRD proteins are…”… HIWI genes… “(???)\n\nThe text should be read very carefully and checked in terms of spelling, style and abbreviations.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Partly\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "8306",
"date": "06 Jun 2022",
"name": "Temidayo S Omolaoye",
"role": "Author Response",
"response": "Comment: The manuscript presented to me for review concerns the genetic causes of male infertility in the Middle East and North Africa (MENA) region. The topic discussed is important and still relevant due to its clinical significance and implications. Based on a literature review (different electronic databases were searched), the authors showed that genetic aberrations (Y chromosome microdeletion, deletion or gene mutation, gene polymorphism or copy number variation, chromosomal disorders, mitochondrial mutation) are a common cause of male infertility in the MENA region. The obtained research results are comprehensively presented in Table 1 and described in the text. Taking into account the obtained data, the authors rightly suggest that genetic tests should be part of the diagnosis of male infertility. Undoubtedly, such diagnostics will allow for proper therapeutic management, especially in the case of using ART. Generally, the text is written correctly in terms of its content. However, the manuscript requires revision prior to indexing. Response: The authors would like to thank the reviewer for the time and effort expended to review this work and thereby adding to the scientific merit of this study. Suggestions made by the reviewer have been addressed appropriately. Comment: The most important remarks are listed below: Abstract: “…30% of these cases remain idiopathic.” This data should be updated. Idiopathic infertility accounts for 30-50% of male infertility (Agarwal et al., 2019,2021). Response: The information has been updated to read “about 30-50% of these cases remain idiopathic”. Comment: There is no information in the Introduction about idiopathic failure. Response: The below sentences have been inserted in the text to address idiopathic infertility, from line 51-56. “It has been reported that around 60% of the total cases are attributable to the male factor, of which up to 50% are idiopathic (Agarwal et al. 2019, 2021). Unlike unexplained male infertility which sometimes is characterized with normal semen parameters, idiopathic male infertility is diagnosed in the presence of altered semen characteristics without an identifiable cause and the absence of female factor infertility (Hamada et al. 2011, Agarwal et al. 2019)”. Comment: “Y chromone (?) microdeletion”; “…P or Q arm of…” should be p arm or q arm Response: Corrected in the text. Line 135. Comment: The content on the molecular structure of the Y chromosome should also be presented in the form of a diagram (structure of the Y chromosome with regions and genes marked). Response: A new diagram has been inserted in the text as Figure 3 Comment: The caption under figure 2 should be corrected: ”…the genetic alteration the genetic alteration.” Response: The repeated sentence has been deleted. Comment: Information on ROS is contained in two sections: “Evidence of genetic mutations in the MENA region” and “Evidence of mitochondria mutation in the MENA region”. I suggest that they be written exhaustively only in the section: “Evidence of mitochondria mutation in the MENA region”. They should be expanded and superseded with the latest literature. The text includes many mental abbreviations. Response: We avoided focusing on ROS because several review articles have elaborated on the matter. However, we have cited more studies that discussed to topic in greater detail for further reference. The sub-section addressing Evidence of Mitochondria Mutation in the MENA region has been updated. Line 388-401. Comment: Section: “CATSPER channel protein”. “Avenarius et al. (2009) carried out a study to report the relationship between variation in the CATSPER1 channel and infertility amongst (???) Iranian men. The study showed that the CATSPER1 channel protein is responsible for the calcium influx during the hyperactivity phase of sperm after ejaculation. Thus, any variation in this protein channel can disrupt the hyperactivity phase, evidently leading to infertility (Avenarius et al. 2009).” This fragment of text should be corrected. Hyperactivation of ejaculated sperm cells (the spermatozoa movement is changed) is the result of their capacitation in the female reproductive system and enables the fertilization process. The authors used too much shortcut. References should be updated. Response: This section of the manuscript has been revised. Please see below and line 266-276 in the text. The study was able to identify insertion mutations, which led to premature stop codons and consequently variation in the CATSPER 1 protein (Avenarius et al. 2009). The CATSPER 1 protein is part of a tetrameric voltage gated calcium channel which are highly conserved in humans and mice. Carlson et al. showed the necessity of CATSPER 1 for Ca2+ entry into the flagellum and for Ca2+ mediated hyperactivated sperm motility (Carlson et al. 2003). Thus, an abnormality in the CATSPER 1 protein may hinder the calcium-mediated sperm functions. Once sperm enters the female reproductive tract, it undergoes the calcium mediated process of capacitation. When capacitation occurs successfully, the sperm is able to carry out its role in fertilization. Thus, it was suggested that variation in the CATSPER 1 channel may hinder the process of capacitation and consequently leading to infertility (Avenarius et al. 2009). Comment: No development of the abbreviation PiRNAs, TDRD; “PIWI (comment of reviewer: gene or protein, italics means gene) and TDRD proteins are…”… HIWI genes… “(???) Response: Statement has been revised appropriately. Comment: The text should be read very carefully and checked in terms of spelling, style and abbreviations. Response: The entire manuscript has been thoroughly proofread."
}
]
},
{
"id": "135107",
"date": "05 May 2022",
"name": "Arnold Peter Paul Achermann",
"expertise": [
"Reviewer Expertise Male infertility",
"micro-TESE",
"azoospermia",
"Non-obstructive azoospermia",
"hypogonadism"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this paper, the authors summarize the current evidence concerning the importance of the genetic causes of male infertility in the Middle East and North Africa (MENA) region.\nThe Abstract offers a clear, synthetic, and complete overview of the messages emerging from the Review. However, the authors should update information about the percentage of idiopathic cases in male infertility.\nAlthough difficult to read of the complex theme, the Review is written linearly and deals with everything related to genetic causes of male infertility in the MENA region in separate chapters.\nI suggest minor corrections:\n\n\"The AZF region is made up of multiple genomic loci, including AZFa, AZFb, AZFc, AZFd. These regions are believed to be responsible for spermatogenesis\" The authors should add that deletions can be isolated or combined in each AZF region.\n\n\"Albeit that the presence of DAZ deletions in both fertile and infertile men question its importance, the former although fertile have lower sperm counts and reduced sperm motility.\" Confused, clarify.\n\nIs the KDM3A gene an autosome dominant or recessive gene?\n\nThe paragraph about (SPATA33) is about the Iranian population studied. However, the authors did not expose it.\n\n\"Nasrin also reported that ROS in testicular tissue and semen may lead to mtDNA microdeletions, which affects the electron transport chain, which is consequently a direct cause of male infertility.\" – there is no reference for this information.\n\n\"It has been demonstrated that sperm retrieval through testicular sperm extraction was possible in patients with AZFC microdeletion but not possible in AZFA and AZFB (Krausz et al. 2000, Hopps et al. 2003). A more recent study by Abur et al. also demonstrated that AR was possible with AZFC deletion (Abur et al. 2019), marking the importance of differentiating between types of Y-chromosome microdeletion before commencing ART.\" – please correct the expressions. It should be AZFa, AZFb, AZFc.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nIs the review written in accessible language? Partly\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "8307",
"date": "06 Jun 2022",
"name": "Temidayo S Omolaoye",
"role": "Author Response",
"response": "Comment: In this paper, the authors summarize the current evidence concerning the importance of the genetic causes of male infertility in the Middle East and North Africa (MENA) region. The Abstract offers a clear, synthetic, and complete overview of the messages emerging from the Review. However, the authors should update information about the percentage of idiopathic cases in male infertility. Although difficult to read of the complex theme, the Review is written linearly and deals with everything related to genetic causes of male infertility in the MENA region in separate chapters. Response: The authors would like to thank the reviewer for the positive remark and for taking the time and effort to review this work, thereby adding to the scientific merit of this study. Suggestions made by the reviewer have been addressed appropriately. The prevalence of idiopathic cases in male infertility have been updated both in the abstract and main text. Comment: I suggest minor corrections: \"The AZF region is made up of multiple genomic loci, including AZFa, AZFb, AZFc, AZFd. These regions are believed to be responsible for spermatogenesis\" The authors should add that deletions can be isolated or combined in each AZF region. Response: The suggested comment has been added in the text. Line 139-140 Comment: \"Albeit that the presence of DAZ deletions in both fertile and infertile men question its importance, the former although fertile have lower sperm counts and reduced sperm motility.\" Confused, clarify. Response: The below sentence has been inserted in the text. Line 163-167 “Although, the presence of DAZ gene copies (DAZ2 or DAZ4) deletions was observed in some fertile men, the deletion of both copies were more frequent in infertile men with oligospermia (Ghorbel et al. 2014). This indicate that the concurrent deletion of DAZ2 and DAZ4 gene copies is associated with male infertility, and that oligospermia seems to be promoted by deleting DAZ4 copy (Ghorbel et al. 2014, Al-Janabi et al. 2020).” Comment: Is the KDM3A gene an autosome dominant or recessive gene? Response: According to the available literature, the dominant or recessive status of KDM3A gene is not yet clarified. However, this gene encodes a zinc finger protein that contains a jumonji domain and plays a role in hormone-dependent transcriptional activation by participating in recruitment to androgen-receptor target genes, which result in H3 'Lys-9' demethylation and transcriptional activation. Additionally, it is involved in spermatogenesis by regulating expression of target genes such as PRM1 and TNP1 which are required for packaging and condensation of sperm chromatin. It functions suggest that it may be a dominant gene. Comment: The paragraph about (SPATA33) is about the Iranian population studied. However, the authors did not expose it. Response: Findings from the study on SPATA33 has been given in details in the text. Comment: \"Nasrin also reported that ROS in testicular tissue and semen may lead to mtDNA microdeletions, which affects the electron transport chain, which is consequently a direct cause of male infertility.\" – there is no reference for this information. Response: The reference has been inserted. Comment: \"It has been demonstrated that sperm retrieval through testicular sperm extraction was possible in patients with AZFC microdeletion but not possible in AZFA and AZFB (Krausz et al. 2000, Hopps et al. 2003). A more recent study by Abur et al. also demonstrated that AR was possible with AZFC deletion (Abur et al. 2019), marking the importance of differentiating between types of Y-chromosome microdeletion before commencing ART.\" – please correct the expressions. It should be AZFa, AZFb, AZFc. Response: Changes have been affected in the entire manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/11-125
|
https://f1000research.com/articles/11-380/v1
|
31 Mar 22
|
{
"type": "Research Article",
"title": "Realisation of Solid-State Electrochromic Devices Based on Gel Electrolyte",
"authors": [
"Benedict Wen-Cheun Au",
"Kah-Yoong Chan",
"Mohd Zainizan Sahdan",
"Abraham Shiau-Iun Chong",
"Dietmar Knipp",
"Benedict Wen-Cheun Au",
"Mohd Zainizan Sahdan",
"Abraham Shiau-Iun Chong",
"Dietmar Knipp"
],
"abstract": "Background: In the last decade, there has been much interest in the area of solid polymer electrolyte (SPE) to address the issues of electrolyte leakage and evaporation in electrochromic devices (ECD). ECD is a state-of-the-art technology having the ability to change from transparent state to opaque state under the influence of a small applied voltage for energy saving applications. Methods: In this work, tungsten oxide (WO3) films were fabricated via the sol-gel spin-coating method. Subsequently, ECDs were assembled based on SPE and liquid polymer electrolyte (LPE), respectively using indium doped tin oxide (ITO) coated glass as conducting electrodes and WO3 films as working electrode. Results: Cyclic voltammetry (CV) results revealed reduced ionic conductivity of conducting ions in SPE based ECD (SECD) owing to increased viscosity by addition of PMMA. However, lesser time was required for the colouration process. LPE based ECD (LECD) showed higher colouration efficiency (CE) compared to its SECD counterpart. This is attributed to its larger optical modulation. Conclusions: This work presents a comparison between the performance of LECD and SECD in terms of electrochromic (EC) and optical properties. They were analysed through CV, chronoamperometry (CA) and ultraviolet-visible (UV-Vis) spectrophotometer. Furthermore, this work provides an insight on the employment of solid-state electrolytes in ECDs in view of the persistent leakage and evaporation problems in ECD implementation.",
"keywords": [
"Electrochromic Device",
"Solid Polymer Electrolyte",
"Tungsten Oxide"
],
"content": "Introduction\n\nElectrochromism is an occurrence where the colour of electrochromic (EC) materials changes upon the application of a minute potential difference.1 Since its discovery by Deb,2 it has generated wide spread interest among researchers in a range of applications, including smart-windows,3 rear-view mirrors4 and sun roofs.5 Lately, researchers have attempted solid polymer electrolytes (SPE) as an alternative to conventional liquid polymer electrolytes (LPE) as a mean to address issues such as electrolyte leakage and stability.6\n\nSPEs are made by adding a polymer material to solidify the polymer electrolyte into a solid thin film layer upon solvent evaporation. Gelatin is one of the polymer materials attempted for Li based SPEs in electrochromic devices (ECDs).7 Ramadan et al. prepared ECD with gelatin cross-linking with formaldehyde, plasticized with glycerol and contained different LiClO4 concentration.8 The device revealed 38% optical modulation at 600 nm wavelength with colouration efficiency (CE) of 23 cm2 C-1. In addition, with its good mechanics, adhesion to electrode and optical properties, it is deemed as promising for EC smart window applications. Poly (methyl-methacrylate) (PMMA) is another polymer material used in fabricating SPEs for ECDs, as it is well-known for its chemistry and lower cost of processing as laminates.9 Anamika assembled a complementary ECD based on PMMA:PC:LiClO4 solid electrolyte leading to a ITO/WO3/PMMA:PC:LiClO4/NiO/ITO structure. This ECD demonstrated fast colouring and bleaching time of 1.2 s and 1.5 s respectively, with a large optical modulation of 50.3% at 630 nm wavelength. On top of that, CE was calculated to be as high as 243 cm2 C-1.10 In another work, Evecan and Zayim produced an all-solid-state ECD using PMMA:PC:LiClO4 as solid electrolyte which had respond times of approximately 10 s. Besides that, the large optical modulation of 48.07% led to a high CE of 68.7 cm2 C-1.11\n\nIn this work, a comparison between LPE and SPE based ECDs is made in terms of EC and optical properties. Propylene carbonate (PC):Lithium perchlorate (LiClO4) was used as LPE, while PC:LiClO4:PMMA was used as SPE in ECD study. Their respective optical and EC properties are elucidated and discussed in this paper.\n\n\nMethods\n\nThis section describes the experimental design. The EC WO3 films here were produced according to the sol-gel spin-coated method in our previous work.12 Tungsten hexachloride (WCl6) powder was adopted as precursor for WO3, absolute ethanol (C2H6O) was used as solvent, glacial acetic acid (CH3COOH) was used as chelating agent and hydrogen peroxide (H2O2) was used as strong oxidizing agent. 1 g of WCl6 powder and 2 ml of glacial acetic acid were added to 20 ml absolute ethanol. The mixture was stirred for 30 minutes before adding 2 ml of H2O2 and subsequently stirred for another 30 minutes at room temperature. Next, the WO3 solution was continuously stirred for two hours at 40 °C to obtain a homogenous clear solution. Preceding the deposition of WO3 films, acetone and IPA were used to wash the ITO coated glass substrates for 10 minutes, respectively. Then, the sol-gel solution was shifted to the ITO coated glass substrates and spun for 30 seconds at 3000 RPM. Subsequently, the fresh WO3 coating was heated at 100 °C on a hotplate for three minutes to allow solvent vaporisation. Multiple coatings were accumulated to obtain a desired film thickness. Lastly, the coated WO3 films were heat-treated at 250 °C for one hour.\n\nThe solid-state ECD was assembled with PC:LiClO4:PMMA solid polymer electrolyte (SPE) sandwiched between WO3 film as the colour changing layer and ITO coated glass as the counter electrode, forming a ITO/WO3/PC:LiClO4:PMMA/ITO device structure. An acrylic frame of 1 mm thickness was used as spacer to store the SPE between the electrodes and the boundaries of the ECD were closed up with silicone sealant to avert moisture from entering the ECD. Identical to the solid-state ECD, PC:LiClO4 liquid polymer electrolyte (LPE) was used for the non-solid-state ECD, forming a ITO/WO3/PC:LiClO4/ITO device structure. Both the sealed solid-state and non-solid state ECDs were dried overnight before measurements were carried out. For simplicity purposes, the SPE based ECD is named as SECD, while the LPE based ECD is named as LECD in this paper.\n\nOptical properties of the ECDs were evaluated by ultraviolet-visible (UV-Vis) spectrophotometer. EC properties were measured using in a two-electrode setup via a potentiostat-galvanostat. The anodic and cathodic peak currents and diffusion coefficient for the insertion and extraction of Li+ ions were analyzed by performing the cyclic voltammetry (CV) measurements between −3.0 V to 3.0 V at a scan rate of 0.1 V s-1. Chronoamperometry (CA) assessments were conducted to analyse the switching kinetics of the ECDs while documenting the transmittances in the dark blue and translucent states in the range of 280 nm to 900 nm wavelength.\n\n\nResults\n\nThe device structure for both SECD and LECD is presented in Figure 1. Sol-gel deposited WO3 films are used as the EC layer and ITO coated glasses are used as the conductive electrodes. The SPE and LPE are sandwiched in between the ECD using an acrylic spacer. To explain further, the WO3 films are the colour changing layer, ITO coated glasses conduct electricity across the ECDs and the SPE and LPE supplies the necessary ions for ECD operation.\n\nCV characteristics of the SECD and LECD are depicted in Figure 2. Upon applying −3.0 V, both the ECDs changed into its dark blue state. This is attributed to the transition from the W6+ state to the W5+ state of the WO3. On the other hand, the ECDs returned to its transparent state when 3.0 V was applied.13 To explain further, ions were inserted into the WO3 layer during the negative voltage cycle and hence its dark blue appearance. In the positive voltage cycle, extracted ions meaning the WO3 layer became transparent again. This reversible reaction can be represented by the chemical equation below14:\n\nThe LECD anodic peak current of 0.253 mA was found to be greater than the 0.184 mA of SECD. Besides, the LECD cathodic peak current of −1.177 mA was also observed to be greater than the −0.865 mA of SECD. These results were further used to compute the diffusion coefficient during insertion and extraction procedure of Li+ ions through the Randles-Sevcik equation16:\n\nCA assessments were conducted to further analyze the electrochemical behaviour of both devices. It was performed with a sweeping voltage of −3 V to 3 V for 60 s while documenting the transmittances in the dark blue and translucent states at 633 nm wavelength, simultaneously. Besides, the switching time for both the ECDs were extracted from the CA results and tabulated in Table 2.\n\nSwitching time represents the time taken to arrive at its steady state. As shown in Table 2, LECD required more time for colouration compared to its SECD counterpart. We speculate that this is due to the difference in Li+ ions in both LPE and SPE during in the colouring process. As explained earlier, the solvation of Li+ ions in PMMA leads to a decrease in the concentration of colouration ions. Consequently, the SECD reaches its steady state faster than the LECD which has higher concentration of colouration ions. It is worth noting that regardless of LPE or SPE, time taken for colouration is longer than decolouration. In the dark blue state, EC WO3 is very conductive while it exhibits insulating nature in the translucent state. This is an indication that transiting from conductive state to insulating states is a much quicker process.19\n\nIn terms of optical properties, the original, coloured and bleached transmittance of SECD and LECD are recorded in Figure 3(a) and 3(b) respectively, under wavelengths between 280 nm and 900 nm as well as its corresponding colour change of the physical ECDs.\n\nBoth ECDs are highly transparent with an approximate 85% in the visible range prior to any measurements. For SECD, the dark blue state exhibited 30% transmittance and the translucent state exhibited 46% with an optical modulation of 16%. On the other hand, LECD had 19% in the coloured state and 40% in the bleached state, which are lower than the SECD. However, the obtained optical modulation of 21% was slightly higher. Bohnke et al. explained that PMMA molecules may solvate the Li+ ions via their negatively charged carbonyl group. This leads to a decrease in the overall amount of Li+ ions needed for colouration process in the SPE.20 Therefore, it reflects on the higher transmittance level of SECD in the coloured state compared to LECD. In the work of Namrata and Awalendra, a systematic shift of the PMMA main XRD peak to a higher angle proved the interaction between LiClO4 and PMMA. Consequently, this resulted in the emergence of possible complexations of Li+ ions with electron abundant sites in the host polymer matrix.21\n\nResults from the optical properties were subsequently utilized to evaluate the colouration efficiency (CE) with the following equation22:\n\n\nConclusions\n\nECDs based on LPE and SPE were produced using ITO coated glasses as a pair of conductive electrodes. Their respective EC properties were discussed and elucidated. CV results showed greater diffusion coefficient in LECD owing to its less viscous nature of the LPE. More time was needed for the colouration process in LECD due to the higher concentration of Li+ ions. Both LECD and SECD had high transparency of approximately 85% in the original state in the visible range. Greater optical modulation was observed in LECD compared to SECD leading to greater CE. This research demonstrated that while possessing inferior EC properties, the implementation of SECDs is the way forward towards a new generation of ECDs where the persistent electrolyte leakage and evaporation problem in conventional LECDs can finally be eliminated.\n\n\nAuthor contributions\n\nBenedict Wen-Cheun Au: Data Curation, Formal Analysis, Investigation, Methodology, Visualization, Writing – Original Draft Preparation.\n\nKah-Yoong Chan: Conceptualization, Formal Analysis, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Review & Editing.\n\nMohd Zainizan Sahdan: Validation\n\nAbraham Shiau-Iun Chong: Conceptualization\n\nDietmar Knipp: Conceptualization, Validation\n\n\nData availability\n\nUnderlying data will be shared upon request.\n\nDryad, https://doi.org/10.5061/dryad.qfttdz0jx\n\nData are available under the terms of the CC0 1.0 Universal (CC0 1.0) Public Domain Dedication.\n\n\nEthical approval number\n\nEA2092021",
"appendix": "Acknowledgements\n\nThis research work is funded by Ministry of Higher Education (MOHE), Malaysia, under The Fundamental Research Grant Scheme (FRGS) (FRGS 2020-1), project ID: FRGS/1/2020/TK0/MMU/02/2. We would like to express our gratitude towards the Ministry of Higher Education (MOHE) Malaysia for financially supporting this work.\n\n\nReferences\n\nKaruppasamy A: Electrochromism and photocatalysis in dendrite structured Ti:WO3 thin films grown by sputtering. Appl. Surf. Sci. 2015; 359: 841–846. Publisher Full Text\n\nAvendaño E, Berggren L, Niklasson GA, et al.: Electrochromic materials and devices: Brief survey and new data on optical absorption in tungsten oxide and nickel oxide films. Thin Solid Films. 2006; 496(1): 30–36. Publisher Full Text\n\nGranqvist CG: Electrochromics for smart windows: Oxide-based thin films and devices. Thin Solid Films. 2014; 564: 1–38. Publisher Full Text\n\nDulgerbaki C, Komur AI, Nohut Maslakci N, et al.: Synergistic tungsten oxide/organic framework hybrid nanofibers for electrochromic device application. Opt. Mater. (Amst). 2017; 70: 171–179. Publisher Full Text\n\nOzkan E, Lee SH, Tracy CE, et al.: Comparison of electrochromic amorphous and crystalline tungsten oxide films. Sol. Energy Mater. Sol. Cells. 2003; 79(4): 439–448. Publisher Full Text\n\nLee HJ, Lee C, Song J, et al.: Electrochromic devices based on ultraviolet-cured poly (methyl methacrylate) gel electrolytes and their utilisation in smart window applications. J. Mater. Chem. C. 2020; 8(26): 8747–8754. Publisher Full Text\n\nAzarian MH, Wootthikanokkhan J: Gelatin-based solid electrolytes for chromogenic windows applications: a review. Ionics (Kiel). 2020; 26(12): 5841–5851. Publisher Full Text\n\nRamadan R, Kamal H, Hashem HM, et al.: Gelatin-based solid electrolyte releasing Li+ for smart window applications. Sol. Energy Mater. Sol. Cells. 2014; 127: 147–156. Publisher Full Text\n\nWu TY, et al.: Study of poly (methyl methacrylate)-based gel electrolyte for electrochromic device. Int. J. Electrochem. Sci. 2013; 8(8): 10720–10732.\n\nKadam AV: Electrochromic properties of ITO/WO3/LiClO4-PC-PMMA-ACN/NiO/ITO framework. Mater. Today Proc. 2020; 23: 352–358. Publisher Full Text\n\nEvecan D, Zayim E: Highly uniform electrochromic tungsten oxide thin films deposited by e-beam evaporation for energy saving systems. Curr. Appl. Phys. 2019; 19(2): 198–203. Publisher Full Text\n\nWen-Cheun Au B, Chan KY, Knipp D: Effect of film thickness on electrochromic performance of sol-gel deposited tungsten oxide (WO3). Opt. Mater. (Amst). 2019; 94(May): 387–392. Publisher Full Text\n\nAu BWC, Chan KY: Effect of precursor solution stirring time on the electrochromic performance of tungsten oxide films. Surf. Eng. 2020; 36(1): 94–99. Publisher Full Text\n\nKalagi SS, Dalavi DS, Pawar RC, et al.: Polymer assisted deposition of electrochromic tungsten oxide thin films. J. Alloys Compd. 2010; 493(1–2): 335–339. Publisher Full Text\n\nKalagi SS, Mali SS, Dalavi DS, et al.: Transmission attenuation and chromic contrast characterization of R.F. sputtered WO3 thin films for electrochromic device applications. Electrochim. Acta. 2012; 85: 501–508. Publisher Full Text\n\nWu CL, Lin CK, Wang CK, et al.: Annealing induced structural evolution and electrochromic properties of nanostructured tungsten oxide films. Thin Solid Films. 2013; 549: 258–262. Publisher Full Text\n\nDeepa M, Sharma N, Agnihotry SA, et al.: Conductivity and viscosity of liquid and gel electrolytes based on LiClO4, LiN (CF3SO2)2 and PMMA. Solid State Ionics. 2002; 152-153: 253–258. Publisher Full Text\n\nKufian MZ, et al.: PMMA-LiBOB gel electrolyte for application in lithium ion batteries. Solid State Ionics. 2012; 208: 36–42. Publisher Full Text\n\nPatel KJ, et al.: Thickness-dependent Electrochromic Properties of Amorphous Tungsten Trioxide Thin Films. J. Nano- Electron. Phys. 2017; 9(3): 03040.\n\nBohnke O, Frand G, Rezrazi M, et al.: Fast ion transport in new lithium electrolytes gelled with PMMA. 2. Influence of lithium salt concentration. Solid State Ionics. 1993; 66(1–2): 105–112. Publisher Full Text\n\nShukla N, Thakur AK: Role of salt concentration on conductivity optimization and structural phase separation in a solid polymer electrolyte based on PMMA-LiClO4. Ionics (Kiel). 2009; 15(3): 357–367. Publisher Full Text\n\nWu CL, Wang CK, Lin CK, et al.: Electrochromic properties of nanostructured tungsten oxide films prepared by surfactant-assisted sol-gel process. Surf. Coat. Technol. 2013; 231: 403–407. Publisher Full Text"
}
|
[
{
"id": "129461",
"date": "19 Apr 2022",
"name": "Soo Kien Chen",
"expertise": [
"Reviewer Expertise Nanomaterials",
"magnetism"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the present communication, the authors evaluated and compared the electrochemical and optical properties of SECD and LECD. It was found that the SECD showed lower diffusion coefficient due to its higher viscosity. Nevertheless, its colouring time is shorter than that of the LECD.\nComment:\n1. Method:\n“Multiple coatings were accumulated to obtain a desired film thickness.” What is the thickness of the film? EC properties were measured using “in” a two-electrode setup via a potentiostat-galvanostat. Reconsider \"in\".\n2. Results and discussion\nP. 4: “Both the anodic diffusion coefficient of 3.261 1013 cm2 s -1 and cathodic diffusion coefficient of 7.189 1012 cm2 s -1 for LECD were computed to be greater than the 6.168 10-13 cm2 s -1 and 1.333 10-11 cm2 s -1 of SECD, respectively.” This behaviour is opposite to that given in Table 1.\n\nP5 - We speculate that this is due to the difference in Li+ ions in both LPE and SPE during “in” the colouring process. Reconsider \"in\".\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8231",
"date": "06 Jun 2022",
"name": "Kah-Yoong Chan",
"role": "Author Response",
"response": "Dear Prof. Dr. Soo, Thank you very much for your comments on our manuscript entitled “Realisation of Solid-State Electrochromic Devices based on Gel Electrolyte”. We have carefully reviewed the comments and have revised the manuscript accordingly. Changes to the manuscript are highlighted in red. Comment Method: 1. “Multiple coatings were accumulated to obtain a desired film thickness.” What is the thickness of the film? Answer: The film thickness is approximately 340 nm. 2.EC properties were measured using “in” a two-electrode setup via a potentiostat-galvanostat. Reconsider “in”. Answer: “In” has been removed from the mentioned sentence Results and discussion P. 4: “Both the anodic diffusion coefficient of 3.261 10-13 cm2 s-1 and cathodic diffusion coefficient of 7.189 10-12 cm2 s-1 for LECD were computed to be greater than the 6.168 10-13 cm2 s-1 and 1.333 10-11 cm2 s-1 of SECD, respectively.” This behaviour is opposite to that given in Table 1. Answer: This is amended in the manuscript. The diffusion coefficients should be the other way round. 2. P-5 - We speculate that this is due to the difference in Li+ ions in both LPE and SPE during “in” the colouring process. Reconsider \"in\". Answer: “In” has been removed from the mentioned sentence."
}
]
},
{
"id": "129458",
"date": "25 Apr 2022",
"name": "Mahesh A. Shinde",
"expertise": [
"Reviewer Expertise Electrochromic devices"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article proposed the Solid polymer electrolyte (SPE) for the replacement of liquid polymer electrolyte (LPE). the implementation of SPE based electrochromic devices (ECD) showing good electrochromic performance then LPE based ECD. The results appear to be compelling and warrant indexing. The manuscript contains interesting results for the field of electrochromic devices, but some explanations are not clearly written and experimental data are not sufficient to discuss the results in detail. I feel the manuscript could be improved when properly addressing the points below.\nThe thickness of WO3 film should be mentioned in the manuscript.\n\nThe electrolyte composition should be explained in the manuscript such as molar ratio and weight percentage.\n\nSPE electrolyte results should be compared with previous literature in tabular form.\n\nWhy did authors measure the electrochromic performance at 633 nm as many previous WO3 based ECD report measure electrochromic performance at 700nm wavelength?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8233",
"date": "06 Jun 2022",
"name": "Kah-Yoong Chan",
"role": "Author Response",
"response": "Dear Prof. Dr. Mahesh A. Shinde, Thank you for your comments on our manuscript titled “Realisation of Solid-State Electrochromic Devices based on Gel Electrolyte”. We have carefully reviewed the comments and have revised the manuscript accordingly. Changes to the manuscript are highlighted in red. Comment: 1. The thickness of WO3 film should be mentioned in the manuscript. Answer: The thickness is approximately of 340 nm and has been added into the manuscript. 2. The electrolyte composition should be explained in the manuscript such as molar ratio and weight percentage. Answer: The electrolyte composition is added to the manuscript. 3. SPE electrolyte results should be compared with previous literature in tabular form. Answer: This summary is in a Review Paper, accepted and to be published in Polymers (Publisher: MDPI). 4. Why did authors measure the electrochromic performance at 633 nm as many previous WO3 based ECD report measure electrochromic performance at 700 nm wavelength? Answer: The work here focuses on visible wavelengths ranging from 350 nm to 650 nm where 700 nm is approaching the infrared region. Besides that, this work is with reference to many existing reports which measures electrochromic properties at 633 nm."
}
]
}
] | 1
|
https://f1000research.com/articles/11-380
|
https://f1000research.com/articles/11-617/v1
|
06 Jun 22
|
{
"type": "Case Report",
"title": "Case Report: Acute myocardial infarction with acute left ventricular failure and acute renal damage following mRNA-1273 vaccination: Possible adverse effect of COVID-19 vaccination?",
"authors": [
"Mohammad Ali Hossain",
"Md. Utba Rashid",
"Sabrina Yesmin Barsha",
"Md. Abdullah Saeed Khan",
"Miah Md. Akiful Haque",
"Mohammad Lutfor Rahman",
"Mosharop Hossian",
"AKM Mohiuddin Bhuiyan",
"Mohammad Hayatun Nabi",
"Mohammad Delwer Hossain Hawlader",
"Mohammad Ali Hossain",
"Sabrina Yesmin Barsha",
"Md. Abdullah Saeed Khan",
"Miah Md. Akiful Haque",
"Mohammad Lutfor Rahman",
"Mosharop Hossian",
"AKM Mohiuddin Bhuiyan",
"Mohammad Hayatun Nabi",
"Mohammad Delwer Hossain Hawlader"
],
"abstract": "Background: Evaluating potential vaccine side effects is often a prerequisite to combat the coronavirus disease 2019 (COVID-19) pandemic more effectively in a low-resource setting where herd immunity could be the most feasible option. Case report: Here, we present, an 80-year-old man with multiple comorbidities was admitted into the coronary care unit at Ibn Sina Medical College Hospital (Dhaka, Bangladesh) with severe central chest pain and respiratory distress after receiving the first dose of Moderna vaccine on July 26, 2021. On admission, his blood pressure was 110/70 mmHg, pulse 90 beats/min, respiratory rate 22 breaths/min, temperature 36.7°C. He had a vesicular breath sound with bilateral basal crepitations and normal heart sounds. On the ECG, significant changes were observed. Other lab findings were significant troponin-I: 1.72 ng/ml, trace protein and glucose in the urine, total white blood cell count: 12820/cm3; HbA1c, 7.5%; serum creatinine, 1.56 mg/dl; serum electrolytes: sodium 133 mmol/L, chloride 92 mmol/L. The patient had a medical history of prior myocardial infarction, diabetes mellitus, and hypertension but no chronic kidney disease, cerebrovascular disease, or bronchial asthma. After admission, he was treated conservatively with necessary medications and monitored periodically. The patient was diagnosed with acute myocardial infarction with left ventricular failure with acute kidney injury on chronic kidney disease with diabetes mellitus and hypertension. He was discharged from the hospital on day six with proper medicinal support with full recovery. Conclusions: Though acute cardiac complications following COVID-19 vaccines are unusual, this case report can contribute to further molecular research to identify the possible role of vaccine compounds in triggering such complications among the general population.",
"keywords": [
"NSTEMI",
"Acute Renal Damage",
"COVID-19",
"Case Report",
"Moderna Vaccine"
],
"content": "Introduction\n\nCoronavirus disease 2019 (COVID-19), a SARS-CoV-2 RNA virus-associated acute respiratory syndrome, arose in Wuhan, China, in December 2019 and spread rapidly throughout the world. Since its Initiation on March 24, 2021, it has affected 246,951,274 people and resulted in approximately 5,004,855 deaths (World Health Organization, 2022). For more than a year, experts worldwide have been confronted with significant challenges in their efforts to treat the disease. COVID-19 therapy research involved repurposing existing medications and the emergence of new treatments and vaccines. Approximately 24 COVID-19 vaccines have been granted emergency approval in various countries, including Comirnaty (BNT162b2), Moderna COVID-19 Vaccine (mRNA-1273), AstraZeneca COVID-19 Vaccine (AZD1222); also known as Covishield, Sputnik V, CoronaVac, BBIBP-CorV, EpiVacCorona, Convidicea (Ad5-nCoV), Covaxin (China) (COVID-19 Vaccine Tracker | RAPS, n.d.). Due to the critical necessity to halt the spread of COVID-19 infections, the traditional procedures for approving novel drugs/vaccines were unable to be completed. These vaccines were approved on an emergency basis before completing all three phases of clinical testing (Wouters et al., 2021). This is a compelling rationale to continue accumulating robust scientific proof for these vaccines by surveillance of adverse outcomes in the public following vaccination. Moreover, the in-depth analysis of the vaccine side effects will further bolster the government’s efforts towards minimizing vaccine myths as well as changing notions in accepting vaccines to curb this situation more tactfully (Haque et al., 2021; Hawlader et al., 2022).\n\nOn December 18, 2020, the Moderna COVID-19 vaccine received emergency authorization for use based on a robust phase three study data (Moderna COVID-19 Vaccine | FDA, n.d.). Moderna observed a 1% rate of major adverse events (Clinical Trial Data | Moderna COVID-19 Vaccine (EUA), n.d.). These significant adverse occurrences were classified as mortality, a life-threatening negative event, inpatient hospitalization, a chronic or considerable impairment in performing routine living functions, or a fetal anomaly or congenital disability (Moderna COVID-19 Vaccine | FDA, n.d.). Additionally, they reported no change in the number of thrombotic episodes between groups (Clinical Trial Data | Moderna COVID-19 Vaccine (EUA), n.d.). So far, there are just a few published reports of primary adverse responses (for Disease Control, 2020; Waheed et al., 2021). This case report discusses a possible severe bad reaction and examines whether a significant adverse reaction can be attributed to the COVID-19 vaccine.\n\n\nCase report\n\nAfter following all the protocols at an authorized vaccination center, an otherwise healthy 80-year-old man with a medical history of prior myocardial infarction (inferolateral), diabetes mellitus, and hypertension received the first dose of the Moderna vaccine on July 26, 2021.\n\nA few hours after vaccination, the patient developed severe central chest pain with respiratory distress at night. The pain was sudden in onset, not relieved by glyceryl tri-nitrate spray, gradually increased, and continued for two days until admission to the coronary care unit (CCU) at Ibn Sina Medical College and hospital (Dhaka, Bangladesh), a tertiary care private hospital of Bangladesh. Previously, in 2012, the patient was diagnosed as a case of myocardial infarction (MI) with five blockages detected in three major coronary vessels on coronary angiography. But the patient didn’t consent for coronary artery bypass grafting due to his extreme age. Since then, he has been using glyceryl tri-nitrate 2–3 sprays daily to relieve angina (it varied depending on activities). He was also on regular medication, including a combined tablet (tab) of amlodipine and atenolol (5 mg + 50 mg) once daily for hypertension, injection insulin human 30/70 (18 units in the morning and 12 units at night) daily with a tab of gliclazide 80 mg once daily for diabetes mellitus, and a combined tab of aspirin and clopidogrel (75 mg + 75 mg) once daily for secondary prevention to prevent similar attacks. He took both anti-diabetic medications for 30 years and the other drugs for 20 years. He had no history of chronic kidney disease, cerebrovascular disease, or bronchial asthma. He was not an alcoholic, but he failed to cease smoking. (Patient’s attendant was told that he was a very irregular smoker, but the patient was elderly and couldn’t specify the amount.)\n\nOn admission, the patient’s blood pressure was 110/70 mmHg (normal range of blood pressure: less than 130/85 mmHg), pulse 90 beats/min (normal range of pulse rate: 60-90 beats/min), respiratory rate 22 breaths/min (normal range of respiratory rate: 12–16 breaths/min), temperature 36.7 °C (normal range of temperature: 36.1°C to 37.2°C). He had a vesicular breath sound with bilateral basal crepitations and normal heart sounds. A 12-lead ECG revealed right bundle branch block (tall R wave in v1) (Figure 1), deep Q waves (>1 mm) in leads II, III, aVF, v3–v6, T wave inversion in the lead II, III, v1, v3–v6. Other lab findings were significant troponin-I, 1.72 ng/ml; urine routine microscopy showed trace protein and glucose (normally, protein and glucose levels in urine should be zero); HbA1c, 7.5% (normal range: 4.5–6.2%); serum creatinine, 1.56 mg/dl (normal range for male: 0.60–1.30 mg/dl); serum electrolytes: sodium 133 mmol/L (normal range: 136–148 mmol/L), chloride 92 mmol/L (normal range: 96–107 mmol/L). The lipid profile and complete blood count reports showed normal findings except for a slightly elevated total white blood cell 12820/cm3 (normal range for adult: 4000–11000/cm3).\n\nAfter admission, the patient was treated conservatively with injection (inj.) of enoxaparin (40 mg), inj. furosemide (20 mg), inj. actrapid (100 IU), tablet (tab) aspirin (75 mg), tab clopidogrel (75 mg), tab trimetazidine dihydrochloride modified release (35 mg), and tab ivabradine (5 mg).\n\nOn the second day, laboratory tests were significant for serum albumin (3.00 g/dl) (normal range: 3.40–5.00 g/dl). On day four after admission, echocardiography was done and showed mild concentric left ventricular hypertrophy, mild mitral regurgitation, and mild left ventricular systolic dysfunction (ejection fraction -48%).\n\nAfter thorough investigation, the patient was diagnosed with acute left ventricular failure (Killip Class-II) with non-ST elevated myocardial infarction with acute kidney injury on chronic kidney disease with diabetes mellitus with hypertension and old myocardial infarction (inferolateral).\n\nAfter five days of staying in the CCU, the patient improved gradually and was discharged with some medications such as human insulin 30/70 injection, tablet (tab) linagliptin (5 mg), combined tab of aspirin and clopidogrel (75 mg + 75 mg), tab rosuvastatin (20 mg), tab trimetazidine dihydrochloride (35 mg), tab carvedilol (6.25 mg), combined tab of furosemide and spironolactone (40 mg + 50 mg), combined tab of furosemide and spironolactone (40 mg + 50 mg) and follow-up advice after seven days with complete blood count, random blood sugar, serum creatinine, serum electrolytes, and serum albumin reports.\n\n\nDiscussion\n\nThe Centers for Disease Control (CDC) estimates that over 800,000 people suffer from MI each year (Fryar et al., 2012), with the incidence occurring at 33% or more in people aged 75 years or more (Yazdanyar & Newman, 2009). This case study examines an unfortunate case of recurrent MI with acute left ventricular failure (ALVF) with acute kidney injury (AKI) after receiving the first dose of the Moderna vaccine (mRNA-1273 SARS-CoV-19 vaccine) in an 80-year-old man who was diabetic, hypertensive, and had a previous history of MI (inferolateral). This incidence does not suggest that the COVID-19 vaccine is directly responsible for MIs, but could be a contributory cause by increasing the heart’s workload (Boivin & Martin, 2021).\n\nAfter the initial trial of mRNA-1273 SARS-CoV-19 vaccine Moderna, typical side effects have been reported, such as a feeling of discomfort at the injection site (92%), exhaustion (70%), fever (15.5%), armpit swelling, or soreness (19.8%), and nausea and vomiting (23%) (Boivin & Martin, 2021). While these adverse effects were considered minor by Moderna, they could be significant stressors for older persons, particularly those with comorbidities. There was concern in Norway that vaccinations with the Pfizer (BNT162b2 mRNA COVID-19 vaccine) vaccine, another mRNA vaccine, were linked to increased mortality in older persons, with 23 fatalities. An inquiry into these deaths revealed that some of the above-mentioned side effects might have contributed to the ends of “frail patients” (Torjesen, 2021). Though not common, a few cases of MI have been reported in the wake of the mRNA-1273 SARS-CoV-19 vaccine. According to Boivin et al., a 96-year-old woman in the United States had an MI one hour after receiving her first dose of Moderna COVID-19 (Boivin & Martin, 2021). Barsha et al. from Bangladesh reported a case of a 77-year-old man not having any traditional risk factors for heart diseases, who developed acute non-ST segment elevation myocardial infarction after two days of mRNA-1273 SARS-CoV-19 vaccination with Moderna (Barsha et al., 2021). According to the CDC, there have been more than 9,367 reports of mortality following the COVID-19 immunization, with no evidence of a relationship to the vaccine until November 5, 2021 (Selected Adverse Events Reported after COVID-19 Vaccination | CDC, n.d.). However, no research on any of these cases has been published, impeding our capability to understand the circumstances behind these fatalities. In India, few reports of deaths in the media due to cardiac arrest after vaccination came from Indian media. The first one occurred in a 43-year-old patient, while the other two occurred in two individuals aged 65 and 75 years (Kumar et al., 2021). But these patients had pre-existing cardiac problems; hence, according to the district and state adverse events following immunization (AEFI) committees, their deaths could be assumed to be coincidental to vaccination (Kumar et al., 2021).\n\nThere is not enough of a dearth of rigorously conducted scientific studies that could report proving a definitive link between COVID-19 immunization and MI. However, a possible link could be argued as vaccination can trigger inflammatory and immunological reactions and thrombosis, if a pre-existing prothrombotic condition is present (Greinacher et al., 2021). A study found 11 instances of unexpected thrombotic events and thrombocytopenia 5–16 days after an AstraZeneca immunization (ChAdOx1 nCov-19 vaccine) (Greinacher et al., 2021). The majority of these (nine individuals) were healthy females with a median age of 36. They experienced thrombotic events such as cerebral venous thrombosis, splanchnic-vein thrombosis, pulmonary embolism, and other types of thrombosis. They found that all vaccinated individuals experienced immune thrombotic thrombocytopenia caused by platelet-activating antibodies against platelet factor 4 (PF4), which clinically resembled autoimmune heparin-induced thrombocytopenia.\n\nSimilarly, Scully et al. documented 23 venous thrombosis and thrombocytopenia events after receiving the first dose of the ChAdOx1 nCoV-19 vaccination (AstraZeneca). The median age of these individuals was 46 years, with the majority being female (60%). They also mentioned PF4-dependent thrombocytopenia as a cause of thrombotic events (Scully et al., 2021).\n\nAccording to a systematic analysis of global risk factors for heart failure, ischemic heart disease was the most significant underlying contributor to acute heart failure admissions in more than 50% of patients in high-income regions and eastern and central European regions (Arrigo et al., 2020). Hypertension was also found to be a consistent factor of heart failure in 17% of patients of the world (Arrigo et al., 2020). Both of these factors were present in our case. These two risk factors might have influenced the development of acute left ventricular failure with MI following the recurrent attack of MI on the day of vaccination, which occurred coincidentally after COVID-19 vaccination.\n\nAcute kidney injury is defined by a sudden decline in kidney function, evidenced by a rise in serum creatinine level with or without decreased urine output. Acute kidney injury is caused by several conditions, including advanced age, diabetes mellitus, and heart failure (Risch & Hess, 2013). In this case, multiple risk factors may have aggravated acute renal damage. In our case, a low blood volume following heart failure might have led to a sharp decline in kidney function, which subsequently recovered after management.\n\nIn this study we explored a case of acute MI with ALVF and critical renal damage AKI after mRNA-1273 SARS-CoV-19 vaccination Moderna COVID-19 vaccination in an elderly older patient with a history of previous MI, coronary artery disease, diabetes mellitus, and hypertension. It is natural to expect that older people with many comorbidities might be affected by potential side effects of vaccination against COVID-19 vaccinations’ possible side effects. However, as the patient had multiple comorbidities, we assume that MI with ALVF and acute renal injury might coincide and the event is less likely to be a consequent of COVID-19 vaccination. We acknowledge that a single case report or case series cannot attribute pathology to the vaccination causality of adverse events with the vaccine. Even large-scale investigations of possible AEFIs, such as those carried out using the Bangladesh government’s Suspected Adverse Event Reporting Form (Directorate General of Drug Administration (DGDA), 2021), can only uncover associations, not causation. Nevertheless, the current findings might increase public awareness of the possibility of a Moderna COVID-19 vaccine-related adverse event and motivate others to report similar cases wherever they arise. In summary, the findings of the current investigation of a critical and severe event following mRNA vaccination against COVID-19 should alert the international scientific community regarding the possibility of such events, particularly among vaccine recipients with multiple comorbidities or pre-existing ischemic heart disease.\n\n\nConsent\n\nWritten informed consent for publication of the clinical details and images was obtained from the patient’s relatives as patient was not in a good physical state to give interview.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReporting guidelines\n\nFigshare: CARE checklist for ‘Case Report: Acute myocardial infarction with acute left ventricular failure and acute renal damage following mRNA-1273 vaccination: Possible adverse effect of COVID-19 vaccination?’. https://doi.org/10.6084/m9.figshare.19638534.v1 (Hossain et al., 2022).",
"appendix": "References\n\nArrigo M, Jessup M, Mullens W, et al.: Acute heart failure. Nat. Rev. Dis. Primers. 2020; 6(1): 16. PubMed Abstract | Publisher Full Text\n\nBarsha SY, Haque MMA, Rahman ML, et al.: A case of acute encephalopathy and non-ST segment elevation myocardial infarction following mRNA-1273 vaccination: possible adverse effect?. Clin. Exp. Vaccine Res. 2021; 10(3): 293–297. PubMed Abstract | Publisher Full Text\n\nBoivin Z, Martin J: Untimely Myocardial Infarction or COVID-19 Vaccine Side Effect. Cureus. 2021; 13(3): e13651. PubMed Abstract | Publisher Full Text\n\nfor Disease Control, C.: MMWR, Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020.2020. Publisher Full Text\n\nFryar CD, Chen T-C, Li X: Prevalence of Uncontrolled Risk Factors for Cardiovascular Disease: United States, 1999–2010.2012.\n\nGreinacher A, Thiele T, Warkentin TE, et al.: Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N. Engl. J. Med. 2021; 384(22): 2092–2101. PubMed Abstract | Publisher Full Text\n\nHaque MMA, Rahman ML, Hossian M, et al.: Acceptance of COVID-19 vaccine and its determinants: evidence from a large sample study in Bangladesh. Heliyon. 2021; 7(6): E07376. PubMed Abstract | Publisher Full Text\n\nHawlader MDH, Rahman ML, Nazir A, et al.: COVID-19 vaccine acceptance in South Asia: a multi-country study. Int. J. Infect. Dis. 2022; 114: 1–10. PubMed Abstract | Publisher Full Text\n\nHossain MA, Rashid MU, Barsha SY, et al.: CARE-checklist-English-2013 sectionwise.pdf. figshare.2022. Online resource. Publisher Full Text\n\nKumar B, Sabbarwal V, Nigam A, et al.: Two case reports of acute ST-elevation myocardial infarction after COVID-19 vaccination: Co-incidence or causal-association?. J. Health Soc. Sci. 2021; 6(2): 293–298. Publisher Full Text\n\nRisch L, Hess B: Pitfalls bei Laborwerten – Elektrolyte, Harnstoff und Kreatinin. Ther. Umschau. 2013; 70(8): 457–464. Publisher Full Text\n\nScully M, Singh D, Lown R, et al.: Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. N. Engl. J. Med. 2021; 384(23): 2202–2211. PubMed Abstract | Publisher Full Text\n\nTorjesen I: Covid-19: Norway investigates 23 deaths in frail elderly patients after vaccination. BMJ. 2021; 372: n149. PubMed Abstract | Publisher Full Text\n\nWaheed S, Bayas A, Hindi F, et al.: Neurological Complications of COVID-19: Guillain-Barre Syndrome Following Pfizer COVID-19 Vaccine. Cureus. 2021; 13(2): e13426. PubMed Abstract | Publisher Full Text\n\nWouters OJ, Shadlen KC, Salcher-Konrad M, et al.: Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment. Lancet. 2021; 397(10278): 1023–1034. PubMed Abstract | Publisher Full Text\n\nYazdanyar A, Newman AB: The Burden of Cardiovascular Disease in the Elderly: Morbidity, Mortality, and Costs. Clin. Geriatr. Med. 2009; 25(4): 563–577. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "263077",
"date": "07 May 2024",
"name": "Wissam Faour",
"expertise": [
"Reviewer Expertise Pharmacology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis case presents the potential side effects of COVID19 vaccine in an 80-year old man suffering of many comorbidities. The patient suffered from sudden angina soon after receiving the vaccine. The authors claimed that the patient also developed AKI. While the case is interesting, some info need to be discussed. What would be a cut off creatinine levels in this patient in order to claim that he suffered from AKI?. Also, no data are shown about the patient’s previous creatinine levels nor after his discharge. Was the patient suffering of proteinuria before vaccination?, and what about his FBS levels before and after vaccination and treatment?. What about the inflammatory markers in this patient (CRP,…). Was the patient previously infected with SARS-Cov2. What was the furosemide effect on the cardiac abnormalities in this patient if any?\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-617
|
https://f1000research.com/articles/10-969/v1
|
27 Sep 21
|
{
"type": "Research Article",
"title": "Prevalence of oral manifestations in patients with lupus erythematosus in a sample of the Egyptian population: a hospital based cross-sectional study",
"authors": [
"Hager Moustafa Saeed",
"Eman Mohammad Amr",
"Alshaimaa Rezk Lotfy Rezk",
"Wesam Abd Elmoneim",
"Eman Mohammad Amr",
"Alshaimaa Rezk Lotfy Rezk",
"Wesam Abd Elmoneim"
],
"abstract": "Background: Several systemic diseases manifest themselves in the oral cavity. Oral manifestations of lupus erythematosus (LE) are associated with a significantly increased risk of cancer. Dentists who are unaware of these lesions will possibly miss them. This cross-sectional study aimed to assess the prevalence of oral manifestations in patients with LE in a sample of the Egyptian population. Methods: A descriptive study was performed on 189 patients attending the Internal Medicine Department, Rheumatology Clinic in EL Qasr EL Ainy Hospital, Cairo University. Every patient was examined clinically after completing a questionnaire. Moreover, patients’ medical records were also evaluated. The oral manifestations were recorded according to the WHO guide to physical examination of the oral cavity and classified according to their morphologic aspects and localization. Results: Out of 189 patients, there were 182 females (96.3%) and seven males (3.7%). The prevalence of oral lesions in LE patients was 55.6%. The most affected site was the tongue 25.7%. The most common clinical aspect was patches, 53%. About 77.1% of the lesions were asymptomatic. 74.3% of the patients had oral candidiasis. The prevalence of skin lesions in LE patients was 37.6%. The most common finding was malar rash 79%. Conclusions: The present study emphasizes the importance of early diagnosis of oral lesions to recognize patients with LE as the WHO considers oral manifestations of LE a widespread state associated with an increased risk of cancer. Also, implementation of oral hygiene measures and treatment to improve patients’ nutritional state and health-related quality of life are recommended.",
"keywords": [
"lupus erythematosus",
"oral manifestations",
"precancerous oral lesions",
"SLE"
],
"content": "Introduction\n\nLupus erythematosus (LE) is an autoimmune disease subdivided into a cutaneous and a systemic form. The prevalence of mucosal involvement in LE patients is debatable.1 The mucosal involvement of LE ranges from 9–45% in systemic lupus erythematosus (SLE) and 3–20% in cutaneous lupus erythematosus (CLE).1 The WHO considers the oral manifestations of LE as a widespread state associated with a significantly increased risk of cancer.2\n\nAs mentioned in the WHO digital manual for the early diagnosis of oral neoplasia (2008), several systemic diseases manifest themselves in the oral cavity. These lesions can precede the symptoms and signs of systemic disease or can coexist with it and dentists who are unaware of these lesions will possibly miss them3\n\nAccording to WHO guides for screening programs (2009),4 most programs are selective and target a subset of the population who are considered to be at the highest risk.5 Consequently, the present study assessed the prevalence of oral manifestations among a sample of Egyptian patients recently diagnosed with lupus erythematosus as they are considered to be at a high risk of developing oral precancerous lesions.\n\n\nMethods\n\nThe present cross-sectional study was performed to assess the prevalence of oral manifestations in patients with lupus erythematosus in a sample of the Egyptian population. The study was held in the Internal Medicine Department, Rheumatology Clinic in EL Qasr EL Ainy Hospital, Cairo University. Hospital data collection started in March 2019 until March 2020.\n\nInclusion criteria: Patients recently diagnosed with lupus erythematosus based on American College of Rheumatology (ACR) criteria. Patients with an anti-nuclear antibody (ANA) positive test were only included in the study. The age of patients was 14–70 years old. Both genders were included. Cigarette smoking patients were included.6\n\nExclusion criteria: Patients who had received any previous therapy for lupus erythematosus. Patients suffering from any other systemic diseases known to influence oral and maxillofacial manifestations. Patients on drug therapy who may have oral mucosal manifestations, which eliminate all the potential confounders.\n\nFor each eligible participant, a full history was obtained through an interview between the investigator and the patient. Demographical data were collected.7 All participants were asked to sign a study-related informed consent. The clinical examination of the oral manifestation was recorded by conventional oral examination (COE) according to the WHO digital manual for physical examination of the oral cavity. The sampled population was classified into two groups. LE patients who had an oral manifestation as true positive oral lesions (TP) and LE patients without oral manifestation as true negative oral lesions (TN).5 The oral manifestations were interpreted according to their clinical aspects and their sites in the oral cavity.7 The diagnosis of oral candidiasis was made by curd-like patches on the tongue or other oral mucosal surfaces, the presence of classic pseudomembranous lesions characterized by a creamy white pseudomembrane.8 Cigarette smoking patients were also assessed.9\n\nThe primary outcome was the prevalence of intraoral manifestations. The secondary outcome was an extraoral and/or perioral finding. Selection bias was minimized by enrolling the participants in the study in consecutive order of them entering the clinic. Non-respondent bias was minimized by explaining to the participants the aim of the study and their importance and role in the study. Incomplete records were excluded from statistical analysis with the cause of an incomplete record reported.\n\nEthical approval for the questionnaire and methodology were approved by the Ethics Committee of the Faculty of Dentistry, Cairo University, Cairo, Egypt (approval number: 19/5/6). All participants gave their informed consent to the interviewer verbally, using the telephone interview as a format for data collection. In addition, a link to the consent form was sent electronically.\n\nSampling was conducted continuously, and the sample size was considered 189 patients with lupus erythematosus with a 95% confidence level, 5% margin of error, and 7.1 maximum deviation of the sample rate. The sample size was calculated using Stats Direct statistical software (version 3.1.17) (An open-access alternative that can provide an equivalent function is the R stats package (RRID:SCR_001905)). Qualitative data were presented as frequencies and percentages. Quantitative data were presented as mean, standard deviation (SD), and 95% confidence interval (95% CI) for the mean values. For qualitative data, Fisher’s Exact Test was used for comparisons regarding qualitative variables. Quantitative data were explored for normality by checking the distribution of data and using tests of normality (Kolmogorov-Smirnov and Shapiro-Wilk tests). Age data showed a parametric distribution. The Student’s t-test was used to compare between patients without and with oral lesions. The significance level was set at P ≤ 0.05. Statistical analysis was performed with IBM SPSS Statistics for Windows, Version 23.0. (Armonk, NY: IBM Corp) (RRID:SCR_019096) (An open-access alternative that can provide an equivalent function is the R stats package (RRID:SCR_001905)).\n\n\nResults\n\nThe group of LE patients was composed of 189 patients. All the sampled patients met the ACR criteria for diagnosis of SLE. CLE wasn’t found among the sampled patients.\n\nThe mean (SD) values for age were 30.5 (9.7%). Only four patients (2.1%) were smokers. Four women (2.2%) were pregnant.\n\nIn this study, the prevalence of oral lesions among SLE patients was 55.6% (105/189 patients). 182 females (96.3%) and 7 males (3.7%). This showed a non-significant relationship in terms of gender in the prevalence of oral manifestations (P-value = 0.465, Effect size = 0.769). There was no statistically significant difference between mean age values in patients with and without oral lesions (P-value = 0.210, Effect size = 0.187). There was no significant relationship between smoking and non- smoking patients. Patient details are summarized in Table 1 and are shown in the underlying data.10\n\n* Significant at P ≤ 0.05.\n\nOf the 105 patients (55.6%) with oral lesions, the most affected site was the tongue 25.7%. Figure 1 displays the site of the oral lesions in descending order. The most common clinical aspect was patches, 53%. Figure 2 displays the clinical aspect of the oral lesions in descending order. Twenty-four patients (22.9%) had a burning sensation while 81 patients (77.1%) were asymptomatic. Seventy-eight out of 105 patients (74.3%) had oral candidiasis.10\n\nThe prevalence of skin lesions was 37.6% (71/189 patients). The most common finding was malar rash, 79%.10 The chart in Figure 3 represents the percentage and descriptions of the skin lesions.\n\nWhile the prevalence of patients with oral and skin lesions was 25.4% (48/189 patients). Table 2 shows the difference in the prevalence of oral manifestations among regions and countries.\n\n\nDiscussion\n\nThe current study assessed the prevalence of the oral manifestation among LE patients in Egypt.\n\nThe present study was conducted on 189 patients: 182 females (96.3%) and seven males (3.7%), and this indicated that LE is more prevalent in Egyptian females than in males. This finding agreed with López-Labady et al.,11 Khatibi et al.,12 Ali et al.,16 as well as Barrio-Díaz et al.,13 who also found that the majority of LE patients were female.\n\nDespite the variation in sample size between all studies, males were less affected by oral manifestations than females.7 There was systemic involvement in all the sampled patients. CLE patients weren’t found in the sampled population. This explains the fact that CLE may be part of the spectrum of SLE or be an entity alone with no systemic features.14\n\nThere was no statistically significant association between the prevalence of gender and oral lesions. Moreover, there was no significant difference between mean age values in patients with and without oral lesions. These findings agreed with Khatibi et al., (2012).12 There was no statistically significant association between smoking and oral manifestations. This agreed with a study by Bourré-Tessier et al.,15 who reported that there was no clear association between smoking and the presence of mucosal ulcers or malar rash.\n\nThe present study showed that the prevalence of oral manifestations was 55.6% (105/189 patients). In a study conducted in Iran, 102 (54.3%) out of 188 patients had oral lesions, while 86 (45.7%) had none.12 In addition to that, a study conducted in Ireland showed that 50% of patients had positive oral findings.16 In Saudi Arabia it was found that mucocutaneous lesions including oral ulcers were reported in 72% of 46 SLE patients.17 Also, De Rossi et al., in 1998, found the prevalence of oral manifestations ranged from 81.3 to 87.5%.12 The highest prevalence was reached at 97% in an Argentinian study.13 On the other hand, a lower prevalence was shown in a Venezuelan study,11 which reported that of the 90 patients diagnosed with LE only 10 patients (11.1%) showed oral mucosal lesions. Collectively, the higher prevalence of oral manifestations in SLE is probably because all tissues are potentially affected as a result of the disease course.1\n\nThe results of the current study revealed that the most affected site was the tongue (25.7%) in just over one-quarter of the patients followed by the palate, lips, buccal mucosa, the gingiva, and the least affected site was the corner of the mouth. Khatibi et al., in 2012, revealed that the sites most commonly affected by oral lesions were the buccal mucosa and the lips.12 A Brazilian study reported that the more frequently affected sites were the buccal mucosa then the hard palate and lower lips.1 While another study found that the commonest site was the hard palate.16 This variation may be attributed to dissimilarity in the exclusion and inclusion criteria of these studies.\n\nInterestingly, one of our patients reported symptoms of numbness and facial sensory impairment, which indicate the involvement of sensory ganglia of the cranial nerves. Loss of taste and dry mouth were reported as the first manifestation of SLE in this patient. The serological result reported that the antinuclear antibody was present in a titer of 1/320, and the CT scan examination of the brain revealed that the patient had had a stroke. This may be attributed to the autoimmune autoantibodies directed against sensory ganglion.18\n\nThe first trigeminal neuropathy (TN) cases in SLE patients were reported in 1971, where TN was stated as the only neurological manifestation of SLE among two cases in their study.19 In 1990 two cases of TN in SLE were reported among 81 studied subjects.20 And then in 2017 one case of TN was reported during a 35-year study of SLE in African American female patients in the USA.21Finally, in 2020 a case of acute severe sensory ganglionopathy was reported in a 24-year-old male SLE patient.18\n\nThe second most frequently affected site for oral manifestations in this study was the palate and this agreed with a previous study conducted in Brasil.1 In third place were the lips; the lower lips were more often affected than the upper lips. This may be attributed to the fact that the lower lips are more exposed to sunlight than the upper lips and to the biological mechanisms of ultraviolet rays (UVR), which induce lupus flare.22\n\nIn our study, patches were reported as the most significant morphologic feature (53.3%). This was followed by ulcers (15.2%), plaques (11.4%), white keratotic striae (8.6%), macules (6.7%), linear erythema (6.7%), and the least common clinical feature was erosive lesions in 3.8% of the patients.\n\nLourenco et al., (2007) reported that oral lesions presented in different clinical aspects, ranging from classic plaques accompanied by central erythema enclosed by a white rim with radiating keratotic striae to a white plaque on a pigmented mucosa and finally to bullous lesions.1 Menzies et al., reported that LE lesions varied from striated/reticular white patches, erosions, ulceration to homogenous white patches.16 Recently, Barrio et al., reported that oral lesions were classified into erythematous patches, honeycomb plaques, lupus cheilitis, chronic plaques, oral discoid lesions, LP-like lesions, keratotic lesions, ulcerative plaques, oral ulcers, pebbly red areas, purpuric lesions, erythema and diffuse palatal petechial erythema.13\n\nThe results of the current study revealed that the clinical appearance of the patches varied from one patient to another. Round erythematous patches were reported in 35.2 % of the lesions. These patches were painless and would bleed on palpation while scaly erythematous patches were observed in 16.2% of the lesions. A scaly white patch was reported in 1.9% of the patients particularly on the lips, these scales were crusted and thick. Barrio et al., (2020) reported that erythematous patches are considered as clinical descriptions of oral lupus lesions.13 Nico et al.,1reported that LE oral lesions manifested as oval non-scarring patches with variable degrees of erosion.1\n\nThe second most significant clinical feature was found to be the ulcer. Ulcers were reported in 15.3% of cases, ranging from ulcers surrounded by a red halo, painless ulcers surrounded by white radiating striae, ulcers surrounded by red radiating striae associated with burning sensation, and round erythematous hemorrhaging ulcers.\n\nMeyer et al., and Ranginwala et al. found that oral ulcers are present in 19% of cases in both of their studies.23 While Khatibi et al., (2012) and Menzies et al., (2018) found that 28.1% and 23.8% of patients showed oral ulcers respectively.12 Barrio et al., (2020) found that oral ulcers were present in 11 of 150 patients with lupus (7%).13 On the other hand, Ali et al. (2012) reported that oral ulcers were present in 72% of patients.24\n\nThe third clinical picture in our study was the plaque. Plaques were reported in 11.4% of the lesions. The clinical appearance ranged from painless red plaques to painful erosive plaques. Lourenço et al., (2007), found that the lesions of the hard palate were red maculae or plaque. In contrast, white lesions were found only in the buccal mucosa.1 Barrio et al. reported that honeycomb plaques on the palate are only present in lupus patients.13 A white plaque on pigmented mucosa was reported by López et al.11 Also, Lourenço et al., reported four cases of classic plaques with central erythema from 46 patients (8.6%).1\n\nIn the current study, painless white keratotic striae came in fourth place at 8.6%. Buccal mucosa was the most affected by white keratotic striae followed by the gingiva. These findings agreed with Lourenço et al., who reported that white lesions (plaque and LP-like striae) were found only in the buccal mucosa.1\n\nThe results of the present study revealed that single and cluster macules were reported in 6.7% of the cases. These red macules were painless, and the palate showed the highest prevalence of macules followed by the gingiva. This was in accordance with López et al., who also reported the presence of red maculae on the hard palate.11 Barrio et al., reported that high activity of the LE was associated with red macules on the soft palate and brown-pigmented macules on the lower gingiva.13\n\nIn the current study, linear erythema was reported in 6.7% of cases. It was noticed on the gingiva and palate. Similarly, Nico et al., 2008 reported that linear erythema and keratosis were observed on the upper palatal gingiva in the patient.1\n\nFinally, erosive lesions were observed in 3.8% of the cases in the present study. These lesions showed no statistically significant association with a particular oral site. A Brazilian study reported erosive lesions on the lips and buccal mucosa.1 Also, erosive and keratotic lesions on the left buccal mucosa were presented in a case report by Nico et al., (2008).1\n\nIn the current study, oral candidiasis was observed in 41% of all the patients. Moreover, (74.3%) patients had oral lesions superinfected by Candida. This agreed with a study conducted in Qatar in which the prevalence of oral Candida was 88.1%.17 Immune system dysregulation is the main cause of Candida infection. The imbalance between innate and adaptive immunity leads to the consequent secretion of pro-inflammatory cytokines (IL-6, IL-8, IL-10, IL-12, TNF-α) in LE, which affects the immune regulation of antifungal activity and proves a correlation between Candida and LE.25\n\nIn the present study, the prevalence of cutaneous lesions in the LE patient was 37.6%. This agreed with Barrio et al., (2020), who also found that 45.3% of patients had cutaneous manifestations.13 About 83.1% of the patients who had cutaneous manifestations were affected on the bridge of the nose and cheek. While the least affected site was the perioral area. The morphology of skin lesions varied from a malar rash (butterfly erythema), hyperpigmentation to disc-shaped patches. In the present study, malar rash was observed in 79% of patients.22\n\nThe prevalence of patients with oral and skin lesions was 25.4% (48/189 patients). Whereas, in a study by Ranginwala et al., (2012), 90.47% of patients had oral lesions along with skin lesions.23\n\n\nRecommendations\n\nFurther studies should be conducted in other regions with a larger sample size and at different time intervals to broaden these findings. Also, additional research could highlight the impact of race, ethnicity, and genetics on the prevalence of oral manifestations of the disease.\n\n\nConclusion\n\nThe present study emphasizes the importance of early diagnosis of oral lesions in patients recognized with LE as the WHO considers oral manifestations of LE as a widespread state associated with an increased risk of cancer. It is also required in order to implement oral hygiene measures and provide treatment to improve patients’ health-related quality of life. Further studies are needed since research has been conducted in only 1 in 10 countries of the world.\n\n\nData availability\n\nDryad: Underlying data for ‘Prevalence of oral manifestations in patients with lupus erythematosus in a sample of the Egyptian population: a hospital based cross-sectional study’, https://doi.org/10.5061/dryad.wstqjq2mv.10\n\nThis project contains the following underlying data:\n\n• Data file 1: Prevalence of oral manifestations in LE patients.xlsx\n\n• Data file 2: Read_me.txt\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Universal Public domain dedication).\n\n\nConsent\n\nAll participants gave their informed consent to the interviewer verbally, using the telephone interview as a format for data collection. In addition, a link to the consent form was sent electronically requesting written consent for publication of the patients’ details.",
"appendix": "References\n\nLourenço SV, de Carvalho FRG, Boggio P, et al.: Lupus erythematosus: Clinical and histopathological study of oral manifestations and immunohistochemical profile of the inflammatory infiltrate. Journal of Cutaneous Pathology. 2007; 34(7): 558–564. Publisher Full Text\n\nWalker DM: Histological Typing of Cancer and Precancer of the Oral Mucosa. 1998; 30. Publisher Full Text\n\nEdens MH, Khaled Y, Napeñas JJ: Introduction to Oral Manifestations of Systemic Diseases: Evaluation of the Patient. Atlas of the Oral and Maxillofacial Surgery Clinics of North America. 2017; 25(2): 85–92. PubMed Abstract | Publisher Full Text\n\nPetersen PE: Oral cancer prevention and control – The approach of the World Health Organization. Oral Oncol. 2009; 45(4-5): 454–460. PubMed Abstract | Publisher Full Text\n\nBrocklehurst PR, Speight PM: Screening for mouth cancer: The pros and cons of a national programme. Br Dental J. 2018; 225(9): 815–819. Publisher Full Text\n\nWei Y: The pathogenesis of systemic lupus erythematosus - An update. Dermatol Res Adv. Nova Science Publishers, Inc; 2014; Vol 2. : 135–160. Publisher Full Text\n\nGlick M: Burket's oral medicine. PMPH USA . 2015; 57: 121.\n\nFangtham M, Magder LS, Petri MA: Oral candidiasis in systemic lupus erythematosus. Lupus. 2014. PubMed Abstract | Publisher Full Text\n\nBickley LS, Szilagyi PG: Bates’ Guide to Physical Examination and History Taking, 11e.2013.\n\nSaeed HM, Amr EM, Rezk ARL, et al.: Prevalence of oral manifestations in patients with lupus erythematosus in a sample of Egyptian population, a hospital based cross-sectional study. Dryad. 2021. Publisher Full Text\n\nLópez-Labady J, Villarroel-Dorrego M, González N, et al.: Oral manifestations of systemic and cutaneous lupus erythematosus in a Venezuelan population. J Oral Pathol Med. 2007; 36(9): 524–527. PubMed Abstract | Publisher Full Text\n\nKhatibi M, Shakoorpour AH, Jahromi ZM, et al.: The prevalence of oral mucosal lesions and related factors in 188 patients with systemic lupus erythematosus. Lupus. 2012; 21(12): 1312–1315. PubMed Abstract | Publisher Full Text\n\ndel Barrio-d P, Manr J, Barrio-d D: Association between oral lesions and disease activity in lupus erythematosus.2020: 349–356. PubMed Abstract | Publisher Full Text\n\nElman SA, Nyberg F, Furukawa F, et al.: Klinische manifestationen des kutanen lupus erythematodes. JDDG. 2019; 76(2): 1124–1137. Publisher Full Text\n\nBourré-Tessier J, Peschken CA, Bernatsky S, et al.: Association of smoking with cutaneous manifestations in systemic lupus erythematosus. Arthritis Care Res. 2013; Publisher Full Text\n\nMenzies S, O’Shea F, Galvin S, et al.: Oral manifestations of lupus. Ir J Med Sci. 2018; 187(1): 91–93. PubMed Abstract | Publisher Full Text\n\nHammoudeh M, Al-momani A, Sarakbi H, et al.: Oral Manifestations of Systemic Lupus Erythematosus Patients in Qatar: A Pilot Study. Int J Rheumatol. 2018; 2018: 1–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLefter S, Monaghan B, McNamara B, et al.: Acute severe sensory ganglionopathy in systemic lupus erythematous. Neuromuscul Disord. 2020. PubMed Abstract | Publisher Full Text\n\nB A, T GB: Trigeminal neuropathy in connective tissue disease. Neurology. 1971; 21(6): 609–614. PubMed Abstract\n\nH NA, S JC, M CJ: Trigeminal sensory neuropathy associated with connective tissue diseases. Neurology. 1990; 40(6): 891–896. PubMed Abstract | Publisher Full Text\n\nKumar V, Kaur J, Pothuri P, et al.: Atypical trigeminal neuralgia: A rare neurological manifestation of systemic lupus erythematosus. Am J Case Rep. 2017; 18: 42–45. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTp M, Hawk J: Ultraviolet Therapy in Lupus. Accessed November 19, 2019. Reference Source\n\nRanginwala AM, Chalishazar MM, Panja P, et al.: Oral discoid lupus erythematosus: A study of twenty-one cases. J Oral Maxillofac Pathol. 2012; 16(3): 368–373. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAli NSM, Zaidan TF: Oral manifestations, oral health status and saliva composition changes in a sample of Iraqi systemic lupus erythematosus patients. J Bagh College Dentistry. 2012; 24(2): 2012.\n\nFerretti C, la Cava A: Overview of the Pathogenesis of Systemic Lupus Erythematosus. In: Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects. Elsevier Inc.; 2016: 55–62. Publisher Full Text\n\nAround L; World THE: Systemic lupus erythematosus in Tunisia: demographic and clinical analysis of 100 patients.2004: 204–211. PubMed Abstract | Publisher Full Text\n\nal Arfaj AS, Khalil N: Clinical and immunological manifestations in 624 SLE patients in Saudi Arabia.PubMed Abstract | Publisher Full Text\n\nAlsaleh J, Jassim V, Elsayed M, et al.: Clinical and immunological manifestations in 151 SLE patients living in Dubai.2008; July 2007: 62–66. PubMed Abstract | Publisher Full Text\n\nSiddiqui H, Shehab D, Umamaheswaran I, et al.: Occasional Series Ð Lupus around the World Systemic lupus erythematosus in KuwaitÐ hospital based study.1998: 434–438.\n\nUthman I, Nasr F, Kassak K, et al.: Systemic.1999. Publisher Full Text\n\nMok CC, Lau CS: Lupus around the World Lupus in Hong Kong Chinese. Publisher Full Text\n\nRabbani MA, Siddiqui BK, Tahir MH, et al.: Systemic lupus erythematosus in Pakistan. Publisher Full Text\n\nPamuk ON, Akbay FG, Dönmez S, et al.: The clinical manifestations and survival of systemic lupus erythematosus patients in Turkey: report from two centers. Lupus. 2013; 22: 1416–1424. PubMed Abstract | Publisher Full Text\n\nAlonso-perez E, Suarez-gestal M, Calaza M, et al.: Association of Systemic Lupus Erythematosus Clinical Features with European Population Genetic Substructure.2011; 6(12). PubMed Abstract | Publisher Full Text | Free Full Text\n\nTikly M, Burgin S, Mohanlal P, et al.: Autoantibodies in Black South Africans with Systemic Lupus Erythematosus: Spectrum and Clinical Associations . 1996; 15.\n\nShahzad F: Systemic Lupus Erythematosus-An Immunological Disorder: Clinical Presentations and Therapeutic Options Article in Biomédica: Revista Del Instituto Nacional de Salud . 2014. Reference Source\n\nCooper G, Parks C, Treadwell E, et al.: Differences by Race, Sex and Age in the Clinical and Immunologic Features of Recently Diagnosed Systemic Lupus Erythematosus Patients in the Southeastern United States. Accessed June 11, 2021. Reference Source"
}
|
[
{
"id": "95501",
"date": "12 Oct 2021",
"name": "Syahrul Sazliyana Shaharir",
"expertise": [
"Reviewer Expertise SLE"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis was an interesting study but I have a few queries:\nIt was mentioned that Egyptian patients recently diagnosed with lupus erythematosus were included in the study. What was the definition of recently diagnosed? Within 3 months of diagnosis or at the onset of diagnosis?\n\n\"Exclusion criteria: Patients who had received any previous therapy for lupus erythematosus\". So were all patients treatment-naïve?\n\nWhat were the example of drugs that may become confounder of oral lesions?\n\nWhat were the questionnaire questions? Kindly elaborate more what were the questions asked to the patients as these data were not presented in the Results section.\n\nResults: the data presented was very minimal. In the methodology it was mentioned that a full history was obtained through an interview. In addition, subjects were also given a set of questionnaire (in which the content of the questions were not clear). The results did not elaborate the “full history” that was obtained. There was no mentioned of other clinical manifestations of SLE apart from skin manifestation. And no data on the background treatment or medications, if present.\n\nIn discussion, the most likely reason for no association between oral lesion with smoking status was due to very small sample size in the smoking arm.\n\nIt was stated in the discussion that oral candidiasis was observed in 41% of all the patients. Moreover, (74.3%) patients had oral lesions superinfected by Candida. This was not mentioned in the Methodology and Results, but what was the difference between oral candidiasis and oral lesions superinfected by Candida? How was the diagnosis made to differentiate the 2 conditions?\n\nThe discussion was too long but the results were too brief. Authors should focus and discuss the results that answer the primary and secondary objectives of the study. Should exclude discussion about the nerve involvement as it was not part of the study objectives.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7602",
"date": "23 Dec 2021",
"name": "Hager Saeed",
"role": "Author Response F1000Research Advisory Board Member",
"response": "It was mentioned that Egyptian patients recently diagnosed with lupus erythematosus were included in the study. What was the definition of recently diagnosed? Within 3 months of diagnosis or at the onset of diagnosis? The Internal Medicine Department, Rheumatology Clinics in EL Qasr EL Ainy Hospital, Cairo University, has two clinics for lupus patients. Clinic One is only for new patient diagnosis, and Clinic Two is for treatment follow-up. New patients arrive at Clinic 1 in search of a diagnosis and are given Medical Record numbers. Clinic 1 was where all of the new patients were diagnosed. Patients with MRN who needed to be followed up on went to clinic 2. The research was carried out at Clinic No. 1. Only patients who were diagnosed immediately according to ACR criteria were included in the study. All of the patients in Clinic One had not previously received any lupus medication. \"Exclusion criteria: Patients who had received any previous therapy for lupus erythematosus\". So were all patients treatment-naïve? Yes, the study was conducted in clinic number one, which is for new patients only. Only patients who were immediately diagnosed were included, as stated in the inclusion criteria. All of the patients in Clinic One was immediately diagnosed and had not previously received any lupus medication. In the thesis, we defined the drugs for lupus treatment as: Systemic Corticosteroids High doses (40 to60 mg/d of prednisone or prednisone equivalent) are used in patients with severe SLE. Doses of 10 mg/d or less are used for milder SLE for treatment of cutaneous and musculoskeletal symptoms not responding to other therapies. (Mehat et al., 2017) Immunosuppressants - Patients who are not responsive to anti-malarials or glucocorticoids should be considered for treatment with immunosuppressive agents for more severe manifestations of the disease (Bernknopf, 2015): Methotrexate. (MTX) is a folic acid analog which inhibits the enzyme dihydrofolate reductase and, as consequences of the proliferation of T cell populations (Bernknopf, 2015). Mycophenolate mofetil and mycophenolate sodium. Decreased activity of this enzyme affects proliferation of B and T lymphocytes induces apoptosis of activated T lymphocytes (Winkelmann, 2013). Azathioprine. is the prodrug of 6- mercaptopurine, Side effects include bone-marrow toxicity, gastrointestinal symptoms and hepatotoxicity (Winkelmann, 2013). Clofazimine. is an antibiotic with immunosuppressive and anti-inflammatory activity traditionally used in the treatment of leprosy (Winkelmann, 2013). BIOLOGIC AGENTS Intravenous immunoglobulin (IVIG). IVIG is the product of pooling immunoglobulin G (IgG) immunoglobulins extracted from donor blood (Winkelmann, 2013). Rituximab. Rituximab is a chimeric anti-CD20 monoclonal antibody that induces depletion of B cells through both antibody-dependent and independent pathways (Winkelmann, 2013). IMMUNOMODULATORS Dapsone - Dapsone is a sulfone that inhibits dihydrofolic acid synthesis and exhibits both antibiotic and anti-inflammatory properties. Thalidomide - The effects of thalidomide are attributed to the inhibition of TNF-alpha synthesis and UVB-induced keratinocyte apoptosis. Lenalidomide - Lenalidomide is a structural analog of thalidomide with more potent immune-modulatory effects and a lower risk of polyneuropathy (Winkelmann, 2013). What were the example of drugs that may become confounders of oral lesions? This point aims to eliminate the confounders. For example, some types of antibiotics cause changes in the microbial flora of the oral cavity and increase candida infection. As mentioned in the following references some drugs induce oral lesions: Oral ulcerations due to drug medications An Update on Drug-induced Oral Reactions A Review of Drug-Induced Oral Reaction Drug-Induced Oral Reactions What were the questionnaire questions? Kindly elaborate more what were the questions asked to the patients as these data were not presented in the Results section. The patient enters Clinic One (new patient clinic). The patient opens a file (include all the Demographical data). The specialized nurse record the vital signs and the history of the patients. After that the patient entered the doctor's clinic and the patient's full history was taken. The patients were examined initially by a rheumatologist and were later be scheduled for an appointment with the same dentist at the same institution, for an oral and dental examination. The study includes a group of patients with a confirmed diagnosis of LE who presented to the Internal Medicine department, rheumatology clinic in EL Qasr EL Ainy hospital - Cairo University. Diagnosis of LE was established based on the criteria established by the American College of Rheumatology based on tests that confirm LE diagnosis (ANA) only was included in the study. Results: the data presented was very minimal. In the methodology it was mentioned that a full history was obtained through an interview. In addition, subjects were also given a set of questionnaire (in which the content of the questions were not clear). The results did not elaborate the “full history” that was obtained. There was no mention of other clinical manifestations of SLE apart from skin manifestation. And no data on the background treatment or medications, if present. Full history was obtained by the rheumatologist to diagnose the patients. The rheumatologist documented the history and the requested investigation in the patient file. In my role as a dentist, if the ANA test is positive I scheduled an appointment, for an oral and dental examination at the same institution. The study focused only on the outcomes that’s why the results demonstrate the demographic and outcomes only. Outcomes: Primary outcome: Prevalence of intraoral manifestations. As ulcer (a defect in the epithelium in the form of a depressed lesion), erythema, white plaque (a solid raised lesion greater than 1 cm in diameter), spots or white striae with a radiating orientation. Secondary outcome: Extraoral and perioral findings. malar rash, photosensitive dermatitis, generalized maculopapular rash, discoid rash, subacute cutaneous lupus erythematosus (SCLE), lupus profundus, erythema multiforme. In discussion, the most likely reason for no association between oral lesion with smoking status was due to very small sample size in the smoking arm. Yes, I agree with you. I wrote this paragraph in the thesis: Smoking cessation is recommended in controlling CLE symptoms (Chang et al., 2016). Studies also report the decrease of chloroquine efficacy in smokers, due to the effect of tobacco on cytochrome P450, which enzymatic system is responsible for the metabolism of this drug. In addition, smoking is related to other risk factors that also influence treatment adherence (Moura et al., 2014). No significant differences were reported in some habits such as smoking or flossing frequency. Studies have reported that SLE patients have a reduced oral health-related quality of life (HRQoL) comparable to their counterparts with severe medical diseases, such as AIDS, diabetes and rheumatoid arthritis (Corrêa et al., 2018). In the multivariate analysis, being a current smoker was associated with the presence of active rash. No clear association was seen between mucosal ulcers and smoking across the various smoking groups. No clear association was seen between smoking and the presence of the ACR criteria of malar rash or mucosal ulcers (Bourré et al. 2013). In contrast to that, Chang reported in a prospective cohort study of CLE patients indicated that the greater disease severity and the worse quality of life measurements in current smokers (Chang et al., 2016). Smoke activates metalloproteinases, that damage the tissue, and cytokines such as interleukin- 6, an important marker of inflammation in lupus (Moura et al., 2014). It was stated in the discussion that oral candidiasis was observed in 41% of all the patients. Moreover, (74.3%) patients had oral lesions superinfected by Candida. This was not mentioned in the Methodology and Results, but what was the difference between oral candidiasis and oral lesions superinfected by Candida? How was the diagnosis made to differentiate the 2 conditions? The diagnosis of oral candidiasis was made by curd-like patches on the tongue or on other oral mucosal surfaces, the presence of classic pseudomembranous lesions characterized by creamy white pseudomembrane (Fangtham et al., 2014). All the oral candidiasis can be rubbed off by swap. In case of white lesions, the candida will be rubbed off but the lesion will not be removed. In this study, we found that 41% of all the sampled patients (189) had oral candidiasis. Moreover, we found that the prevalence of oral candidiasis (seventy-eight (87) out of 105) was (74.3%). Oral candidosis (OC) is subdivided into primary and secondary. Secondary infections are superimposed on other diseases of the oral mucous membranes, such as oral lichen planus (OLP), a chronic inflammatory disease. Oral Mucosal T-Cell Responses to C. Albicans: Fungal infection is one of variant well-known opportunistic infections in patients with SLE. Candida is the commonest opportunistic fungal infection recognized. Host factors such as decreased salivary flow rate or smoking are associated with the raised oral carriage rate of Candida. SLE can significantly decrease the salivary flow rate compared to healthy individuals (Fangtham et al., 2014). Resistance to the fungal infections caused by C. Albicans needs coordinated action of the innate and adaptive immune responses, during which the activation of systems activate the secretion of multiple of primary cytokines and expression of co-stimulatory molecules. (McIntyre, 2001) See diagram here: https://f1000researchdata.s3.amazonaws.com/linked/396723.ReviewforLW.PNG Schematic representation of the important interactions between the immune system of the host, and bacterial microbiota and C. Albicans in the GI tract (Cottier et al., 2012). TNF-α is liberated by macrophages during the early phase of the inflammatory response to fungus attracts and activates neutrophils to become antifungal effectors. The production of IL-4 is dependent on the amount of fungus present in the infection site. IL-10 was first described as a cytokine that had potent anti-inflammatory activity (McIntyre, 2001). As the reason of the consequent secretion of pro-inflammatory cytokines (IL-6, IL-8, IL-10, IL-12, TNF-α) in LE, these cytokines act as a potent anti-inflammatory and this affects immune regulation of antifungal effector. This proves the correlation between candida and LE (Ferretti et al., 2016). A study conducted in USA reported that oral candidiasis can be found in conjunction with occult esophageal infection. This indicates that, disseminated Candida infection can originate from the oral cavity (Fangtham et al., 2014). This may indicate the presence of xerostomia in LE increases susceptibility to oral infections, mainly oral candidiasis (Fangtham et al., 2014). In a study conducted in Japan, all patients with xerostomia showed the pathophysiology of atrophicans oral candidiasis. In addition, the prevalence of oral candidiasis was significantly higher in patients with xerostomia than in controls (Shinozaki, S., et al. 2012). Also, Torres had conducted a study to assess the correlation between salivary flow rates and Candida counts it was found that the frequency of Candida colonization was (67.9%) (Torres et al., 2002). In addition to that, SLE disease activity is a risk factor for Candida infection since, high SLE disease activity is associated with invasive fungal infections (Fangtham et al., 2014). Interestingly, the prevalence of oral candida in African patient may be attributed to ethnicity. Whereas, African-American ethnicity had a higher risk of oral candidiasis (Fangtham et al., 2014). On the other hand, opportunistic infections, particularly Candida infections, are more common in patients with SLE because of altered immune status (Cojocaru et al., 2011). The discussion was too long but the results were too brief. Authors should focus and discuss the results that answer the primary and secondary objectives of the study. Should exclude discussion about the nerve involvement as it was not part of the study objectives. Yes, you have a valid point of view. To clarify your doubts about the results. According to the author's guide, I couldn’t add all the tables and figures. In terms of nerve involvement, this case explains that the first symptom of nerve involvement could be numbness. Among the sampled patients, one of the present study patients reported symptoms from involvement of sensory ganglia of multiple cranial nerves such as facial sensory impairment and facial numbness (gasserian ganglion of trigeminal nerve), loss of taste (geniculate ganglion of facial nerve). Additional contributing factor to the loss of taste could be dry mouth. This was the first manifestation of SLE. The serological result reported that antinuclear antibody was present in a titre of 1/320. The CT scan examination of the brain reported that there was a stroke. Interestingly, the first trigeminal neuropathy (TN) case in SLE patients was reported in 1971 where TN has been reported as the only neurological manifestation of the SLE among 2 cases. (Ashworth et al., 1971). Also, in 1990 Hagen et al. reported 2 cases of TN in SLE among 81 studied subjects. More recently, Kumar et al. (2017) reported one case of TN during the course of SLE in 35 years African American woman patient in USA. Finally, Lefter et al. (2020) reported a case with acute severe sensory ganglionopathy in 24 years man through the course of SLE. This proves that TN can be caused by autoimmune response and immune complex deposition in the vessels. The diagnosis of TN is based on the characteristic clinical picture, which is considered the key clinical features and physical examination showing no clinical evidence of neurological deficit or mild sensory impairment in trigeminal nerve distribution (Kumar et al., 2017). Furthermore, Facial numbness, paresthesia, dysesthesia, and pain have been reported most frequently; TN may be the first feature of SLE or might follow the onset of the disease, usually developing slowly over the course of the illness (Hagen, 1990). Autoantibodies against the ganglionic acetylcholine receptor, reported in the serum of 12.5% SLE patients, might play a role in the autonomic disturbance of these patients (Kumar et al., 2017). The most important thing, that tongue stiffness can be the initial symptom of an autoimmune disease (Rajevac et al., 2020)."
}
]
},
{
"id": "101743",
"date": "05 Jan 2022",
"name": "Laura B. Lewandowski",
"expertise": [
"Reviewer Expertise SLE",
"global health",
"pediatric rheumatology",
"genetics",
"translational research"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI think this paper has some merit - there is data here on one of the most common clinical manifestations in a specific regional cohort. However, the current version lacks focus and organization, and I cannot recommend indexing in the current format.\nThe authors should consider a revision which focuses on the clinical description of oral lesions, both type and location, in their cohort. They should compare overall demographics and clinical features, and specific oral manifestations in their cohort to the published literature. Then they should state any unique features of their cohort in regards to oral lesions in SLE. Some of the introduction and discussion needs major reorganization and removal of statements that do not have evidence.\nLupus erythematosus (LE) is an autoimmune disease subdivided into a cutaneous and a systemic form - It seems that the authors only included SLE patients based on 1997 ACR Criteria. If so, this distinction is distracting from the focus of the paper.\nIntroduction:\n\"The prevalence of mucosal involvement in LE patients is debatable.\" - There are multiple reports on mucosal involvement in SLE. Authors should state there is a range based on population and cite the following: 1, 2, 3\n\n\"The WHO considers the oral manifestations of LE as a widespread state associated with a significantly increased risk of cancer.” - This is not validated in the SLE literature. The citation listed here is a book review and does not support this claim.\n\nInclusion criteria: Patients recently diagnosed with lupus erythematosus based on American College of Rheumatology (ACR) criteria. How did the authors define a recent diagnosis?\n\nPatients with an anti-nuclear antibody (ANA) positive test were only included in the study.\n\nExclusion criteria - Patients who had received any previous therapy for lupus erythematosus. Authors should state treatment of naïve patients in the inclusion criteria.\n\n\"Patients on drug therapy who may have oral mucosal manifestations, which eliminate all the potential confounders\" - untrue. Reduced confounding due to medication effect.\n\n\"The diagnosis of oral candidiasis was made by curd-like patches on the tongue or other oral mucosal surfaces, the presence of classic pseudomembranous lesions characterized by a creamy white pseudomembrane\" - was this confirmed by any culture or biopsy?\n\nResults:\nTable 1 should include an overall demographic data for all participants- age, sex, smoking, presence of oral lesions.\n\nTable 1 should be Table 2.\n\nFigure 1 - would change to anatomical sites of oral lesions. How did the authors standardize the bounds of each lesion?\n\nFigure 3: I am a bit confused about the inclusion of the data on the skin manifestations. Unless the authors have a specific hypothesis they would like to explore with this data, it seems out of place in this paper on oral lesions in SLE.\n\n\"The sampled population was classified into two groups. LE patients who had an oral manifestation as true positive oral lesions (TP) and LE patients without oral manifestation as true negative oral lesions (TN).\" - I think this language is confusing, as they do not discover false positives or negatives in this study. I would change this to present or absent.\n\nDiscussion:\n\"CLE patients weren’t found in the sampled population\" - they were excluded based on methods stated above.\n\n\"Interestingly, one of our patients reported symptoms of numbness and facial sensory impairment, which indicates the involvement of sensory ganglia of the cranial nerves. Loss of taste and dry mouth were reported as the first manifestation of SLE in this patient. The serological result reported that the antinuclear antibody was present in a titer of 1/320, and the CT scan examination of the brain revealed that the patient had had a stroke. This may be attributed to the autoimmune autoantibodies directed against sensory ganglion\":\n1. This belongs in results.\n2. How does the stroke, which I am assuming is an ischemic stroke in a specific area associated with the deficit, support antibodies against sensory ganglia? This is confusing and needs to be clarified by the authors. Did the patient have positive anti-phospholipid antibodies?\n\n\"In the current study, oral candidiasis was observed in 41% of all the patients. Moreover, (74.3%) patients had oral lesions superinfected by Candida.\" - this was based on appearance and not culture/biopsy? I think this needs to be removed as this is not confirmed Candida according to the methods.\n\nConclusion:\nThe link to cancer is not substantiated by current evidence and needs to be removed. I agree that more research in diverse settings is critical. Do the authors have a citation for the claim that research is only conducted in 1 in 10 countries? All research? Research on SLE? If no citation please make a more broad statement.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "7669",
"date": "03 Feb 2022",
"name": "Hager Saeed",
"role": "Author Response",
"response": "Dear Laura, Thanks for your valuable report, I appreciate all your efforts to write this constructive report. I do my efforts to be concise in the paper as this paper is the summary of the thesis defense which is about 150 pages. Unfortunately, I couldn’t share the full thesis with you to learn more from your wide experience. The clinical description of oral lesions, both type and location references Burket’s Oral Medicine, 12th Edition - Michael Glick - Google Books. Accessed August 23, 2021. https://books.google.com.eg/books?hl=en&lr=&id=cBEqCAAAQBAJ&oi=fnd&pg=PR1&dq=burket%E2%80%99s+oral+medicine.&ots=hkfOb1399V&sig=GjVjm9Gg5OGxOsyAph5UwMfx_XQ&redir_esc=y#v=onepage&q=burket%E2%80%99s%20oral%20medicine.&f=false This reference was used in • Khatibi M, Shakoorpour AH, Jahromi ZM, Ahmadzadeh A. The prevalence of oral mucosal lesions and related factors in 188 patients with systemic lupus erythematosus. Lupus. 2012 Oct;21(12):1312–5. • Hammoudeh M, Al-momani A, Sarakbi H, Chandra P, Hammoudeh S. Oral Manifestations of Systemic Lupus Erythematosus Patients in Qatar: A Pilot Study. International Journal of Rheumatology. 2018;2018:1-7. doi:10.1155/2018/6052326 • Hadidi KT El, Medhat BM, Baki NMA, Kafy HA, Abdelrahaman W, Yousri AY. Characteristics of systemic lupus erythematosus in a sample of the Egyptian population : a retrospective cohort of 1109 patients from a single center. 2018;(December 2017):1–9. Introduction: • \"The prevalence of mucosal involvement in LE patients is debatable.\" - There are multiple reports on mucosal involvement in SLE. Authors should state there is a range based on population and cite the following: 1, 2, 3 Thank you for this valuable addition. • \"The WHO considers the oral manifestations of LE as a widespread state associated with a significantly increased risk of cancer.” – Thank you for this valuable addition. I removed this part. • Inclusion criteria: Patients recently diagnosed with lupus erythematosus based on American College of Rheumatology (ACR) criteria. How did the authors define a recent diagnosis? The Internal Medicine Department, Rheumatology Clinics in EL Qasr EL Ainy Hospital, Cairo University, has two clinics for lupus patients. Clinic One is only for new patient diagnosis, and Clinic Two is for treatment follow-up. New patients arrive at Clinic 1 in search of a diagnosis and are given Medical Record numbers. Clinic 1 was where all of the new patients were diagnosed. Patients with MRN who needed to be followed up on went to clinic 2. The research was carried out at Clinic No. 1. Only patients who were diagnosed immediately according to ACR criteria were included in the study. All of the patients in Clinic One had not previously received any lupus medication. • Exclusion criteria - Patients who had received any previous therapy for lupus erythematosus. Authors should state treatment of naïve patients in the inclusion criteria. Yes, the study was conducted in clinic number one, which is for new patients only. Only patients who were immediately diagnosed were included, as stated in the inclusion criteria. All of the patients in Clinic One were immediately diagnosed and had not previously received any lupus medication. In the thesis, we defined the drugs for lupus treatment as: Systemic Corticosteroids High doses (40 to60 mg/d of prednisone or prednisone equivalent) are used in patients with severe SLE. Doses of 10 mg/d or less are used for milder SLE for treatment of cutaneous and musculoskeletal symptoms not responding to other therapies. (Mehat et al., 2017) Immunosuppressants - Patients who are not responsive to anti-malarials or glucocorticoids should be considered for treatment with immunosuppressive agents for more severe manifestations of the disease (Bernknopf, 2015): • Methotrexate. (MTX) is a folic acid analog which inhibits the enzyme dihydrofolate reductase and, as consequences of the proliferation of T cell populations (Bernknopf, 2015). • Mycophenolate mofetil and mycophenolate sodium. Decreased activity of this enzyme affects proliferation of B and T lymphocytes induces apoptosis of activated T lymphocytes (Winkelmann, 2013). • Azathioprine. is the prodrug of 6- mercaptopurine, Side effects include bone-marrow toxicity, gastrointestinal symptoms and hepatotoxicity (Winkelmann, 2013). • Clofazimine. is an antibiotic with immunosuppressive and anti-inflammatory activity traditionally used in the treatment of leprosy (Winkelmann, 2013). BIOLOGIC AGENTS • Intravenous immunoglobulin (IVIG). IVIG is the product of pooling immunoglobulin G (IgG) immunoglobulins extracted from donor blood (Winkelmann, 2013). • Rituximab. Rituximab is a chimeric anti-CD20 monoclonal antibody that induces depletion of B cells through both antibody-dependent and independent pathways (Winkelmann, 2013). IMMUNOMODULATORS • Dapsone - Dapsone is a sulfone that inhibits dihydrofolic acid synthesis and exhibits both antibiotic and anti-inflammatory properties. • Thalidomide - The effects of thalidomide are attributed to the inhibition of TNF-alpha synthesis and UVB-induced keratinocyte apoptosis. • Lenalidomide - Lenalidomide is a structural analog of thalidomide with more potent immune-modulatory effects and a lower risk of polyneuropathy (Winkelmann, 2013). • \"The diagnosis of oral candidiasis was made by curd-like patches on the tongue or other oral mucosal surfaces, the presence of classic pseudomembranous lesions characterized by a creamy white pseudomembrane\" - was this confirmed by any culture or biopsy? According to Hopkins Lupus Cohort. The diagnosis of oral candidiasis was made by the presence of classic pseudomembranous lesions characterized by creamy white, curd-like patches on the tongue or on other oral mucosal surfaces. Oral candidiasis was defined at every visit by visual inspection of the oral cavity by one rheumatologist (Dr. Michelle Petri). Fangtham M, Magder LS, Petri MA. Oral candidiasis in systemic lupus erythematosus. Lupus. 2014; Results: • Table 1 should include an overall demographic data for all participants- age, sex, smoking, presence of oral lesions. Thank you for this constructive addition. • Table 1 should be Table 2. Thank you for this constructive addition. I should back to the editor in this point. • Figure 1 - would change to anatomical sites of oral lesions. How did the authors standardize the bounds of each lesion? according to the methodology, we follow the mentioned references in the clinical description and clinical site. Burket’s Oral Medicine, 12th Edition - Michael Glick - Google Books. Accessed August 23, 2021. https://books.google.com.eg/books?hl=en&lr=&id=cBEqCAAAQBAJ&oi=fnd&pg=PR1&dq=burket%E2%80%99s+oral+medicine.&ots=hkfOb1399V&sig=GjVjm9Gg5OGxOsyAph5UwMfx_XQ&redir_esc=y#v=onepage&q=burket%E2%80%99s%20oral%20medicine.&f=false • Figure 3: I am a bit confused about the inclusion of the data on the skin manifestations. Unless the authors have a specific hypothesis they would like to explore with this data, it seems out of place in this paper on oral lesions in SLE. Thank you for this constructive addition. According to your direction, We removed this part. • \"The sampled population was classified into two groups. LE patients who had an oral manifestation as true positive oral lesions (TP) and LE patients without oral manifestation as true negative oral lesions (TN).\" - I think this language is confusing, as they do not discover false positives or negatives in this study. I would change this to present or absent. Thank you for this constructive addition. According to your direction, We amend it. Discussion: • \"CLE patients weren’t found in the sampled population\" - they were excluded based on methods stated above. Thanks for your notification, but we didn’t exclude CLE. All the sampled patients had systemic involvement. • \"Interestingly, one of our patients reported symptoms of numbness and facial sensory impairment, which indicates the involvement of sensory ganglia of the cranial nerves. Loss of taste and dry mouth were reported as the first manifestation of SLE in this patient. The serological result reported that the antinuclear antibody was present in a titer of 1/320, and the CT scan examination of the brain revealed that the patient had had a stroke. This may be attributed to the autoimmune autoantibodies directed against sensory ganglion\": Thank you for this constructive addition, I removed the case. But, to clarify your doubts the patients was positive anti-phospholipid antibodies • \"In the current study, oral candidiasis was observed in 41% of all the patients. Moreover, (74.3%) patients had oral lesions superinfected by Candida.\" - this was based on appearance and not culture/biopsy? I think this needs to be removed as this is not confirmed Candida according to the methods. Thank you for this constructive addition, I removed this part. Conclusion: • The link to cancer is not substantiated by current evidence and needs to be removed. I agree that more research in diverse settings is critical. Do the authors have a citation for the claim that research is only conducted in 1 in 10 countries? All research? Research on SLE? If no citation please make a more broad statement. Thank you for this constructive addition, I amended this part. But to clarify your doubts, this was mentioned by another reviewer as only 1/10 of all countries in the world assessed the prevalence of oral manifestation in lupus erythematosus."
},
{
"c_id": "8015",
"date": "01 Apr 2022",
"name": "Hager Saeed",
"role": "Author Response",
"response": "I hope you're doing well. In accordance with your report, we have submitted the third version. If you have any further questions, please let us know so we will make the necessary changes. Thank you for the detailed instructions."
}
]
}
] | 1
|
https://f1000research.com/articles/10-969
|
https://f1000research.com/articles/11-615/v1
|
06 Jun 22
|
{
"type": "Study Protocol",
"title": "Reporting of health equity considerations in equity-relevant observational studies: Protocol for a systematic assessment",
"authors": [
"Omar Dewidar",
"Tamara Rader",
"Hugh Waddington",
"Stuart G Nicholls",
"Julian Little",
"Billie-Jo Hardy",
"Tanya Horsley",
"Taryn Young",
"Luis Gabriel Cuervo",
"Melissa K Sharp",
"Catherine Chamberlain",
"Beverley Shea",
"Peter Craig",
"Daeria O Lawson",
"Anita Rizvi",
"Charles Shey Wiysonge",
"Tamara Kredo",
"Miriam Nkangu Nguliefem",
"Elizabeth Ghogomu",
"Damian Francis",
"Elizabeth Kristjansson",
"Zulfiqar Bhutta",
"Alba Antequera Martin",
"G J Melendez-Torres",
"Tomas Pantoja",
"Xiaoqin Wang",
"Janet Jull",
"Janet Hatcher Roberts",
"Sarah Funnell",
"Howard White",
"Alison Krentel",
"Michael Johnson Mahande",
"Jacqueline Ramke",
"George A Wells",
"Jennifer Petkovic",
"Peter Tugwell",
"Kevin Pottie",
"Lawrence Mbuagbaw",
"Vivian Welch",
"Tamara Rader",
"Hugh Waddington",
"Stuart G Nicholls",
"Julian Little",
"Billie-Jo Hardy",
"Tanya Horsley",
"Taryn Young",
"Luis Gabriel Cuervo",
"Melissa K Sharp",
"Catherine Chamberlain",
"Beverley Shea",
"Peter Craig",
"Daeria O Lawson",
"Anita Rizvi",
"Charles Shey Wiysonge",
"Tamara Kredo",
"Miriam Nkangu Nguliefem",
"Elizabeth Ghogomu",
"Damian Francis",
"Elizabeth Kristjansson",
"Zulfiqar Bhutta",
"Alba Antequera Martin",
"G J Melendez-Torres",
"Tomas Pantoja",
"Xiaoqin Wang",
"Janet Jull",
"Janet Hatcher Roberts",
"Sarah Funnell",
"Howard White",
"Alison Krentel",
"Michael Johnson Mahande",
"Jacqueline Ramke",
"George A Wells",
"Jennifer Petkovic",
"Peter Tugwell",
"Kevin Pottie",
"Lawrence Mbuagbaw",
"Vivian Welch"
],
"abstract": "Background: The mitigation of unfair and avoidable differences in health is an increasing global priority. Observational studies including cohort, cross-sectional and case-control studies tend to report social determinants of health which could inform evidence syntheses on health equity and social justice. However, the extent of reporting and analysis of equity in equity-relevant observational studies is unknown. Methods: We define studies which report outcomes for populations at risk of experiencing inequities as “equity-relevant”. Using a random sampling technique we will identify 320 equity-relevant observational studies published between 1 January 2020 to 27 April 2022 by searching the MEDLINE database. We will stratify sampling by 1) studies in high-income countries (HIC) and low- and middle-income countries (LMIC) according to the World Bank classification, 2) studies focused on COVID and those which are not, 3) studies focused on populations at risk of experiencing inequities and those on general populations that stratify their analyses. We will use the PROGRESS framework which stands for place of residence, race or ethnicity, occupation, gender or sex, religion, education, socioeconomic status, social capital, to identify dimensions where inequities may exist. Using a previously developed data extraction form we will pilot-test on eligible studies and revise as applicable. Conclusions: The proposed methodological assessment of reporting will allow us to systematically understand the current reporting and analysis practices for health equity in observational studies. The findings of this study will help inform the development of the equity extension for the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) reporting guidelines.",
"keywords": [
"Observational studies",
"health equity",
"research reporting",
"research methodology",
"study design"
],
"content": "Introduction\n\nLess than a decade remains until the 2030 deadline set by the United Nations to meet the 17 Sustainable Development Goals1 aimed at global economic, social, and environmental transformation. One of the 17 goals, and a cross-cutting theme across several others,2 is health equity, defined as the absence of differences in health that are avoidable and unjust.3 The achievement of health equity as a priority has been widely endorsed by several international organizations4,5 and resonates with the moral imperative of social justice and recognition of human rights principles.\n\nA major challenge is the lack of evidence that includes thoughtful, rigorous collection of health equity data to inform program development and policymaking.6 In fact, global organizations such as the World Health Organization (WHO) and the Pan American Health Organization (PAHO) have called for the improvement of equity considerations in the reporting of research.7–10 Thus, the integration of health equity in research is needed in both primary and secondary research.11–14 In primary research, observational studies are particularly well-suited for investigating health equity as they often include populations at risk of experiencing inequities.15,16 Observational studies are analytical or descriptive studies evaluating a research question without changing exposure to an intervention.17 In the absence of a control group, they can be descriptive in nature but do not permit the investigation of causal associations.18 Observational studies predominate in health-related research,19,20 and are used to investigate numerous types of research questions, such as detecting rare or late adverse effects of treatments and to explore complex systems.21 Furthermore, observational studies have highlighted the vast inequities in society during the COVID-19 pandemic,22 and simultaneously, have had an important role in informing public health responses.23,24\n\nThe well-known STROBE (Strengthening Reporting of Observational studies in Epidemiology) reporting guideline, which is intended to be used for the reporting of observational studies, is used by over 60% of authors of observational studies.25 However, despite widespread use of the STROBE reporting guidelines, there is a persistent lack of integration and reporting of sex and gender (among other dimensions) in observational studies.26–28 Comprehensive reporting in research is essential to assess its reliability, reproducibility and methodological rigour, and ensure that the research meets the needs of the potential users.29 Using reporting guidelines contributes to meeting these goals by increasing the completeness and transparency of research papers.30–33 The inadequate reporting may be, in part, due to lack of guidance on reporting equity items in such studies.\n\nComplex health systems questions and addressing social determinants of health may require multi-stakeholder and intersectoral collaboration and engagement, for which equity perspectives can serve as a linchpin.34 Observational studies also allow for addressing questions on health policy, health systems, and health services organization, delivery, prioritization, and implementation.35–37 Different frameworks are available to describe factors associated with health equity.38,39 The Campbell and Cochrane Equity Methods Group, for example, proposes using the PROGRESS-Plus framework. This acronym is widely used and stands for Place of residence, Race or ethnicity, Occupation, Gender or sex, Religion, Education, Socioeconomic status, and Social capital.39 The “plus” accounts for additional characteristics that could result in inequitable health outcomes. Although the reporting on equity in observational research would increase the value of research outcomes through the recognition of how these dimensions impact interventions, the application and use of equity frameworks in reporting health research are not yet standard practice. Therefore, our objective is to systematically evaluate how equity-relevant observational studies describe characteristics of their samples, design features and analysis, and interpretation of their findings across PROGRESS-Plus; we also aim to use the findings of this study to inform the development of an equity reporting guideline.\n\n\nMethods\n\nFigure 1 outlines the overarching process to be followed in the conduct of this study; from identifying relevant studies at title and abstract stage to data extraction and analysis.\n\nWe will include health equity-relevant observational studies from all settings, published between 1 January 2020, and 27 April 2022. We define health equity, health equity-relevant studies and observational studies in Table 1. We chose to focus on equity-relevant studies, since these are most likely to have methods of describing populations experiencing inequities, and are most likely to include methods to assess similarities or differences in effects for populations experiencing inequities.\n\nWe will not include studies focused on Indigenous populations in this evaluation, as they will be assessed in a separate but complementary study led by Indigenous researchers as it will require a different sampling approach and methodological assessment. We decided not to use “Plus” criteria for eligibility since they require a greater deal of judgement regarding the contextual factors that may result in inequities. We will exclude case series and case reports since they do not include a reference population or comparison group enabling assessment of differences across PROGRESS factors.\n\nBased on consultation with our interdisciplinary team of researchers and decision-makers, and patients and public, we will use a three-factor, randomized sampling strategy to balance: 1) studies in high-income countries (HIC) and low- and middle-income countries (LMIC) according to the World Bank classification, 2) studies focused on COVID-19 and those which are not, 3) studies focused on populations experiencing inequities and those that stratify their analyses. We chose to stratify by country because of the importance of the context and resources in LMIC settings which affect health inequities both among LMIC and between LMIC and HIC,43–45 Given the evidence on exacerbation of inequities during the COVID-19 pandemic, we decided to ensure balance across studies related to COVID-19 and those that are not.46\n\nAlthough we chose only three factors for the sampling strategy, we will assess all aspects of PROGRESS-Plus in the included studies; thus other populations experiencing inequities will be included, such as people who are living with low income, homeless, migrants, asylum-seekers, and racialized individuals. Table 2 lists examples of studies that meet our eligibility criteria.\n\nWe will randomly select a sample of 320 equity-relevant observational studies, since assessing all potential eligible studies would be unmanageable for our review team. To ensure we assess a sample that provides comparable results, we conducted sample size calculation for binary outcomes (categorical questions for consideration of equity in the studies) with 95% confidence intervals of ± 6% for observed proportions of 50% (i.e. assuming that half of the studies would report at least one PROGRESS characteristic). This sample size has also been used in similar studies.56–59 We acknowledge that the study does not have sufficient power to allow a comparison of reporting across the three prioritized groups, so we will only report data descriptively. Eligible studies will be exported into Microsoft Excel and sorted using a random sequence using the built-in random-number generator. We will sample the studies as specified in Table 3.\n\nCOVID+: studies related to COVID-19, COVID-: studies not related to COVID-19. LMIC: Low-middle income countries, HIC: High Income countries.\n\nWe have designed a search strategy in collaboration with a librarian (TR) experienced in systematic reviews, using a method designed to optimize term selection.60 A validated search filter to identify equity-focused studies was adapted for use in this study,61 and additional terms to increase retrieval of papers about indigenous populations were added (lines 213-232).62,63 These were developed in collaboration with our Indigenous Steering Committee. Studies related to Indigenous populations will be identified from these search terms and will be utilized to conduct an independent but highly complementary study focused on Indigenous populations.\n\nWe used a validated search filter for observational studies with two extra terms to retrieve cross-sectional studies.64 We further added the terms “Instrumental variable”, “discontinuity design”, “interrupted time series”, “discontinuity design”, “matching”, “synthetic control” and “difference-in-difference” to our search strategy to ensure that we capture observational econometric studies that meet our eligibility criteria. Review articles and randomized controlled trials will be excluded from these results using validated study design filters for Ovid MEDLINE.65 The draft search strategy is stored in the Open Science Framework (OSF) repository (Extended data67). We will test the search strategy with a set of 10 studies that we identify to be eligible.\n\nWe will restrict our search to the last two years because we are interested in describing current analysis and reporting of equity, not trend over time. This period also captures the girth of the literature published throughout the pandemic. We conducted a preliminary search of Ovid MEDLINE for papers published between 1 January 2020, to 17 April 2022 and obtained 16,263 citations. Due to the high volume of results retrieved, we decided that searching only one database would be feasible. In the conduct of this study, we expect an adequate number of observational studies in this period to meet our eligibility criteria.\n\nStudies will be screened at title and abstract level by a single investigator using DistillerSR software.66 One investigator will screen the full texts of studies, and OD will validate. Conflicts will be resolved through discussion with a third reviewer at weekly meetings. We will use the DistillerSR randomization function to randomly sample citations at a set interval of 20% of unreviewed citations until we reach the planned sample size.\n\nAt full-text screening, we will tag eligible studies according to our prioritized topics (Type of equity relevance, country income setting, COVID-19 research).\n\nData will be extracted independently by two extractors. We will develop and pretest a data extraction form using DistillerSR. We will conduct training on the data collection with data extractors using sets of three to five studies at a time, until there is 80% agreement across all items between extractors. Conflicts will be resolved by discussion between extractors and reaching consensus. We will develop a data dictionary to ensure consistent extraction across team members and refine during pre-testing.\n\nWe will capture study characteristics including the purpose of the study (focused on populations experiencing inequities or whether the study included general populations in which there may be populations experiencing inequities), title/abstract, background/rationale, study design, population characteristics, results, analyses, interpretation of applicability and discussion. We will collect details on the motivation behind studies for a separate evaluation of the way equity is defined in these studies and the motivation for studying equity-seeking populations. The complete list of items is provided in our OSF repository (Extended data67).\n\nWe will assemble the author contact details for a separate survey of authors (of the included studies) to ask about engagement with populations experiencing inequities, since we believe that engagement with populations experiencing inequities informs better reporting on health equity. The reason for conducting the survey is because we expect that some of the results related to equity would not be well reported in the articles.\n\nWe will descriptively present the reporting of each item for the observational studies in our sample by tabulating the data for each item to assess the frequency of reporting. We will conduct subgroup analysis on studies that considered health equity as a reason for conducting the study.\n\nOur findings will be shared on pre-print servers and submitted for peer-review publication. In addition, we plan on sharing our findings on Twitter and at relevant conferences for wider dissemination.\n\n\nDiscussion\n\nThe primary objective of this study will be to describe the reporting and analysis of equity in equity-relevant observational studies. By focusing on studies that meet this criteria, we will document studies that have missed opportunities for providing information regarding populations at risk of experiencing inequities. Moreover, this exercise may help us identify examples of equity considerations in observational studies, according to our candidate items for the equity extension for STROBE reporting guideline, to illustrate how and to what extent they are presented in the literature.\n\nOur study is not without limitations. First, our search of only MEDLINE would be expected to yield studies mostly from HIC and focused on clinical topics. However, we plan to mitigate this selection bias by purposefully stratifying sampling across country income setting and randomly selecting a sample from the eligible studies. Second, although a third of early COVID-19 literature has been shared as preprints, we will not include studies from pre-print servers as studies in peer-review journal articles tend to show substantial improvements in the quality of reporting compared to pre-prints. Therefore, it may not be appropriate to pool preprints with peer-reviewed published articles. Future work could aim to investigate the difference in reporting of health equity in articles published in pre-print servers compared to peer-reviewed articles.\n\nThe proposed list of extraction items is extensive and provides several gateways for future projects to fill gaps in understanding the integration and reporting of equity in research. Using the results of this methodological assessment, we plan to conduct a sociological discourse analysis of motivation for assessing health equity in equity-relevant observational studies. In accordance with the plan for this extension, we will conduct an independent study on Indigenous research, led by Indigenous researchers, to identify and describe well-reported studies using the CONSIDER checklist. Furthermore, the selective sampling across prioritized groups provides an opportunity to conduct more focused investigations, tailored to each respective topic (i.e. LMIC, COVID-19 research).\n\n\nData availability\n\nNo data are associated with this protocol.\n\nOpen Science Framework: STROBE-equity reporting guidelines, https://osf.io/cp3z2.67\n\nThis project includes the following extended data:\n\n• Search strategy.docx\n\n• Extraction items mapped to the STROBE-Equity candidate items.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe would like to acknowledge our partners and collaborators on the STROBE-Equity team.\n\nIndigenous Research Steering Committee: Catherine Chamberlain (Australia), Sarah Funnell (Canada), Billie-Jo Hardy (Canada), Matire Harwood (Aotearoa New Zealand), Michelle Kennedy (Australia).\n\nPatients and Public Steering Committee: Holly Ellingwood (Canada), Regina Greer-Smith (USA), Clara Juando-Prats (Canada), Janet Jull (Canada), Bev Shea (Canada), Janice Tufte (USA).\n\nKnowledge Users Steering Committee: Marc Avey (Canada), Luis Gabriel Cuervo (USA), Tanya Horsley (Canada), Tamara Kredo (South Africa), Elizabeth Loder (USA), Melissa Sharp (Ireland), Laura Weeks (Canada), Howard White (UK).\n\nTechnical Oversight Committee: Elie A. Akl (Lebanon), Alba Antequera (Barcelona (Spain)), Zulfiqar A. Bhutta (Canada), Peter Craig (Scotland), Omar Dewidar (Canada), Alassane Dicko (Canada), Cindy Feng (Canada), Isabel Fortier (Canada), Damian Francis (USA), Elizabeth Ghogomu (Canada), Janet Hatcher-Roberts (Canada), Alison Krentel (Canada), Elizabeth Kristjansson (Canada), Laurenz Langer (South Africa), Daeria O. Lawson (Canada), Julian Little (Canada), Olivia Magwood (Canada), Michael Johnson Mahande (Tanzania), Lawrence Mbuagbaw (Canada), G.J. Melendez- Torres (UK), David Moher (Canada), Ainsley Moore (Canada), Loveline Lum Niba (Cameroon), Stuart G. Nicholls (Canada), Miriam Nkangu (Canada), Stephen G. Noorduyn (Canada), Ekwaro Obuku (Uganda), Patrick M. Okwen (Cameroon), Tomas Pantoja (Chile), Jennifer Petkovic (Canada), Mark Petticrew (UK), Kevin Pottie (Canada), Tamara Rader (Canada), Jacqueline Ramke (Aotearoa New Zealand), Alison Riddle (Canada), Larissa Shamseer (Canada), Hugh Sharma Waddington (UK), Peter Tanuseputro (Canada), Peter Tugwell (Canada), Erik Von Elm (Switzerland), Harry Wang (Canada), Xiaoqin Wang (Canada), George Wells (Canada), Charles S. Wiysonge (South Africa), Luke Wolfenden (Australia), Taryn Young (South Africa).\n\nAll the team members have consented to be listed in the manuscript.\n\n\nReferences\n\nDecade of Action - United Nations Sustainable Development: United Nations. http\n\nSDG 10: Health and reduced inequalities. World Health Organization Regional Office for Europe.Reference Source\n\nWhitehead M: The concepts and principles of equity and health. Int. J. Health Serv. 1992; 22(3): 429–445. Publisher Full Text\n\nBraveman PA, Kumanyika S, Fielding J, et al.: Health disparities and health equity: the issue is justice. Am. J. Public Health. 2011; 101 Suppl 1: S149–S155. PubMed Abstract | Publisher Full Text\n\nPottie K, Welch V, Morton R, et al.: GRADE equity guidelines 4: considering health equity in GRADE guideline development: evidence to decision process. J. Clin. Epidemiol. 2017; 90: 84–91. PubMed Abstract | Publisher Full Text\n\nWelch V, Dewidar O, Tanjong Ghogomu E, et al.: How effects on health equity are assessed in systematic reviews of interventions. Cochrane Database Syst. Rev. 2022; 2022(1): Mr000028. Publisher Full Text\n\nThe WHO strategy on research for health. World Health Organization;2012.Reference Source\n\nThirteenth General Programme of Work 2019-2023. World Health Organization.Reference Source\n\nEtienne C, Abbasi K, Cuervo LG: Research for health in the Americas. BMJ. 2018; 362: k2944. Publisher Full Text\n\nPromoting health equity, gender and ethnic equality, and human rights in COVID-19 responses: Key considerations. Pan American Health Organization;2020.Reference Source\n\nBrownson RC, Kumanyika SK, Kreuter MW, et al.: Implementation science should give higher priority to health equity. Implement. Sci. 2021; 16(1): 28. PubMed Abstract | Publisher Full Text\n\nWelch VA, Norheim OF, Jull J, et al.: CONSORT-Equity 2017 extension and elaboration for better reporting of health equity in randomised trials. BMJ. 2017; 359: j5085. Publisher Full Text\n\nWelch V, Petticrew M, Tugwell P, et al.: PRISMA-Equity 2012 extension: reporting guidelines for systematic reviews with a focus on health equity. PLoS Med. 2012; 9(10): e1001333. PubMed Abstract | Publisher Full Text\n\nWelch VA, Akl EA, Guyatt G, et al.: GRADE equity guidelines 1: considering health equity in GRADE guideline development: introduction and rationale. J. Clin. Epidemiol. 2017; 90: 59–67. PubMed Abstract | Publisher Full Text\n\nMarmot M, Bell R: The Sustainable Development Goals and Health Equity. Epidemiology. 2018; 29(1): 5–7. Publisher Full Text\n\nAntequera A, Lawson DO, Noorduyn SG, et al.: Improving Social Justice in COVID-19 Health Research: Interim Guidelines for Reporting Health Equity in Observational Studies. Int. J. Environ. Res. Public Health. 2021; 18(17). PubMed Abstract | Publisher Full Text\n\nReeves BC, Deeks JJ, Higgins JP, et al.:Chapter 24: Including non-randomized studies on intervention effects.Higgins JPT, Thomas J, Chandler J, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions. Cochrane;2021. version 6.2 (updated February 2021).\n\nGrimes DA, Schulz KF: An overview of clinical research: the lay of the land. Lancet. 2002; 359(9300): 57–61. PubMed Abstract | Publisher Full Text\n\nFunai EF, Rosenbush EJ, Lee MJ, et al.: Distribution of study designs in four major US journals of obstetrics and gynecology. Gynecol. Obstet. Investig. 2001; 51(1): 8–11. PubMed Abstract | Publisher Full Text\n\nScales CD, Norris RD, Peterson BL, et al.: Clinical research and statistical methods in the urology literature. J. Urol. 2005; 174(4 Pt 1): 1374–1379. Publisher Full Text\n\nvon Elm E , Altman DG, Egger M, et al.: Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007; 335(7624): 806–808. PubMed Abstract | Publisher Full Text\n\nGlover RE, van Schalkwyk MCI , Akl EA, et al.: A framework for identifying and mitigating the equity harms of COVID-19 policy interventions. J. Clin. Epidemiol. 2020; 128: 35–48. PubMed Abstract | Publisher Full Text\n\nTenforde MW, Fisher KA, Patel MM: Identifying COVID-19 Risk Through Observational Studies to Inform Control Measures. JAMA. 2021; 325(14): 1464–1465. PubMed Abstract | Publisher Full Text\n\nGuidance for implementing non pharmacological public health measures in populations in situations of vulnerability in the context of COVID-19. Pan American Health Organization;2020.Reference Source\n\nSharp MK, Bertizzolo L, Rius R, et al.: Using the STROBE statement: survey findings emphasized the role of journals in enforcing reporting guidelines. J. Clin. Epidemiol. 2019; 116: 26–35. PubMed Abstract | Publisher Full Text\n\nDewidar O, Podinic I, Barbeau V, et al.: Integrating sex and gender in studies of cardiac resynchronization therapy: a systematic review. ESC Heart Fail. 2022; 9(1): 420–427. PubMed Abstract | Publisher Full Text\n\nPark H, Dewidar O, Tanjong-Ghogomu E, et al.: Reporting and analysis of Sex and Gender in Transitions of Care for Older Adults: A Methods Study. University of Ottawa. J. Med. 2022; 11(2). Publisher Full Text\n\nJahn I, Börnhorst C, Günther F, et al.: Examples of sex/gender sensitivity in epidemiological research: results of an evaluation of original articles published in JECH 2006–2014. Health Res. Policy Syst. 2017; 15(1): 11. PubMed Abstract | Publisher Full Text\n\nSimera I, Moher D, Hirst A, et al.: Transparent and accurate reporting increases reliability, utility, and impact of your research: reporting guidelines and the EQUATOR Network. BMC Med. 2010; 8: 24. PubMed Abstract | Publisher Full Text\n\nJin Y, Sanger N, Shams I, et al.: Does the medical literature remain inadequately described despite having reporting guidelines for 21 years? - A systematic review of reviews: an update. J. Multidiscip. Healthc. 2018; 11: 495–510. PubMed Abstract | Publisher Full Text\n\nStevens A, Shamseer L, Weinstein E, et al.: Relation of completeness of reporting of health research to journals' endorsement of reporting guidelines: systematic review. BMJ. 2014; 348: g3804. PubMed Abstract | Publisher Full Text\n\nMünter NH, Stevanovic A, Rossaint R, et al.: CONSORT item adherence in top ranked anaesthesiology journals in 2011: A retrospective analysis. Eur. J. Anaesthesiol. 2015; 32(2): 117–125. Publisher Full Text\n\nTurner L, Shamseer L, Altman DG, et al.: Does use of the CONSORT Statement impact the completeness of reporting of randomised controlled trials published in medical journals? A Cochrane review. Syst. Rev. 2012; 1: 60. PubMed Abstract | Publisher Full Text\n\nChircop A, Bassett R, Taylor E: Evidence on how to practice intersectoral collaboration for health equity: a scoping review. Crit. Public Health. 2015; 25(2): 178–191. Publisher Full Text\n\nCiapponi A, Lewin S, Herrera CA, et al.: Delivery arrangements for health systems in low-income countries: an overview of systematic reviews. Cochrane Database Syst. Rev. 2017; 2017. Publisher Full Text\n\nPantoja T, Opiyo N, Lewin S, et al.: Implementation strategies for health systems in low-income countries: an overview of systematic reviews. Cochrane Database Syst. Rev. 2017; 2017(9): Cd011086. Publisher Full Text\n\nWiysonge CS, Paulsen E, Lewin S, et al.: Financial arrangements for health systems in low-income countries: an overview of systematic reviews. Cochrane Database Syst. Rev. 2017; 2017(9): Cd011084. Publisher Full Text\n\nGender-based analysis plus (GBA+). Government of Canada;Reference Source\n\nO'Neill J, Tabish H, Welch V, et al.: Applying an equity lens to interventions: using PROGRESS ensures consideration of socially stratifying factors to illuminate inequities in health. J. Clin. Epidemiol. 2014; 67(1): 56–64. PubMed Abstract | Publisher Full Text\n\nJull J, Whitehead M, Petticrew M, et al.: When is a randomised controlled trial health equity relevant? Development and validation of a conceptual framework. BMJ Open. 2017; 7(9): e015815. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: European Observatory on Health Systems and Policies. Glossary. 2009.\n\nBenchimol EI, Smeeth L, Guttmann A, et al.: The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. PLoS Med. 2015; 12(10): e1001885. PubMed Abstract | Publisher Full Text\n\nOrach CG: Health equity: challenges in low income countries. Afr. Health Sci. 2009; 9 Suppl 2: S49–S51. PubMed Abstract\n\nFreeman T, Gesesew HA, Bambra C, et al.: Why do some countries do better or worse in life expectancy relative to income? An analysis of Brazil, Ethiopia, and the United States of America. Int. J. Equity Health. 2020; 19(1): 202. PubMed Abstract | Publisher Full Text\n\nKruk ME, Gage AD, Joseph NT, et al.: Mortality due to low-quality health systems in the universal health coverage era: a systematic analysis of amenable deaths in 137 countries. Lancet. 2018; 392(10160): 2203–2212. PubMed Abstract | Publisher Full Text\n\nBambra C, Riordan R, Ford J, et al.: The COVID-19 pandemic and health inequalities. J. Epidemiol. Community Health. 2020; 74(11): 964–968. PubMed Abstract | Publisher Full Text\n\nWang F, Cao J, Yu Y, et al.: Epidemiological characteristics of patients with severe COVID-19 infection in Wuhan, China: evidence from a retrospective observational study. Int. J. Epidemiol. 2021; 49(6): 1940–1950. PubMed Abstract | Publisher Full Text\n\nPartnership A-S: Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study. Lancet. 2020; 396(10265): 1829–1840. Publisher Full Text\n\nTromans S, Chester V, Harrison H, et al.: Patterns of use of secondary mental health services before and during COVID-19 lockdown: observational study. BJPsych Open. 2020; 6(6): e117. PubMed Abstract | Publisher Full Text\n\nBarua R, Lang K: School Entry, Educational Attainment, and Quarter of Birth: A Cautionary Tale of a Local Average Treatment Effect. J. Hum. Cap. 2016; 10(3): 347–376. Publisher Full Text\n\nBaqui P, Bica I, Marra V, et al.: Ethnic and regional variations in hospital mortality from COVID-19 in Brazil: a cross-sectional observational study. Lancet Glob. Health. 2020; 8(8): e1018–e1026. PubMed Abstract | Publisher Full Text\n\nFagbamigbe AF, Kandala NB, Uthman AO: Demystifying the factors associated with rural–urban gaps in severe acute malnutrition among under-five children in low- and middle-income countries: a decomposition analysis. Sci. Rep. 2020; 10(1): 11172. PubMed Abstract | Publisher Full Text\n\nLazarus JV, Wyka K, Rauh L, et al.: Hesitant or Not? The Association of Age, Gender, and Education with Potential Acceptance of a COVID-19 Vaccine: A Country-level Analysis. J. Health Commun. 2020; 25(10): 799–807. Publisher Full Text\n\nZakeri R, Bendayan R, Ashworth M, et al.: A case-control and cohort study to determine the relationship between ethnic background and severe COVID-19. EClinicalMedicine. 2020; 28: 100574. PubMed Abstract | Publisher Full Text\n\nSamuels EA, Orr L, White EB, et al.: Health Care Utilization Before and After the “Muslim Ban” Executive Order Among People Born in Muslim-Majority Countries and Living in the US. JAMA Netw. Open. 2021; 4(7): e2118216-e. PubMed Abstract | Publisher Full Text\n\nPetkovic J, Jull J, Yoganathan M, et al.: Reporting of health equity considerations in cluster and individually randomized trials. Trials. 2020; 21(1): 308. PubMed Abstract | Publisher Full Text\n\nPage MJ, Shamseer L, Altman DG, et al.: Epidemiology and Reporting Characteristics of Systematic Reviews of Biomedical Research: A Cross-Sectional Study. PLoS Med. 2016; 13(5): e1002028. PubMed Abstract | Publisher Full Text\n\nTaljaard M, McRae AD, Weijer C, et al.: Inadequate reporting of research ethics review and informed consent in cluster randomised trials: review of random sample of published trials. BMJ. 2011; 342: d2496. PubMed Abstract | Publisher Full Text\n\nMoher D, Tetzlaff J, Tricco AC, et al.: Epidemiology and reporting characteristics of systematic reviews. PLoS Med. 2007; 4(3): e78. PubMed Abstract | Publisher Full Text\n\nBramer WM, de Jonge GB , Rethlefsen ML, et al.: A systematic approach to searching: an efficient and complete method to develop literature searches. J. Med. Libr. Assoc. 2018; 106(4): 531–541. PubMed Abstract | Publisher Full Text\n\nPrady SL, Uphoff EP, Power M, et al.: Development and validation of a search filter to identify equity-focused studies: reducing the number needed to screen. BMC Med. Res. Methodol. 2018; 18(1): 106. PubMed Abstract | Publisher Full Text\n\nUmaefulam V, Kleissen T, Barnabe C: The representation of Indigenous peoples in chronic disease clinical trials in Australia, Canada, New Zealand, and the United States. Clin. Trials. 2022; 19(1): 22–32. PubMed Abstract | Publisher Full Text\n\nUpadhyay N, Aparasu R, Rowan PJ, et al.: The association between geographic access to providers and the treatment quality of pediatric depression. J. Affect. Disord. 2019; 253: 162–170. PubMed Abstract | Publisher Full Text\n\nStudy design search filters: BMJ Best Practice.Reference Source\n\nSearch Filters for MEDLINE in Ovid Syntax and the PubMed translation. McMaster University.Reference Source\n\nDistillerSR: Version 2.35. Evidence Partners.2022. Accessed May 25 2022.Reference Source\n\nDewidar O, Welch V, Rizvi A: STROBE-Equity methods study.2022, May 26. Publisher Full Text"
}
|
[
{
"id": "151179",
"date": "16 Dec 2022",
"name": "Khic-Houy Prang",
"expertise": [
"Reviewer Expertise Health services and systems research",
"evaluation and implementation science",
"mixed-methods research"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to read your study protocol which aims to develop a health equity reporting guideline for observational studies. I commend the authors on undertaking an ambitious review across diverse settings and population groups to identify health equity relevant items. Further clarifications about the health equity definition, inclusion and exclusion criteria of the review are required.\nI agree that health equity is important to capture in observational studies, however health equity is rather a difficult construct to measure that embody many social determinants and individual factors that influence access to care and ultimately health outcomes. I am unclear how you will differentiate between health equity studies and non-health equity studies. Most (if not all) observational studies will generally include a demographic table of their sample, as such based on your inclusion criteria then all studies would be considered a health equity-relevant study? I am not sure whether sub-group analysis will be enough to identify health equity studies as these studies may reflect health disparity? How will you differentiate between health equity and health disparity studies? Perhaps it might help to narrow the focus to intersectionality analysis?\n\nThe definition of population at risk of experiencing inequities is broad and includes all type of population. It would be difficult to identify as this is likely to be dependent on the disease and the context, and the comparison group. Will all the LMICs studies automatically be considered a population at risk because of the setting? What about specific population groups in HICs? You gave some examples of at-risk groups such as migrants and asylum seekers. Will it be worth considering at the outset who these groups are and narrow the scope of the review?\n\nCan you clarify why you chose PROGRESS Plus over other health equity frameworks to guide the review?\n\nThe inclusion criteria are observational studies and observational econometric studies. What about quasi-experimental and natural experiment studies given the focus on COVID studies?\n\nThe proposed review includes a systematic search approach but does not include any quality assessment or risk of bias. Could you please clarify what type of review this is?\n\nIs there a chance that you may missed studies using only one search engine? What about the grey literature? Will limiting the time period to two years (2020-2022) skew your search to predominantly COVID studies given the prioritisation of COVID studies published during this period over non-COVID studies?\n\nGiven that your research question is rather broad and does not focus on a specific population groups, interventions or health outcomes, the search strategy is rather complex. It seems to be based on the factors in the PROGRESS framework, I wonder if it would be useful to limit the search to observational study designs and heath equity-related terms, although noting that studies without using health equity-related terms will unlikely be picked up in the search. Given that the focus of the study is on health equity specifically, then perhaps it may be better to focus on such studies and describe what these studies have reported? Best practice for systematic and scoping reviews involves two investigators screening the full text articles.\n\nThere are almost 40 authors listed in the paper. This seems excessive for a protocol paper, with most of the authors’ contribution limited to reviewing and editing. Do all members in each of the committees warrants authorship?\n\nMinor edits: A typo in figure 1 ‘experiencing inequities’. In tables 2 and 3, it would be helpful perhaps to not use ‘COVID +’ or ‘COVID –‘ as the headers as it appeared to denote COVID studies with positive or negative results, perhaps COVID-related studies and non-COVID related studies may be more suitable? Reference required on page 7 regarding the survey - ‘ […] that engagement with populations experiencing inequities inform better reporting on health equity’.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "183191",
"date": "17 Aug 2023",
"name": "Ihoghosa Iyamu",
"expertise": [
"Reviewer Expertise Health services research",
"Digital health equity",
"sexual health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThanks for the opportunity to review this study protocol. It focuses on an important topic of health equity analyses and reporting in scientifica articles and this is very important. There are however opportunities to provide additional detail that can improve the quality and replicability of the study.\nMy comments are outlined as major and minor comments below:\nMajor comments\n\nThere appears to be a struggle to balance feasibility with rigour and the idea of a comprehensive study. For example, while the authors note their intent to search only one database as a limitation, I wonder if it makes sense to have a more specific question that allows the team search more databases to ensure a less biased sampling frame for the study. The Cochrane group recommends searching Embase and Medline at least, in addition to other registries. https://training.cochrane.org/handbook/current/chapter-04\nIf the questions are more specific, that might be achieved.\n\nMore specific details are needed for the screening procedures. Are the authors screening all the 16,000 plus titles and abstracts returned in the search, is there some automation going into the screening process especially because the authors use DistillerSR? Further, some studies do stratified analyses of outcomes as sub-analyses but may not include this in the abstract. Are there chances that your current approach and framing of the questions may miss these sort of studies? What is the protocol to ensure that papers of interest are not inadvertently excluded due to the current strategy. On the random sampling, it would also be great to know if this is a sampling with replacement or not.\n\nThe authors describe a follow-up survey as part of this study but only do so in passing. Questions about the survey include; What kinds of questions will you be asking? Is it a simple \"did you engage with populations experiencing inequities?\", How do you define engagement? What will be your threshold for saying engagement was done or not done? More information is required for clarity on this.\n\nOne also wonders why only a 2 year window was chosen for the study. One wonders if the last 2 years appropriately capture scientific practices and protocols or if this period is greatly biased by COVID and not necessarily reflective of the spectrum of practices within the scientific community. For example, were engagements with historically marginalized communities not altered during the pandemic? How is that reflected in the studies included?\n\nOne is not sure about the framework being adhered to in this study. For example, is there a PRISMA guideline or something similar that this largely follows?\nMinor comments\n\nThe first instance of \"equity-relevant\" studies should be accompanied by a reference to the definition. This was only done later and could be confusing.\n\nWhat is the justification for 80% agreement? What would that amount to in terms of say a Cohen's Kappa or some other standardized form of agreement metrics?\n\nAuthors state they will only use the PROGRESS framework, but in sections of the manuscript, they refer to PROGRESS-Plus\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-615
|
https://f1000research.com/articles/11-614/v1
|
06 Jun 22
|
{
"type": "Genome Note",
"title": "The complete genome sequence of elite bread wheat cultivar, “Sonmez”",
"authors": [
"Bala Ani Akpinar",
"Philippe Leroy",
"Nathan Watson-Haigh",
"Ute Baumann",
"Valerie Barbe",
"Hikmet Budak",
"Bala Ani Akpinar",
"Philippe Leroy",
"Nathan Watson-Haigh",
"Ute Baumann",
"Valerie Barbe"
],
"abstract": "High-yielding crop varieties will become critical in meeting the future food demand in the face of worsening weather extremes and threatening biotic stressors. The bread wheat cultivar Sonmez-2001 is a registered variety that is notable for its performance under low-irrigation conditions, which further improves upon irrigation. Additionally, Sonmez-2001 is resilient against certain biotic stressors, particularly soil-borne pathogens. Here, we provide a reference-guided whole genome sequence of Sonmez-2001, assembled into 21 chromosomes of the A, B and D genomes and totaling 13.3 gigabase-pairs in length. Additionally, a de novo assembly of an additional 1.05 gigabase-pairs was generated that represents either Sonmez-specific sequences or sequences that considerably diverged between Sonmez and Chinese Spring. Within this de novo assembly, we identified 35 gene models, of which 11 were high-confidence, that may contribute to the favorable traits of this high-performing variety. We identified up to 24 million sequence variants, of which up to 2.4% reside in coding sequences, that can be used to develop molecular markers that should be of immediate use to the cereal community.",
"keywords": [
"Wheat",
"genome sequencing",
"Triticum aestivum",
"yield",
"Sonmez"
],
"content": "Introduction\n\nTriticum aestivum cv. Sonmez-2001 (Sonmez, hereafter) is a registered, elite bread wheat variety that has been bred particularly for drylands. Accordingly, Sonmez exhibits remarkable tolerance against drought and performs considerably better than its ancestor, Bezostaya-1, in terms of yield, stress tolerance and disease resistance. Sonmez variety is notable for high yield and grain quality, building up to ≈15% protein content, under rain-fed conditions, both of which further improve with supplemental irrigation. Sonmez is also highly resistant against causal agents of devastating diseases, in particular, cereal cyst nematode and yellow rust. Sonmez has superior resistance against soil-borne pathogens and exhibit good tolerance against diseases affecting leaves and inflorescence. Due to these attributes, Sonmez is the cultivar of choice for most of the Central Anatolian Plateau. Facing a fast-growing world population, estimated to reach over 9 billion people in the next three decades, and changing climate trends with destructive effects on agriculture, securing the food demand of upcoming generations will require extensive improvements in crop yields. With cereals being the staple food for the developing world, Sonmez is a promising candidate that can contribute to meeting this demand. Here, we report a reference-guided sequence of the Sonmez genome, and its comparative analysis with the reference species, Triticum aestivum genotype Chinese Spring, for which extensive data, including a high-quality genome sequence, is available.\n\n\nMethods\n\nA paired-end (PE) library with an insert size of 350 base-pair was produced and sequenced on Illumina HiSeq 4000 platform at Genoscope, National Center of Sequencing, (Évry-Courcouronnes, France), generating almost 3.3 billion 2×150 bp reads. The 970.6 gigabase-pair (Gbp) of PE reads passing quality filters were mapped against the T. aestivum Chinese Spring (CS) RefSeq v1.0 genome1 in a two-step approach. In the first step, an ungapped alignment was performed using BioKanga v3.4.5 using default parameters but allowing for two mismatches per 100 bp (--substitutions=2). In the second step, the unmapped reads were mapped with Bowtie2 v2.3.0,2 allowing a single insertion/deletion of length ≤ 9 bp with zero mismatches (--very-sensitive --ignore-quals --mp 999,999 --np 999 --rdg 10,1 --rfg 10,1 --score-min L,-19,0 --n-ceil L,0,0). Read alignments from both mapping steps were merged using Sambamba v0.6.5.3 Regions containing read alignments with insertions/deletions were identified and re-aligned using GATK v3.7 using default parameters with minor modifications (LODThresholdForCleaning=0.4 defaultBaseQualities=30).\n\nSequence variations, including single nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms (indels) were called by BCFtools v1.3.1 on pileups generated by SAMtools v1.3.1.4 Homozygous SNP and indel variants were identified using GATK’s SelectVariants to retain only variants with no support for the CS reference allele at a series of read depth thresholds (1, 5, 10, 20, 30 and 40). BEDTools v2.26.0 intersect tool was used to identify intersects between gene annotation coordinate ranges and the identified variants. Homozygous variants were analysed by SNPeff v4.3i5 to estimate their impact in the context of the CS RefSeq v1.0 High Confidence gene annotations, excluding intergenic regions (-no-intergenic). Using all identified homozygous variants, we recalled the reference to generate a “Sonmez genome sequence v1.0”. Where there was no coverage of the CS reference, we softmasked the Sonmez genome sequence. It should be noted that these softmasked bases could represent regions which are either deletions in Sonmez or insertions in CS.\n\nFinally, the read pairs that remained unmapped following the two-step alignment approach were assembled de novo to uncover Sonmez-specific genomic contigs. k-mers of length 71 bp and occurring ≥ 9 times in the unmapped reads were extracted using KMC v3.0.1.6 These extracted k-mers were assembled into contigs using merutensils v0.7.15 kextend command; contigs < 250 bp in length were filtered out. This assembly approach ensures that contig extension only occurs if there is an unambiguous 1 bp extension possible in the input k-mer data set. Methylobacterium are well documented, common contaminants of reagents used in Illumina sequencing. As such, contigs showing high sequence identity to one of several Methylobacterium genomes (NZ_CP006992.1, NC_010511.1, NZ_CP017640.1, CP001029.1, AP014813.1, AP014810.1) or phiX (NC_001422.1) were also filtered out. These de novo assembled sequences are referred as “Sonmez-specific contigs” hereafter.\n\n\nResults\n\nIn total, 13.3 Gbp (91.51%) of the 14.5 Gbp CS reference genome assembly were covered by Sonmez reads, with a mean depth of coverage of ≈50×, enabling an almost complete, first construction of the Sonmez genome. Additionally, sequences that are either unique to Sonmez (e.g. introgressions) or significantly divergent compared to CS were used to build up a de novo assembly. This assembly totaled 1.05 Gbp in length, with the longest contig being 15,887 bp (N50=427 bp, N90=269 bp). An updated version (v5.3p01) of the TriAnnot pipeline7 optimized for wheat was used to generate similarity-based and ab initio gene models and annotate repetitive elements on contigs that are longer than 10 kilobases. While the de novo assembly was highly fragmented, compared to the recalled Sonmez genome, we were still able to pick up 35 gene models, of which 11 were high-confidence (Extended data8).\n\nWe identified between 3.15 – 23.96 million variants, depending on the coverage threshold used, of which between 0.03 – 3.23% were indel variants (Extended data9,10). We found that 1.47 – 2.39% of all variants fell within the RefSeq v1.0 High Confidence gene annotations (Extended data9). Of these, approx. 40% fell within coding regions. Of the homozygous variants supported by ≥ 5 reads, we observed approximately one variant per 500 bp in the A and B genomes and approximately one variant per 4,000 bp in the D genome.\n\nHere, we present the complete genome of the elite wheat variety Sonmez, notable for its performance under low-irrigation conditions. In the face of climatic extremes and other factors that challenge the food safety of upcoming generations, genome sequences of multiple genotypes, varieties and close relatives will not only help us understand complex traits, such as yield and stress responses, but also enable us to efficiently explore the genetic diversity within germplasms for favorable genotypes and/or traits for crop improvement through the use of molecular tools.\n\n\nData availability\n\nSonmez complete genome sequence v1.0 and de novo assembly are available from the dedicated URGI database.\n\nFigshare: Sonmez_Extended_Data1, https://doi.org/10.6084/m9.figshare.16992337.8\n\nThis project contains the following extended data:\n\n- Extended_data1_Sonmez_TriAnnotAnalysis_v1.xlsx (Gene models and repeat annotations of Sonmez-specific contigs)\n\nFigshare: Sonmez_Extended_Data2, https://doi.org/10.6084/m9.figshare.16992322.v3.9\n\nThis project contains the following extended data:\n\n- Extended_data2_Sonmez_vs_CS_variantsummary_v1.pdf (Summary information of sequence variants between Sonmez and CS)\n\nFigshare: Sonmez_Extended_Data3, https://doi.org/10.6084/m9.figshare.16992388.v2.10\n\nThis project contains the following extended data:\n\n- Sonmez.alt_fasta.vcf. (Homozygous SNP/indel variants identified between Sonmez and CS)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe acknowledge BFF for supporting science for 20 years. Their advocacy for unwavering belief, has been invaluable in integrating and transferring data to knowledge.\n\n\nReferences\n\nIWGSC: Shifting the limits in wheat research and breeding using a fully annotated reference genome. Science 2018; 361(6403). PubMed Abstract | Publisher Full Text\n\nLangmead B, Salzberg S: Fast gapped-read alignment with Bowtie 2. Nat. Methods 2012; 9: 357–359. PubMed Abstract | Publisher Full Text\n\nTarasov A, Vilella AJ, Cuppen E, et al.: Sambamba: fast processing of NGS alignment formats. Bioinformatics 2015; 31(12): 2032–2034. PubMed Abstract | Publisher Full Text\n\nDanecek P, Bonfield JK, Liddle J, et al.: Twelve years of SAMtools and BCFtools. GigaScience. 2021; 10(2): giab008. PubMed Abstract | Publisher Full Text\n\nCingolani P, Platts A, Wang le L, et al.: A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 2012; 6(2): 80–92. Publisher Full Text\n\nKokot M, Dlugosz M, Deorowicz S: KMC 3: counting and manipulating k-mer statistics. Bioinformatics 2017; 33(17): 2759–2761. PubMed Abstract | Publisher Full Text\n\nLeroy P, Guilhot N, Sakai H, et al.: TriAnnot: A Versatile and High Performance Pipeline for the Automated Annotation of Plant Genomes. Front. Plant Sci. 2012; 3: 5. PubMed Abstract | Publisher Full Text\n\nExtended Data 1: Gene models and repeat annotations of Sonmez-specific contigs. DOI: 10.6084/m9.figshare.16992337\n\nExtended Data 2: Summary information of sequence variants between Sonmez and CS. Figshare. DOI: 10.6084/m9.figshare.16992322\n\nExtended Data 3: Homozygous SNP/indel variants identified between Sonmez and CS. Figshare. DOI: 10.6084/m9.figshare.16992388"
}
|
[
{
"id": "140014",
"date": "13 Jun 2022",
"name": "Søren K. Rasmussen",
"expertise": [
"Reviewer Expertise Molecular plant breeding",
"quality traits",
"plant genetic resources",
"grain cereals and legumes"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nA draft genome sequence of the hexaploidy wheat ‘Sonmez’, a Turkish wheat bread cultivar, is presented. A large number of sequence variants are identified, and as expected the highest density of these putative SNP markers are located on the A- and B-genome and much lower number on the D-genome. This can facilitate efficient markers-assisted selection taking advantage of Sonmez drought tolerance as emphasized.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Yes",
"responses": []
},
{
"id": "140013",
"date": "13 Jun 2022",
"name": "Zahide Neslihan Öztürk Gökçe",
"expertise": [
"Reviewer Expertise Transcriptomics of abiotic stress tolerance"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the article, the authors performed reference-guided whole genome sequencing of an elite wheat cultivar Sonmez having high yield under stress conditions and specified with resistance against some biotic factors. The data are well presented and the information provided will be of great use for scientific community in the development of abiotic stress resilient wheat cultivars. Therefore my recommendation is to be accepted for indexing as it is. Best regards\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Yes",
"responses": []
},
{
"id": "140015",
"date": "24 Jun 2022",
"name": "Gabriel Doredo Perez",
"expertise": [
"Reviewer Expertise Molecular biology."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript “The complete genome sequence of elite bread wheat cultivar, “Sonmez””, published on F1000Research by Akpinar et al, is an interesting work on structural genomics, covering both re-sequencing of 21 chromosomes of the A, B and D genomes (13.3 Gbp), as well as de novo sequencing (1.05 Gbp). Such latter interesting result represents either Sonmez-specific sequences, or sequences that considerably diverged between Sonmez and Chinese Spring (used as reference genome). The de novo assembly identified 35 gene models, of which 11 were annotated with high-confidence, that may contribute to the favorable traits of this variety. A total of 24 million sequence variants were identified, of which up to 2.4% reside in coding sequences.\nInterestingly, the Sonmez cultivar is resilient against certain biotic stressors, particularly soil-borne pathogens. Besides, it is notable for its performance under low-irrigation conditions. Therefore, this work is particularly relevant in the current trend of global warming and climate change, including worldwide drought. Comparison of wheat genomes will allow to decipher complex traits, like abiotic and biotic stresses. That should allow the development of molecular markers for wheat breeding. These developments will help to address future food demand for a growing worldwide population.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-614
|
https://f1000research.com/articles/11-613/v1
|
06 Jun 22
|
{
"type": "Research Article",
"title": "Optimization of the structure of bionic finger segment prosthesis using generative design",
"authors": [
"Agus Triono",
"Mahros Darsin",
"Arsi Fathurrahman",
"Santoso Mulyadi",
"Nasrul Ilminnafik",
"Agus Triono",
"Arsi Fathurrahman",
"Santoso Mulyadi",
"Nasrul Ilminnafik"
],
"abstract": "Background: Bionic hand prosthesis helps restore the original hand function. A survey on prosthetic users concluded that 79% thought that their devices were \"too heavy\". Therefore, the weight of the prosthesis is a major cause of user discomfort and fatigue. This research was aimed at the reduction of hand mass bionic prosthesis by optimizing the structure of the fingers with generative design methods. Methods: The materials used were Acrylonitrile butadiene styrene plastic and Nylon 6, and the manufacturing method used Additive Manufacturing. The prosthesis was designed with a lighter finger structure with a max displacement of 2 mm and a maximum safety factor of 4. Results: Generative design produced more than 80 designs. The selection of the best design was based on the status of design solutions, research limitations, visual aesthetics, recommendation values, and validation of mechanical performances. The best is the SS-2. This design has an 80% lighter mass with the highest safety factor of 3.79, the lowest stress of 5.26 MPa, and the maximum displacement of 0.61 mm. Conclusion: Based on the exploration scheme, the generative design could produce more than 80 design solutions. The selection of the best design was based on the status of design solutions, research limitations, visual aesthetics, recommendation values, and validation of mechanical performances in the design. Design validation was carried out by simulating finite element analysis with static stress study methods in selected design candidates with input study cases similar to generative design exploration schemes. Finally, SS – 2 design was the best design produced by the generative design method with the highest factor of safety value of 3.79. Also gives an advantage to a stress value of at least 5.26 MPa in cases of segment loading, as well as the maximum displacement value of 0.61 mm.",
"keywords": [
"Generative design",
"bionic hand",
"design optimization",
"finger prosthesis"
],
"content": "Introduction\n\nIn Indonesia, work accident data has recorded more than 120,000 cases until October 2020. Based on this data, there were 4,275 cases of disability.1 Psychologically, disability due to work accidents can lead to sadness, not being able to accept the change in one’s circumstances, feelings of anger, bordering suicidal thoughts.2 To reduce this impact, many technologies have been created and developed such as hand bionic prostheses to replace almost half of the original hand functions with a wide variety of driving systems of the prostatic hand. Belter et al. (2021) who studied mechanical design and performance specifications of anthropomorphic prosthetic hands, showed that human hands have an average weight of 400 g at the wrist limit, excluding the weight of the forearm. Additionally, the survey of prosthetic hand users in the same study has indicated that 79% of users considered the prosthesis they use to be too heavy. Therefore, the weight of the prosthesis is a major contributor to discomfort and fatigue due to its use.3\n\nMany prosthetic research studies have been found that focus on the development of components of the driving system. Examples include Shin et al. (2012) combining three drive system mechanisms: distributed actuation, dual mode twisting actuation, and EM joint locking mechanism.4 Ventigmilia (2012) used a gearbox on a thumb drive system. With this gear box, thumb twisting motion was well-articulated.5 Gràcia (2015) utilized of 3D printing and self-assembly of driving systems and electronic components.6 Wang et al. (2017) developed a flexure hinge based on a two-electrode myoelectric control system.7 Dannereder et al. (2018) in effort to strengthen grip, they add driving force to the wrist using a linear drive system on each of the fingers.8\n\nTo create a lighter and stronger bionic finger structure, there needs to be a design optimization study that uses generative design methods. In previous research, generative methods were also used in the optimization of a component. This method was chosen as a form of design automation in design exploration and optimization. Generative design is an optimization technology as well as a fast and easy cloud-based design exploration. As a global leader in design and technology, Autodesk believes that this method can provide more than one design alternative based on the design goals that have been determined using loading parameters, safety factors, materials, and manufacturing methods. As a result, this method simultaneously produces multiple design solutions based on predetermined design goals and limitations. The resulting design tends to have a more natural shape because of its approach that mimics the evolution of nature in design.9\n\nGenerative design method has been discovered in recent research to make innovative design development. Francalanza et al. (2018) produced the robot manipulator designs with the same structural integrity, but with significantly minimized weight.10 Buonamici et al. (2020) designed a robotic gripper arm from ASTM A36 steel with a mass of 33.6 kg and a maximum displacement of 2.19 mm using Milling 5 axis manufacturing, which is lower than designs produced by additive manufacturing methods.11 Nisar et al. (2021) produced a mechanical pedal design that reduces weight by more than 40% and has a safety factor of 1.5.12 Matsunaka (2021) used milling manufacturing 5 axes to produce an arrowhead with a weight reduction of more than 50% from 1,531 grams to 633 grams.13 Rajput et al. (2021) produced lightweight foot and calf prosthetics using a combination of generative design and topological optimization.14 However, these studies did not explain the process of choosing the design of the many designs produced by the generative design. In addition, Buonamici (2020) stated that the designs produced by generative designs are very diverse, as they have different mechanical performance characteristics from one design to another.11 The consideration in choosing the best design as the final product is very unclear. Therefore, this study aims to determine the design selection steps based on reasonable criteria. In this research, optimization studies were conducted on the structure of the proximal segment of the finger (Figure 1), with a case study showing the hand in the hook grip position while carrying a 10 kg load.\n\n\nMethods\n\nBroadly speaking, this research is software-based because all activities from design to simulation rely heavily on the use of relevant software. The Autodesk Inventor Professional software (version 2021) with an alternative open-source version for student (https://www.autodesk.com/education/edu-software/overview?sorting=featured&filters=individual) was used to design bionic hands as research objects as shown in Figure 1. The generative design stage using Autodesk Fusion 360 was also used for the design validation stage. The validation stage used simulated finite element analysis (FEA) up to static stress studies.\n\nThe loading scheme on the bionic hand was achieved by using the hook grip position for lifting heavy objects (10 kg). In this position, the load was assumed to be equally distributed among the four finger segments, i.e., the index finger, middle finger, ring finger, and little finger. Therefore. the load on one proximal finger segment can be calculated by equation 1.\n\nFrom equation 1, static load found on one finger segment was 2.5 kg or equivalent to 24.5 Newton. Considering the flexibility factor, the load was adapted to four different loading angles, including angles 90°, 75°, 60°, and 45°. The load was applied to surfaces that were in direct contact with the objects, namely on the segment and the connection of the proximal segment with the middle segment. The direction of gravity was in line with the load. The optimization objective was a mass reduction with max displacement at 2 mm and min safety factor 2, summarized in Table 1.\n\nThe complete generative design scheme can be seen in Figure 2, where the preserved region or the part retained in the design is marked in red (fix geometry). Design exploration was carried out with two different configurations, namely without the starting shape and with the starting shape. The difference in the outcomes of the two categories will be coded as O and SS, respectively. The starting shape was the initial design of the finger segment, which was marked by dimensioned parts of the image. The bionic hand referenced the anthropometry of people aged 18 – 22 years.15\n\n\nResults\n\nThe generative design produced more than 80 design solutions or so-called outcomes that were divided into two categories of design solution status: completed and converged. Completed status is a design that has been successful through the generative design process, however the resulting performance does not meet the criteria of design parameters or errors occured when one or more geometries are indicated separately. While the status of converged design solutions is a design with mechanical performance that has met the minimum criteria of design parameters.9 The results of generative design exploration have been summarized in Tables 2 and 3 based on the materials and manufacturing methods. In design solutions with additive manufacturing, there were limits in the form of manufacturing orientation direction, minimum thickness, and overhang angle. However, unrestricted manufacturing does not limit design solutions as mentioned above, therefore the geometry of the resulting design solutions tends to vary.\n\nThe results of the exploration were mapped on a scatter plot graph generated by the software (Autodesk Fusion 360 - Generative Design) in Figure 3. The graph makes it easy for users to map the mechanical performance of each design, within the constraints of mechanical performance which contains a design with converged solution status. The design with a maximum displacement of 2 mm and a factor of safety of at least 2 to a maximum of 4 falls under the limitation of the research.\n\nWithin the parameters of the research limitation, there are 55 designs that have converged status. However, there needs to be observation and consideration in terms of visual aesthetics in each design. The generative design also provides recommendation values based on mechanical performance in each design. The value feature of the recommendation aims to assist the designer in making decisions on the final design to proceed to the next stage.9 It is expected that the analysis process can select the designs that have the feasibility of mechanical performance factors and visual aesthetics. Consideration factors used include design neatness and feasibility for the manufacturing process. Figure 4 shows visually identifiable defect design criteria based on (a) poor surface quality, (b) irregularly formed design geometry, (c) unsymmetrical geometry, and (d) geometry that exceeds the starting shape limit.\n\n(a) poor surface quality, (b) irregularly formed design geometry, (c) unsymmetrical geometry, and (d) geometry that exceeds the starting shape limit.\n\nDefect design in generative design outcomes can be formed due to the adjustment of the limitations of manufacturing methods used as parameters of generative design. When the main parameters of mechanical criteria are maintained constantly on each outcome, the software sometimes fails to produce geometric details in the design.11 After careful observation, several outcomes have a better level of feasibility in terms of visual aesthetics or a design with feasible criteria that can be identified based on good surface quality, irregular and symmetrical design geometry, and a geometry that does not exceed the limit of the initial shape. The design with feasible criteria can be seen in Figure 5. Data on the mechanical performance of feasible design and the recommendation values of each category can be seen in Tables 4 and 5.\n\nBased on recommended value, four designs with the highest recommended values from each category were selected. The design candidate can be seen in Figure 6 with different color identities, (a) O - 2, (b) O - 22, (c) SS - 2, and (d) SS - 6. Furthermore, design validation by simulation of finite element analysis (FEA) in static stress study with input study is the same as the exploration scheme of generative design in Figure 6.\n\n\nDiscussion\n\nThe simulation data is illustrated with a graph in Figure 7 that shows a ratio of factors of safety based on (a) load case segment and (b) load case pin. The SS - 2 design was superior even though the mass was lower than the O - 2 design in the load case category. In the pin load cases category, the O - 22 design was superior to other designs. But the factor of safety on the load case pin for this design was below 2. This is due to the highest stress experienced by this design in the case of loading.\n\nHowever, the O - 22 design had a higher Von-Mises stress value when compared to the SS -2 design. The graph in Figure 8 shows the ratio of stress based on (a) load cases segment and (b) load cases pin. The graph shows, the SS - 2 design was superior with the lowest stress value of 5.26 MPa. The SS - 26 design with a higher factor of safety value in the pin load cases category, had a greater stress value compared to the SS - 2 design. Safety factors that were below 2 before, are in the same area as the highest stress area.\n\nThat is related to the geometry formed so that the distribution of stress in each design has different characteristics. Based on these observations, the O - 22 design had many critical points on its geometry, while the other three designs had the same critical area. However, the critical area is very small as can be seen in Figure 9 which shows the critical areas of design (a) O - 2, (b) O - 22, (c) SS - 2, and (d) SS - 26.\n\nCritical areas of design can be minimized in the post-processing by editing and adding more geometric volumes to the design. It can also improve the mechanical performance of the design with further analysis and observation to validate. The O - 22 design had the highest displacement value compared to other designs. While the O - 2 design with the lowest displacement value was superior in the category of pin load cases (Figure 10). But all displacement that occurred in each design was still below 2 mm.\n\nHowever, in the category of load cases segment, SS - 2 and SS - 26 design had a relatively low displacement value in comparison to the O - 2 design which is a maximum of 0.61 mm. This gives priority back to the SS - 2 design. Therefore, according to the selection criteria introduced, the SS - 2 design has been proven to have a better mechanical performance compared to other design candidates. The software's recommended values in Table 3 for SS design - 2 have also become more acceptable as the best result of this validation procedure. It also reinforces the reason for making the SS - 2 design the best design produced by the generative design method. In addition, with the use of the generative design method, this study has indicated the process of choosing the best design with the following criteria illustrated in Figure 11. The criterion specified in this study can therefore be useful in future research that applies generative design methods.\n\nGD - Generative Design.\n\n\nConclusion\n\nPrevious reports had shown that the weight of the prosthesis is a major contributor to the discomfort and fatigue of the amputee. As such, this study aimed to reduce the mass of the bionic hand prosthesis by optimizing the structure of the fingers with generative design methods. Based on the results of this study several conclusions can be drawn. Firstly, based on the exploration scheme, the generative design can produce more than 80 design solutions. Secondly, the selection of the best design was carried out through a sequence of criteria, including the status of design solutions, research limitations, visual aesthetics, recommendation values, and validation of mechanical performances in the design. Design validation is done by simulating finite element analysis with static stress study methods in selected design candidates with input study cases similar to generative design exploration schemes. Finally, SS - 2 design is the best design produced by the generative design method with the highest factor of safety value of 3.79. This design also gives an advantage to a stress value of at least 5.26 MPa in cases of segment loading, as well as a maximum displacement value of 0.61 mm.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required\n\n\nAuthor contributions\n\nAgus Triono: Conceptualization, Format Analysis, Methodology, Supervision, Writing - Original Draft Preparation\n\nMahros Darsin: Methodology, Supervision, Writing - Review & Editing\n\nArsi Fathurrahman: Conceptualization, Modeling, Analysis, Writing - Original Draft Preparation\n\nNasrul Ilminnafik: Validation, Writing - Original Draft Preparation\n\nSantoso Mulyadi: Validation, Data curation",
"appendix": "References\n\nKetenagakerjaan BPJS: BPJAMSOSTEK Sudah Tangani 129.305 Kasus Kecelakaan Kerja di Indonesia.2020. (accessed Apr. 05, 2021). Reference Source\n\nSenra H, Oliveira RA, Leal I, et al.: Beyond the body image: A qualitative study on how adults experience lower limb amputation. Clin. Rehabil. 2012; 26(2): 180–191. PubMed Abstract | Publisher Full Text\n\nBelter JT, Segil JL, Dollar AM, et al.: Mechanical design and performance specifications of anthropomorphic prosthetic hands: A review. J. Rehabil. Res. Dev. 2013; 50(5): 599–618. PubMed Abstract | Publisher Full Text\n\nShin YJ, Kim S, Kim KS: Design of prosthetic robot hand with high performances based on novel actuation principles. IFAC Proceedings Volumes (IFAC-PapersOnline). 2013; vol. 46(no. 5): pp. 313–318. Publisher Full Text\n\nVentimiglia P: Design of a Human Hand Prosthesis.2012.\n\nGràcia AC: Design and Implementation of a Bionic Hand. Universitat de Lleida; 2015.\n\nWang N, Lao K, Zhang X: Design and Myoelectric Control of an Anthropomorphic Prosthetic Hand. J. Bionic Eng. 2017; 14(1): 47–59. Publisher Full Text\n\nDannereder F, et al.: Development of a 3D-Printed Bionic Hand with Muscle- and Force Control. Proceedings of the Austrian Robotics Workshop 2018. 2018; no. July: pp. 59–66. Publisher Full Text\n\nAutodesk: Product Documentation.2021. (accessed May 05, 2021). Reference Source\n\nFrancalanza E, Fenech A, Cutajar P: Generative design in the development of a robotic manipulator. Procedia CIRP. 2018; 67: 244–249. Publisher Full Text\n\nBuonamici F, Carfagni M, Furferi R, et al.: Generative design: An explorative study. ResearchGate. 2020; 18(1): 144–155. Publisher Full Text\n\nNisar MM, Zia S, Fenoon M, et al.: Generative Design of a Mechanical Pedal. Int. J. Eng. Manag. Sci. 2021; 6(1): 48–58. Publisher Full Text\n\nMatsunaka Y: How a Generative-Design Japanese Archery Bow Is Reviving a Revered Sport. Redshift. 2021. (accessed Jun. 04, 2021). Reference Source\n\nRajput S, Burde H, Singh US, et al.: Optimization of the prosthetic leg using generative design and compliant mechanism. Mater. Today Proc. May 2021; 46: 8708–8715. Publisher Full Text\n\nPurnomo H: Hand Anthropometry Measurements Age 18 to 22 Years Sleman Regency, Yogyakarta.2014; no. 2004: pp. 106–112."
}
|
[
{
"id": "197110",
"date": "04 Sep 2023",
"name": "Patricia Capsi-Morales",
"expertise": [
"Reviewer Expertise Upper limb prostheses",
"mechatronic design of hands",
"myoelectric control"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe second sentence of the abstract would require a citation. Please, rephrase it and avoid the use of strong claims on the abstract as references can not be used.\nThe sentence “The selection of the best design was based on the status of design solutions, research limitations, visual aesthetics, recommendation values, and validation of mechanical performances in the design.” Used in the conclusions of the abstract is an exact repetition of part of the results. Again with “method with the highest factor of safety value of 3.79. Also gives an advantage to a stress value of at least 5.26 MPa in cases of segment loading, as well as the maximum displacement value of 0.61 mm.” at the end of the abstract. Repetitions or results are not required in the conclusions of the abstract.\nIn the introduction, the discussion of Indonesia appears to be notably specific in the context of the overarching topic. Conversely, the use of cases of disability is very generic. I would recommend to put particular emphasis on citing instances of amputation for greater relevance and coherence.\nThe beginning of the introduction appears overly general and somewhat unnecessary. To make it more straightforward and scientifically sound, it is advisable to concisely state the primary research contribution and emphasize its importance.\nReplace \"bionic\" with \"prosthetic\" or \"robotic,\" as \"bionic\" typically implies a human-machine interface, which is not the primary focus in this context.\nFigure 1 presents a rather generic image that lacks specific information about its version. It is advisable to include an image featuring a single finger initially. Subsequently, once the final phalange design is determined, it is suggested to reiterate the definitive characteristics of the design at the results.\nWhat do you mean by “hook grip position” exactly, where is the load placed? You should include some details here and refer to Figure 2 when defining the optimization process.\nThe following sentence is not clear to me, especially on the terminology: “Design exploration was carried out with two different configurations, namely without the starting shape and with the starting shape.”\nAfter the following sentence, “Consideration factors used include design neatness and feasibility for the manufacturing process.” I would recommend to include an example to clarify the decision making, as well as for “defect design”.\nIn Figure 7, a higher factor safety means a better solution right? Please explain “better” in both plots as this graphs are not very clear and should be self-explainable by the plot and the caption.\nIn Figure 8, I would appreciate a scheme about the testing conditions, or where this stress is collected, is it the max stress value for each piece?\nIn conclusion, the statement \"reduce the mass of the bionic hand prosthesis\" may appear overly optimistic. To align with the actual contribution, it is recommended to use more realistic language, referring to the reduction of mass in the prosthetic hand phalange instead of a bionic prosthesis. The same issue occurs with the title or the paper in general, as there is no optimization of a “hand”. To accurately convey the research's contribution and maintain transparency, it is advisable to revise the title and content to clearly highlight the noteworthy aspect of the study. Otherwise, the authors create unmet expectations already from the title.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "262518",
"date": "09 May 2024",
"name": "Alok Prakash",
"expertise": [
"Reviewer Expertise Biomedical instrumentation",
"signal processing",
"control system",
"Hand prosthesis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper seems interesting. However, there are few comments need to be incorporated before its acceptance: 1. Introduction section lack an appropriate rationale. 2. Methods section has been written superficially i.e., significant information seems missing. 3. Authors are encouraged to add few more significant references. And also advised to discuss their obtained results with available literature. It would be better to include a comparison table in the discussion section. 4. what are the main limitations/shortcoming of the proposed research? This must be clearly mentioned in the conclusion section. Also, the future aspect of this work.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-613
|
https://f1000research.com/articles/11-522/v1
|
13 May 22
|
{
"type": "Research Article",
"title": "Sustainable development of smart cities and smart territories based on the model of minimizing externalities",
"authors": [
"Guldana Kuandykovna Suyendikova",
"Sergey Evgenievich Barykin",
"Sergey Mikhailovich Sergeev",
"Irina Vasilievna Kapustina",
"Yuri Krupnov",
"Natalia NikolaevnaShchepkina",
"Sergey Mikhailovich Sergeev",
"Irina Vasilievna Kapustina",
"Yuri Krupnov",
"Natalia NikolaevnaShchepkina"
],
"abstract": "The development of conceptual models of a digital city poses numerous challenges for developers. The public sector concept model has become one of the most difficult models to use. When developing algorithms to find a solution, the multidirectional interests of businesses and public institutions are combined. This type of model reflects the most acute and urgent problems faced by megapolises with regard to combining numerous localized services provided to the community in a limited territory. The administrations of both cities and regions (the scale of the smart territories) must make decisions concerning overcoming the barriers existing between the profits of commercial structures, the negative externalities generated by their activities, and the social benefits to the population in the territory under their control. It is necessary to solve this problem to achieve the effective management of enterprises belonging to the segment of long-term participants in various business activities, interacting with the surrounding social and business environment in a complex. This study takes into account the complex structures of the economic processes characteristic of megacities. The periodicity of economic processes is also taken into account. When choosing an optimization criterion, functions reflecting the level of internalization of responsibility for external effects were considered. The authors propose a mathematical model that can be used as part of the management decision support systems software, aiming at taking into account the externalities of a wide range of national, institutional, business, and social activities.",
"keywords": [
"Smart Cities",
"Digital Platforms",
"Sustainable Development",
"Digital Interactions",
"Smart Territories",
"Agglomeration",
"Satellite-Cities."
],
"content": "Introduction\n\nSeveral possible actions from a comprehensive perspective could be significant in Post-COVID recovery.1–4 The state as a whole, from the point of view of the economy, is a set of enterprises, both institutional and commercial. When studying economic processes at the top level, profits, common interests, and obligations must be taken into account.5,6 Additionally, it is important to introduce formalisms for the effect of externalities, which occur everywhere. Besides entrepreneurial activity, state institutions of the defense department, medicine, transport, education, etc., operate in each country. When modeling externalities, it is important to take into account both their positive and negative aspects based on the activities of all market entities.\n\nAny reaction can be the genesis in the general case, and therefore it is necessary to not be limited to the field of ecology in smart cities and in the smart territories considering the larger scale.7 The consequences of a social nature are much wider and deeper.8 Such damage to society will first be taken into account when monitoring the economic indicators of the current activities of any market participants.\n\nAs a rule, such analysis uses the methods of surrogate markets. In turn, this direction, which is usually referred to as an indirect market method or proxy market, is divided into several pricing principles.\n\nSince, at present, there is no definitive methodology able to theoretically cover the problem in general, we will consider the dependencies of externalities in the form of a function, the arguments concerning which are the characteristics of economic activity.9 An additional circumstance complicating any activity is the uncertainty of market conditions. Here, the methods of the stochastic process theory are used, which makes it possible to form adequate mathematical models.10 However, it must be taken into account that the indicators of distribution functions are not static. In the process of solving the problem, a set of algorithms are defined and the economic criteria used is justified. When evaluating a set of planned calculation results, special attention should be paid to finding a balance between the additional burden on the enterprise—i.e., on internalization and the indicators of the profitability of its activities. Based on this set of conditions, the formalisms of the mathematical model should be built. Similarly, non-commercial activities must be accounted for. This is necessary in order to assess the social factor in the activities of state institutions themselves in terms of their social and economic efficiency.\n\nIn this case, optimization is carried out by searching for the extrema of functionality, taking into account the inclusion of externalities in the market mechanism for evaluating performance. The results obtained may be a set of regulatory measures using institutional mechanisms. These include dispositive, strategic, restrictive, and stimulating components that form the basis of administrative management and legislative acts that are implemented in both the concepts of preventive behavior and prevention of damage, as well as in the more general concepts of the preservation and development of the social environment.11\n\n\nMethods\n\nImproving the smart city concept is essential to meet the demand of growing urban conglomerates to maintain comfort12 and improve the quality of urbanization.13,14 Regulation of the internal flows of megacities is the main focus of maintaining the quality of urbanization.15 Ignoring environmental requirements to reduce landscape characteristics, which will occur without striving to maintain the structure and functions of the regional ecological system.16 Urbanization policy is closely related to a wide range of objectives, including transport policy, the provision of public infrastructure, and the provision of modern security and management facilities.17 Urbanization affects the condition and viability of green infrastructure and its maintenance as a source of ecosystem services, which will allow the development of effective policies for land use, sustainable urban development and infrastructure management.18 A recent study suggested the sustainable development of smart cities as a complex structure of interconnected organizations that influence the level of everyday life of the population.19\n\nThe authors developed a formalized description to solve the problem at hand. The methods presented in the literature operate, as a rule, with the tools of correlation and regression analysis.20 To find the optimal solution under the conditions of market uncertainty and to apply the optimization methods correctly, a more complex mathematical model is needed.\n\nSince the processes of economic activity have some duration in terms of time and also have a complex nature based on changes in seasonal indicators, the authors used a combination of methods.21 Among them, we note the theory of the calculus of variations, methods for solving differential equations, the theory of mathematical games, and the main provisions5,6 of methods used for finding optimal control.22,23\n\n\nResults\n\nIn order to describe the processes under study, we introduce a number of parameters that describe business and government activities. The mathematical model we propose is based on the application of methods for finding optimal solutions.\n\nWe introduce the concept of the number (N) of enterprises. All of them work in this limited area. Let us take into account the fact that these enterprises have negative externalities as an external influence. In the case of additional costs for each enterprise, the effect of negative externalities can be reduced.\n\nWe denote P¯=p1p2…pNas the vector of searching for the optimal equilibrium solution. Searching for options for such solutions is carried out inside anN -dimensional cube of economic situations. We make the calculation specific for N=3, since in this case the result can be visualized. Let us enter the value of additional expenses ω. This amount reflects the need to spend additional money when planning work aimed at minimizing damage from the externalities produced.\n\nNext, we take into account the possible differences in the scale of enterprises, such as the differences in damage ψ∗ and ψ. We summarize the calculation model and data in Table 1.\n\nTo calculate, we assume that p¯i=1−pi, ∀i and calculate the product of the vector below:\n\nBy applying the solution-finding rule24 to the formulated conditions, we obtain two inequalities. The calculated ratios reflect possible market equilibrium conditions. First, we need to define the conditions for the lower bound:\n\nThe next calculation step allows us to determine the upper limit:\n\nWe then carry out simple transformations and obtain the system:\n\nThe calculation process used for each enterprise is similar. As a result, one obtains a system of equations for calculating the boundaries necessary for making decisions:\n\nAll possible solutions are limited within the multidimensional cube of situations. Such visualization is applicable to the three-dimensional case considered in this example and is used solely for clarity. In the case of N=3, this can be visualized in Figure 1. At the cube corners, the economic indicators associated with externalities are marked.\n\nAs a result of solving the system of equations, we obtain a set of regions for p1p2p3. The vector values belong to the multidimensional space of situations that satisfy the Nash equilibrium condition. The obtained data is represented in the simplest way by constructing volumetric diagrams of the solution in any package of mathematical applied programs. An analysis of the obtained equations shows that the domains of admissible solutions belong to the intersection of planes with hyperbolic surfaces.\n\nThe calculation results for the two participants in production activities are shown in Figures 2 and 3.38 The third solution differs only in terms of the orthogonal rotation of the axes in which the diagram is built.\n\nNote that the equations are hyperbolic surfaces, with several intersection points giving the desired solution. To do this, it is sufficient, for example, to transform Equations (2) and (3) to the following form:\n\nIn this case, the variation in the boundaries forms multidimensional dependencies, as presented in Figures 2 and 3.\n\nThe first version of the result reflects a trivial solution p¯1p¯2p¯3=0. In addition to this case, it is possible to obtain stable states in two more variants. The calculation of the second vector makes it possible to determine the components that satisfy the equilibrium conditions:\n\nLet us calculate the third case of equilibrium in a similar way. The desired vector is equal to:\n\n\nDiscussion\n\nEach calculated value is applied in different conditions. For the administration of cities and regions, the decision is made in order to overcome a number of barriers. This applies primarily to the disagreement between the profits of commercial structures, the negative externalities generated by their activities, and the social benefit of the population in the controlled territory. In the case of the dispositive method of legal regulation, the first (trivial) solution is applied everywhere.\n\nThis decision (presented in Figures 2 and 3) can be interpreted as the unwillingness of the participants in production activities to bear the costs of transforming external effects into internal ones.25\n\nThe second equilibrium solution accounts for restrictive measures. This approach requires the application of regulatory standards.\n\nThe third result of the decision involves the application of radical measures of restriction.\n\nThe listed measures have an economic character. The application of these restrictions obliges economic entities to conduct their activities while taking into account the interests of society. This will also generally affect the state of the entire economic system.26–30\n\nIt should be emphasized that the presented equations of the mathematical model reflect the situation for N=3 participants in commercial activities. This is explained by the fact that, in this case, it is possible to visualize the calculation results. The equations developed for the mathematical model can be scaled. At the same time, the number of participants31 in economic activities is not limited. In addition, the dependencies describing economic indicators can also have an arbitrary form. This only increases the dimension of the externalities model. All calculations were implemented using Microsoft Excel (Microsoft, 2022) (RRID:SCR_016137).\n\nThe application of the obtained results in the organization of the life of modern megapolises is especially relevant. Due to the aggravated environmental situation, problems of both a social and economic nature are actively manifested in them. The effective work of the authorities will be based on a scientifically grounded methodology for solving problems related to the economics of the environment. Therefore, the efficient use of public resources is emphasized as among the major tasks that must be completed. The task of business analysis aimed at developing recommendations for authorities and governments is to take into account multidirectional processes. On the one hand, there is an increased burden on resources and a decrease in the quality indicators of these resources, and it is necessary to evaluate the negative externalities. For the economic indicators of the metropolis, the standard26 of living of the population depends on the activities of all types of businesses and on enterprises that create profit and employment. The results presented by the authors of this paper and the mathematical model32,33 make it possible to develop a solution algorithm. Based on this, it is possible to create expert systems. The development of large metropolitan areas and industrial centers is accompanied by data exchange flows. Modern big data technologies and statistical analysis provide operational economic information for calculations based on mathematical models. Such systems are promising for use in the environmental, social, and corporate management of a smart city at the top level of planning.\n\nHigh rates of urbanization have caused large-scale shifts in the entire structure of relationships (relationships between business entities operating in a given territory, administration, and the population as a user of public resources). The dynamics of the mutual influence of different types of activity have intensified. Over the past decade, the world has come to increasingly rely on scientific and technological achievements. This inevitably entails negative consequences, which, in conditions with a high concentration of population and industry, inevitably create problems of both a social and economic orientation. The nature of these externalities is not determined solely by their impact on the environment. The quality of life in general is also negatively affected. The desire of the population to move to megapolises is determined by the high-quality standards of the living environment, and if radical measures are not taken to regulate the entire infrastructure, we will see the opposite effect. The functioning of numerous social institutions, public utilities, the service sector, and the industrial sector should be coordinated within smart city digital platforms.\n\nThe development of algorithms for making intelligent decisions is only possible today by combining digital data flows, big data technologies, and information communications into a single system. Decision criteria can be multifaceted. Science-based accounting of the balance between profit affecting the welfare and minimizing the negative impact of industrial urbanization is needed. The solution to socio-territorial problems depends on the quality of management decision-making algorithms. These should be based on mathematical models that are close to reality and methods for finding optimal solutions.\n\n\nConclusion\n\nUrbanization reflects a global trend. Consolidation into large megapolises is based on a multifaceted process involving the development of society as a whole. Megapolises, alpha cities, and the neighborhoods of such agglomerations, at present, house up to half of the world’s population and the majority of industrial enterprises. The smart city concept has no alternative today. The set of expert algorithms within the framework of the smart city conceptual model is intended primarily for decision-makers in each of the sectors of the economy. As a result, the development of directives for business organizers, systems, and services necessary for a megapolis is carried out based on calculated and economically sound principles. In many ways, the work of the e-government is guided by similar principles. The main principles are still the commitment to sustainable development34 and maintaining the quality of life of the population.27,35 The authors propose a complex approach to consider the socially oriented combination of ICT (information, and communication technology) tools for the rational use of resources to improve life quality indicators. The authors are attempting to develop smart city concept considering the public sector concept model (PSCM). The authors’ recommendations aimed at organizations that provide services and manage data in cities. The proposed approach addresses the interoperability of systems and data-sharing so that information from different sources can be normalized, classified, shared and understood, with the derivation of data linked back to previous layers and the impact of decisions observable in operational data. The stated principles of formalization are the basis for the development of a mathematical model. The use of the decision algorithm serves as a rationale for making a number of management decisions. At present, the concentration of business and cultural activity on a limited territorial scale dominates. This gives rise to the need to determine the feasibility of internalizing the numerous effects that arise from business or governmental activities. The presented technique makes it possible to formalize these according to the principle of externalities and to apply a multidimensional balance calculation to minimize the possible damage caused. It is necessary for management structures36 or administration bodies to exclude decision-making37 based on heuristic methods. It is necessary to carry out the analysis on a verified, scientifically based calculation. The result of mathematical modeling will be the optimization of the amount of expenses that must be borne by various members of the business community. It should be noted that today, in the decision-making process, dynamic analyses of the situation in the economy using digital twins are not carried out and methods for finding optimal solutions are not applied. All of these shortcomings occur for many reasons. These include the imperfection of methods and the complexity of taking into account many factors. We would also point to the lack of correct theoretical models and digital twins of processes in megacities based on accounting for economic indicators.\n\n\nData availability\n\nFigshare: Figures.xls https://doi.org/10.6084/m9.figshare.19692205.v138\n\nThis project contains the following underlying data:\n\n- Figures.xls (This is the data used for the calculations shown in this research paper). The EXCEL application contains the visualization of calculations according to the formulas presented in the work.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nEthical approval\n\nNot applicable (No use of individual human data in this article).",
"appendix": "Acknowledgments\n\nWe are thankful to the Ministry of Science and Higher Education of the Russian Federation for the financial support of this project.\n\n\nReferences\n\nRuan W-Q, Zhang S-N: Can tourism information flow enhance regional tourism economic linkages?. J. Hosp. Tour. Manag. 2021 Dec; 49(November): 614–623. Publisher Full Text\n\nKoç B, Küçükergin KG, Dimanche F: How destructive are negative tourist-to-tourist interactions despite the mitigating effect of optimism?. J. Destin. Mark. Manag. 2022 Mar; 23(February): 100693. Publisher Full Text Reference Source\n\nSun W, Chien PM, Ritchie BW, et al.: When compatriot tourists behave badly: The impact of misbehavior appraisal and outgroup criticism construal. J. Destin. Mark. Manag. 2022 Mar; 23(February): 100695. Publisher Full Text\n\nBulchand-Gidumal J: Post-COVID-19 recovery of island tourism using a smart tourism destination framework. J. Destin. Mark. Manag. 2022 Mar; 23: 100689. Publisher Full Text\n\nProvotorov VV, Sergeev SM, Hoang VN: Countable stability of a weak solution of a parabolic differential-difference system with distributed parameters on the graph. Vestn. Saint Petersbg. Univ. Appl. Math. Comput. Sci. Control Process. 2020; 16(4): 402–414. Publisher Full Text Reference Source\n\nProvotorov VV, Sergeev SM, Van NH: Point control of a differential-difference system with distributed parameters on the graph. Vestn. Saint Petersbg. Univ. Appl. Math. Comput. Sci. Control Process. 2021; 17(3): 277–286. Publisher Full Text Reference Source\n\nGarcia-Ayllon S, Miralles JL: New Strategies to Improve Governance in Territorial Management: Evolving from “Smart Cities” to “Smart Territories.”. Procedia Eng. 2015; 118: 3–11. Publisher Full Text Reference Source\n\nLeroux E, Pupion P-C: Smart territories and IoT adoption by local authorities: A question of trust, efficiency, and relationship with the citizen-user-taxpayer. Technol. Forecast Soc. Change. 2022 Jan; 174(September 2021): 121195. Publisher Full Text\n\nKaplow BL: Optimal control of externalities in the presence of income taxation. Int. Econ. Rev. (Philadelphia). 2012 May 1; 53(2): 487–509. Publisher Full Text\n\nBuchanan JM, Stubblebine WC: Externality. Economica. 1962 Nov 22; 29(116): 371. Publisher Full Text Reference Source\n\nMilstein T, Castro-Sotomayor J: Routledge Handbook of Ecocultural Identity. Milstein T, Castro-Sotomayor J, editors. Routledge Handbook of Ecocultural Identity. Abingdon, Oxon; New York, NY: Routledge; 2020; 1–497. Reference Source\n\nDeloitte: Government Trends 2020. Deloitte Insights.2020; 88. Reference Source\n\nMacchiarola FJ, Sassen S: The Global City: New York, London, Tokyo. Polit. Sci. Q. 1992; 107(2): 370. Publisher Full Text Reference Source\n\nKrižnik B: Transformation of deprived urban areas and social sustainability: A comparative study of urban regeneration and urban redevelopment in Barcelona and Seoul. Urbani izziv. 2018 Jun; 29(1): 83–95. Publisher Full Text Reference Source\n\nMarrone M, Peterlongo G: Where platforms meet infrastructures: digital platforms, urban resistance and the ambivalence of the city in the Italian case of Bologna. Work. Organ Labour Glob. 2020 Jan 1; 14(1): 119–135. Publisher Full Text\n\nSu L, Fan J, Fu L: Exploration of smart city construction under new urbanization: A case study of Jinzhou-Huludao Coastal Area. Sustain. Comput. Informatics Syst. 2020 Sep; 27: 100403. Publisher Full Text\n\nPradhan RP, Arvin MB, Nair M: Urbanization, transportation infrastructure, ICT, and economic growth: A temporal causal analysis. Cities. 2021 Aug; 115(September 2019): 103213. Publisher Full Text\n\nMiroshnyk NV, Likhanov AF, Grabovska TO, et al.: Green infrastructure and relationship with urbanization – Importance and necessity of integrated governance. Land Use Policy. 2022 Mar; 114(January 2021): 105941. Publisher Full Text\n\nZhao X, Xiao W, Wu L, et al.: Intelligent city intelligent medical sharing technology based on internet of things technology. Futur. Gener. Comput. Syst. 2020 Oct; 111: 226–233. Publisher Full Text Reference Source\n\nPrataviera E, Vivian J, Lombardo G, et al.: Evaluation of the impact of input uncertainty on urban building energy simulations using uncertainty and sensitivity analysis. Appl. Energy. 2022 Apr; 311(November 2021): 118691. Publisher Full Text\n\nTanner J: Neumann, John von/Morgenstern, Oskar: Theory of Games and Economic Behavior. Arnold HL, editor. Kindlers Literatur Lexikon (KLL). Stuttgart: J.B. Metzler; 2020; p. 1–3. Publisher Full Text\n\nRota Bulò S, Bomze IM: Infection and immunization: A new class of evolutionary game dynamics. Games Econ. Behav. 2011 Jan; 71(1): 193–211. Publisher Full Text\n\nde Magalhães ST , Magalhães MJ, Sá VJ: Establishment ofAutomatization as a Requirement for Time Management Input Modules in Project Management Information Systems for Academic Activities – A Game Theory Approach. Procedia Comput. Sci. 2015; 64: 1157–1162. Publisher Full Text\n\nHeifetz A, Meier M, Schipper BC: Comprehensive rationalizability. Games Econ. Behav. 2019 Jul; 116: 185–202. Publisher Full Text\n\nSergeev SM, Starodubtsev YI, Kravets OJ, et al.: Algorithm of ecological solutions in the smart city concept. J. Phys. Conf. Ser. 2020 Nov 1; 1679(5): 052040. Publisher Full Text\n\nBorisoglebskaya LN, Provotorov VV, Sergeev SM, et al.: Mathematical aspects of optimal control of transference processes in spatial networks. IOP Conf. Ser. Mater. Sci. Eng. 2019; 537(4): 042025. Publisher Full Text\n\nZhabko AP, Shindyapin AI, Provotorov VV: Stability of weak solutions of parabolic systems with distributed parameters on the graph. Vestn. Saint Petersbg. Univ. Appl. Math. Comput. Sci. Control Process. 2019; 15(4): 457–471. Publisher Full Text Reference Source\n\nPilipenko OV, Provotorova EN, Sergeev SM, et al.: Automation engineering of adaptive industrial warehouse. J. Phys. Conf. Ser. 2019; 1399(4): 044045. Publisher Full Text\n\nArtemov MA, Baranovskii ES, Zhabko AP, et al.: On a 3D model of non-isothermal flows in a pipeline network. J. Phys. Conf. Ser. 2019; 1203(1): 012094. Publisher Full Text\n\nKrasnov S, Sergeev S, Zotova E, et al.: Algorithm of optimal management for the efficient use of energy resources. Kalinina O, editor. E3S Web Conf. 2019 Aug 9; 110: 02052. Publisher Full Text\n\nBarykin SY, Kapustina IV, Sergeev SM, et al.: Developing the physical distribution digital twin model within the trade network. Acad. Strateg. Manag. J. 2021; 20(1): 1–18. Reference Source\n\nProvotorov VV, Provotorova EN: Optimal control of the linearized Navier— Stokes system in a netlike domain. Vestn. Saint Petersbg. Univ. Appl. Math. Comput. Sci. Control Process. 2017; 13(4): 431–443. Publisher Full Text Reference Source\n\nPodvalny SL, Podvalny ES, Provotorov VV: The Controllability of Parabolic Systems with Delay and Distributed Parameters on the Graph. Procedia Comput. Sci. 2017; 103(October 2016): 324–330. Publisher Full Text\n\nBarykin SE, Smirnova EA, Chzhao D, et al.: Digital Echelons and Interfaces within Value Chains: End-to-End Marketing and Logistics Integration. Sustainability. 2021 Dec 16; 13(24): 13929. Publisher Full Text Reference Source\n\nBarykin SE, Borisoglebskaya LN, Provotorov VV, et al.: Sustainability of Management Decisions in a Digital Logistics Network. Sustainability. 2021 Aug 18; 13(16): 9289. Publisher Full Text Reference Source\n\nBarykin SY, Kapustina IV, Sergeev SM, et al.: Algorithmic foundations of economic and mathematical modeling of network logistics processes. J. Open Innov. Technol. Mark Complex. 2020; 6(4): 1–16. Publisher Full Text\n\nGolosnoy AS, Provotorov VV, Sergeev SM, et al.: Software engineering math for network applications. J. Phys. Conf. Ser. 2019 Dec 1; 1399(4): 044047. Publisher Full Text\n\nKuandykovna Suyendikova G, Kapustina IV: Data calculation for: Sustainable Development of Smart Cities and Smart Territories Based on the Model of Minimizing Externalities2.xls. figshare. Dataset. 2022. Publisher Full Text"
}
|
[
{
"id": "137829",
"date": "19 May 2022",
"name": "Bilal Khalid",
"expertise": [
"Reviewer Expertise Smart Cities",
"Sustainable Practices",
"De-carbonization",
"Immigrant Entrepreneurship",
"Global Value Chains",
"Industry 4.0",
"Digital Transformations",
"Technology Adoption",
"Consumer behavior",
"Public Policy"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract:\nThe background section of the abstract is too long, the authors should consider revising it to not more than two sentences. Because of the length of the background, the authors did not provide much information about the study in the abstract. The part above where it says “This study takes into account….” Is ideally where the authors start talking about this study. The other parts above it should be condensed into two sentences.\n\nThe abstract should be written with the following in mind, aim/problem, objective(s), theory, methods, results, discussion, conclusions and limitations. These aspects where applicable should be touched briefly in the abstract.\n\nExternalities seem to be a very important concept in this study, yet it only appears once towards the end of the abstract. This is part of the problem being studied and should be reflected earlier in the abstract.\nIntroduction:\nThe authors should provide a better explanation for the term “externalities” and how it affects the conceptualization of sustainable development of smart cities and smart territories.\n\nCases of the impacts of externalities on the sustainable development of smart cities and territories should be provided if they are available in studies or practical examples.\n\nThe authors should provide clarification of what they mean by “The consequences of a social nature are much wider and deeper.” It is not enough to provide citations, a context should be provided to show the relationship between the statement and the problem to research hopes to address.\n\nThe authors should elaborate on how market uncertainty affects the sustainable development of smart cities and territories.\nMethods:\nThe first paragraphs in the Methods section should be moved to the Introduction. This section should start from the second paragraph – “The authors developed….” The authors should expand the discussion on the Methods once the first paragraph is deleted, this enables them to discuss the Methods in detail.\n\nThe Methods require further clarification to understand the specific correlation and regression tools to be employed.\nResults:\nThe first two paragraphs of the results section can be moved to the methods section as it seems to describe actions that will lead to results, not the findings itself. The results should only contain the derivatives from what was proposed in the Methods section.\n\nThe second line of the third paragraph contains a spacing error, kindly correct – “…carried out inside anN- dimension….”\n\nAuthors should present the results and provide a clearer explanation, rather than using statistical jargon and equation.\nDiscussion:\nThe last sentence of the analysis of the result that informs that calculations were implemented using Microsoft Excel should be taken to the Methods section. The discussion is only for the implications of your results.\n\nThe discussion should analyze the implication of the equations and figures presented in the results. How do they affect the sustainable development of smart cities and smart territories? Please also consider citing the following articles:\nChaiyasoonthorn, W., Khalid, B., & Chaveesuk, S. (2019, August). Success of Smart Cities Development with Community’s Acceptance of New Technologies. Proceedings of the 9th International Conference on Information Communication and Management.1 Khalid, B., & Naumova, E. (2021). Digital transformation of the Russian venture ecosystem under the impact of the COVID-19. In Global Challenges of Digital Transformation of Markets (pp. 313–329). Nova Science Publishers, Inc.2\n\nThere is a little linkage between the literature and the results in the discussion section. Try to connect the literature to the discussion to understand how the findings impact smart cities and smart territories.\nConclusion:\nThe conclusion should summarize the research, make recommendations and state the limitations of the study if any. Instead, the conclusion seems to be an extension of the discussion. “Megapolises’ appears three times in the conclusion, twice in the discussion, and once in the abstract. Throughout the manuscript, it does not appear in the introduction, methods, and results. It needs to be situated in the introduction section and methods.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8300",
"date": "06 Jun 2022",
"name": "Guldana Kuandykovna Suyendikova",
"role": "Author Response",
"response": "Dear Dr Bilal Khalid Thank you for your constructive comments on our manuscript ‘Sustainable development of smart cities and smart territories based on the model of minimizing externalities’ The suggestions offered by you have been immensely helpful, and we also appreciate your full consideration to our paper. As per Your instructions, I have included all of Your comments point by point individually, indicating exactly how we addressed each concern or problem and describing the changes we have made. The revisions have been approved by all four authors and I have again been chosen as the corresponding author. The revised manuscript was formatted according to the journal formatting criteria. We hope the revised manuscript will better suit F1000Research but are happy to consider further revisions if any, and we thank you for your interest in our research. REVIEWER COMMENTS, AUTHOR RESPONSES AND MANUSCRIPT CHANGES Comment 1: The background section of the abstract is too long, the authors should consider revising it to not more than two sentences. Because of the length of the background, the authors did not provide much information about the study in the abstract. The part above where it says “This study takes into account….” Is ideally where the authors start talking about this study. The other parts above it should be condensed into two sentences. Response: Thank you for the identification of this confusion. We have restructured the abstract. The sentences were shortened. Comment 2: The abstract should be written with the following in mind, aim/problem, objective(s), theory, methods, results, discussion, conclusions and limitations. These aspects where applicable should be touched briefly in the abstract. Response: Thank you! The aim, methods, results and conclusion were provided in the revised version. Comment 3: Externalities seem to be a very important concept in this study, yet it only appears once towards the end of the abstract. This is part of the problem being studied and should be reflected earlier in the abstract. Response: Thank you for highlighting this issue. This confusion was removed and the mentioned term was duly placed in the beginning of the abstract. Comment 4: The reviewer asked about the following: The authors should provide a better explanation for the term “externalities” and how it affects the conceptualization of sustainable development of smart cities and smart territories. Response: Here by investigation we explained this term in the introduction in the revised version in order to clarify the confusion. Comment 5: Cases of the impacts of externalities on the sustainable development of smart cities and territories should be provided if they are available in studies or practical examples. Response: Thank you so much. We agree to this modification. The explanation was disclosed with more details in the introduction. Comment 6: The authors should provide clarification of what they mean by “The consequences of a social nature are much wider and deeper.” It is not enough to provide citations, a context should be provided to show the relationship between the statement and the problem to research hopes to address. Response: Thank you so much for this suggestion and modification. We followed the comments accordingly in the revised version. Comment 7: The authors should elaborate on how market uncertainty affects the sustainable development of smart cities and territories. Response: Yes by this we mean that market uncertainty affects the sustainable development of smart cities and territories. Changes made accordingly in the revised version. Comment 8: The first paragraphs in the Methods section should be moved to the Introduction. This section should start from the second paragraph – “The authors developed….” The authors should expand the discussion on the Methods once the first paragraph is deleted, this enables them to discuss the Methods in detail. Response: Thank you. We made the relevant amendments. Comment 9: The Methods require further clarification to understand the specific correlation and regression tools to be employed. Response: We changed the manuscript accordingly. It is corrected now and all clarification was provided in the revised version. Comment 10: The first two paragraphs of the Results section can be moved to the methods section as it seems to describe actions that will lead to results, not the findings themselves. The results should only contain the derivatives from what was proposed in the Methods section. Response: Thank you so much for identifying this confusion. We had moved this sentence in the revised version. Comment 11: The second line of the third paragraph contains a spacing error, kindly correct – “…carried out inside anN- dimension….” Response: Changes made in the revised version. Comment 12: Authors should present the results and provide a clearer explanation, rather than using statistical jargon and equation. Response: This has been provided in the revised version. Comment 13: The last sentence of the analysis of the result that informs that calculations were implemented using Microsoft Excel should be taken to the Methods section. The discussion is only for the implications of your results. Response: The appropriate changes were made in the revised version. Comment 14: The discussion should analyze the implication of the equations and figures presented in the results. How do they affect the sustainable development of smart cities and smart territories? Please also consider citing the following articles: Chaiyasoonthorn, W., Khalid, B., & Chaveesuk, S. (2019, August). Success of Smart Cities Development with Community’s Acceptance of New Technologies. Proceedings of the 9th International Conference on Information Communication and Management.1 Khalid, B., & Naumova, E. (2021). Digital transformation of the Russian venture ecosystem under the impact of the COVID-19. In Global Challenges of Digital Transformation of Markets (pp. 313–329). Nova Science Publishers, Inc. Response: The mentioned sources have been added in the revised manuscript. Comment 15: There is a little linkage between the literature and the results in the discussion section. Try to connect the literature to the discussion to understand how the findings impact smart cities and smart territories. Response: We made these changes in the revised version. Comment 16: The conclusion should summarize the research, make recommendations and state the limitations of the study if any. Instead, the conclusion seems to be an extension of the discussion. “Megapolises’ appears three times in the conclusion, twice in the discussion, and once in the abstract. Throughout the manuscript, it does not appear in the introduction, methods, and results. It needs to be situated in the introduction section and methods. Response: The conclusion was revised by your comments."
}
]
},
{
"id": "137833",
"date": "20 May 2022",
"name": "Jakub Kubiczek",
"expertise": [
"Reviewer Expertise Decision making",
"Corporate Social Responsibility",
"Sustainable Development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Authors, I am grateful for the opportunity to read and review your text.\nIn my opinion, there are many approaches to your research problem, but this is the science of finding and proposing new one. I believe that the text is written correctly - although a few adjustments need to be made. I agree with reviewer 1 in many respects, but I believe that these amendments are not too complex and none of them disparages your text. You can find detailed comments below.\nTechnical issues related to the structure of the article\nShorten the abstract to make it more specific. I would remove the introduction to the problem because the abstract should contain the essence itself. At the same time, I would add the most important results of the study.\n\n“As a rule, such analysis uses the methods of surrogate markets. In turn, this direction, which is usually referred to as an indirect market method or proxy market, is divided into several pricing principles \". You write “usually” - it would be useful to support it with some other article.\n\nYou have defined the research gap very well and proposed a way to fill it, but there is no clearly defined purpose of the article.\n\nIn the results section, \"the Nash equilibrium condition\" appears - it would be nice to mention what it means somewhere.\n\nThe figures are not signed - \"Source: own study.\"\n\nPlease, number the patterns continuously - they should all have a number.\n\nPlease, divide the conclusions into certain sections as this is too chaotic at the moment.\n\nSubstantive issues\nThe authors mention the pandemic, but do not detail how it affected the externalities. Which externalities are connected with the post-pandemic situation?\n\nThe authors should clarify suggesting a mathematical model as part of the management decision support.\n\nI miss the justification that the presented model has potential. Therefore, I propose to note the potential of proposed model and its practical implication opportunities.\n\nDo the authors mean that the nature of a sustainable development is connected with the smart territories’ development. If so, in what way? Please refer it to the proposed model.\n\nAre there any recommendations for authorities and governments based on the developed model?\n\nDo the researchers propose making urbanization on the basis of sustainable development?\n\nAre the principles of formalization used as the basis for a mathematical model?\n\nCould the developed model be qualified as the optimization of the amount of expenses that must be borne by various members of the business community?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8301",
"date": "06 Jun 2022",
"name": "Guldana Kuandykovna Suyendikova",
"role": "Author Response",
"response": "Dear Jakub Kubiczek Thank you for your important comments on our manuscript ‘Sustainable development of smart cities and smart territories based on the model of minimizing externalities’ Your recommendations have been immensely helpful, and we also appreciate your full consideration to our paper. As per your instructions, i have included all of your comments point by point individually, indicating exactly how we addressed each concern or problem and describing the changes we have made. The revisions have been approved by all four authors and I have again been chosen as the corresponding author. The revised manuscript was formatted according to the journal formatting criteria. We hope the revised manuscript will better suit F1000Research but are happy to consider further revisions if any, and we thank you for your interest in our research. REVIEWER COMMENTS, AUTHOR RESPONSES AND MANUSCRIPT CHANGES Comment 1: Shorten the abstract to make it more specific. I would remove the introduction to the problem because the abstract should contain the essence itself. At the same time, I would add the most important results of the study. Response: Thank you! We have made the relevant changes in the revised version. Comment 2: The reviewer asked for the methods of the following: “As a rule, such analysis uses the methods of surrogate markets. In turn, this direction, which is usually referred to as an indirect market method or proxy market, is divided into several pricing principles \". You write “usually” - it would be useful to support it with some other article. Response: Thank you for the identification of this confusion. The appropriate explanation was provided in the revised version. Comment 3: You have defined the research gap very well and proposed a way to fill it, but there is no clearly defined purpose of the article. Response: Thank You for highlighting this confusion. This confusion was removed and the purpose was written. Comment 4: In the results section, \"the Nash equilibrium condition\" appears - it would be nice to mention what it means somewhere. Response: We described the mentioned approach more precisely. Comment 5: The figures are not signed - \"Source: own study.\". Response: Thank you so much. We agree to this modification. The figures are duly signed. Comment 6: Please, number the patterns continuously - they should all have a number. Response: Thank you so much for this suggestion and modification. We followed the comments accordingly in the revised version. Comment 7: Please, divide the conclusions into certain sections as this is too chaotic at the moment. Response: Yes by this we mean logical explanation. Changes made accordingly in the revised version. Comment 8: The authors mention the pandemic, but do not detail how it affected the externalities. Which externalities are connected with the post-pandemic situation? Response: Thank you. We explained the externalities accordingly. Comment 9: The authors should clarify suggesting a mathematical model as part of the management decision support. Response: Thank you. We explained the mathematical model as part of the management decision support. Comment 10: I miss the justification that the presented model has potential. Therefore, I propose to note the potential of proposed model and its practical implication opportunities. Response: Thank you so much for identifying this confusion. We had added the potential of the model. The same has been elaborated well in the revised version. Comment 11: Do the authors mean that the nature of a sustainable development is connected with the smart territories’ development. If so, in what way? Please refer it to the proposed model. Response: We mean that the nature of a sustainable development is connected with the smart territories’ development. Comment 12: Are there any recommendations for authorities and governments based on the developed model? Response: This has been explained in the revised version. Comment 13: Do the researchers propose making urbanization on the basis of sustainable development? Response: Thank you so much for identifying this confusion. We had added the explanation of the model in the revised version. Comment 14: Are the principles of formalization used as the basis for a mathematical model? Response: We mean that the principles of formalization are used as the basis for a mathematical model implemented for the development of smart territories. Comment 15: Could the developed model be qualified as the optimization of the amount of expenses that must be borne by various members of the business community? Response: This has been explained in the revised version."
}
]
},
{
"id": "137831",
"date": "23 May 2022",
"name": "Mui Yee Cheok",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAfter reviewing the research paper and other reviewers' comments I agree with the reviewers and especially many important points raised by reviewer 1, However, the following are the comments and suggestions from my side to the authors. The authors should incorporate the following suggestions and revise the manuscript.\nThe abstract needs revision and restructuring. The abstract should be revised by adding the objectives, conclusions and future scope of the proposed work.\n\nWord “Externalities” is repeatedly used in the title as well as in the abstract it is not defined and the term is required to explain in the introduction\n\nMarket uncertainty is a wide concept that is required to explain in this paper’s context.\n\nIt is advised to add more literature data in the introduction section to understand the research problem, The research contributions of the present work in the existing body of knowledge should be summarized in the introduction section.\n\nPaper novelty & research objectives should be added at the end of section 1 (Introduction).\n\nIt is advised to explain the findings of Table 1 in the text, similar all figures should be discussed in the discussion section and support some of your important findings with the past studies.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8302",
"date": "06 Jun 2022",
"name": "Guldana Kuandykovna Suyendikova",
"role": "Author Response",
"response": "Dear Mui Yee Cheok Thank you for your valuable comments on our manuscript ‘Sustainable development of smart cities and smart territories based on the model of minimizing externalities’ Your recommendations have been immensely helpful, and we also appreciate your full consideration to our paper. As per your instructions, we have included all of your comments point by point individually, indicating exactly how we addressed each concern or problem and describing the changes we have made. The revisions have been approved by all four authors and I have again been chosen as the corresponding author. The revised manuscript was formatted according to the journal formatting criteria. We hope the revised manuscript will better suit F1000Research but are happy to consider further revisions if any, and we thank you for your interest in our research. REVIEWER COMMENTS, AUTHOR RESPONSES AND MANUSCRIPT CHANGES Comment 1: The abstract needs revision and restructuring. The abstract should be revised by adding the objectives, conclusions and future scope of the proposed work. Response: Thank you! We have restructured the abstract in the revised version. Comment 2: Word “Externalities” is repeatedly used in the title as well as in the abstract it is not defined and the term is required to explain in the introduction. Response: Thank you for the identification of this confusion. The explanation was provided in the revised version. Comment 3: Market uncertainty is a wide concept that is required to explain in this paper’s context. Response: Thank you for highlighting this confusion. The explanation was duly provided. Comment 4: It is advised to add more literature data in the introduction section to understand the research problem, The research contributions of the present work in the existing body of knowledge should be summarized in the introduction section. Response: Here by investigation, we added the description in the introduction. Comment 5: Paper novelty & research objectives should be added at the end of section 1 (Introduction). Response: Thank you so much. We agree to this modification. The novelty was disclosed in the introduction. Comment 6: It is advised to explain the findings of Table 1 in the text, similar all figures should be discussed in the discussion section and support some of your important findings with the past studies. Response: Thank you so much for this suggestion. We followed the comments accordingly in the revised version."
}
]
},
{
"id": "137830",
"date": "24 May 2022",
"name": "Esra Sipahi Dongul",
"expertise": [
"Reviewer Expertise Business",
"management",
"organizational behavior"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors talk about smart cities. Please elaborate with some concrete example not more than a paragraph.\nPlease provide more detail about all of the methods used.\n\nPlease specify what you mean when you use the term of the multidimensional cube of situations.\n\nAre the economic indicators associated marked with externalities?\n\nWhat is the sense of the expression 3? This need to be elaborated well.\n\nPlease explain with concrete examples the theoretical base of the the mathematical model.\n\nLight up the term “green infrastructure”.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8303",
"date": "06 Jun 2022",
"name": "Guldana Kuandykovna Suyendikova",
"role": "Author Response",
"response": "Dear Esra Sipahi Dongul Thank you for your precious comments on our manuscript ‘Sustainable development of smart cities and smart territories based on the model of minimizing externalities’ Your recommendations helped polished the manuscript, and we also appreciate your full consideration to our paper. As per your instructions, we have included all of your comments points by point individually, indicating exactly how we addressed each concern or problem and describing the changes we have made. The revised manuscript was formatted according to the journal formatting criteria. We hope the revised manuscript will better suit F1000Research but are happy to consider further revisions if any, and we thank you for your interest in our research. REVIEWER COMMENTS, AUTHOR RESPONSES AND MANUSCRIPT CHANGES Comment 1: Please provide more detail about all of the methods used. Response: Thank You! We have clarified the methods in the revised version. Comment 2: Please specify what you mean when you use the term of multidimensional cube of situations. Response: Thank you for your comment. We described the meaning of the multidimensional cube of situations. Comment 3: Are the economic indicators associated marked with externalities? Response: Thank You for highlighting this confusion. This confusion was removed and we described the logical connection between the economic indicators and externalities. Comment 4: What is the sense of the expression 3? This need to be elaborated well. Response: We elaborated the revised version in order to clarify the confusion. Comment 5: Please explain with concrete examples the theoretical base of the mathematical model. Response: Thank you so much. We agreed with these Comments and duly explained the theoretical base of the mathematical model. Comment 6: Light up the term “green infrastructure”. Response: Thank you so much for this suggestion. We followed the comments accordingly in the revised version."
}
]
}
] | 1
|
https://f1000research.com/articles/11-522
|
https://f1000research.com/articles/11-600/v1
|
01 Jun 22
|
{
"type": "Case Report",
"title": "Case Report: Central retinal artery occlusion following sildenafil intake",
"authors": [
"Anis Mahmoud",
"Fatma Abid",
"Molka Khairallah",
"Fatma Sakji",
"Hassen Ibn Hadj Amor",
"Hala Attia",
"Sameh Mbarek",
"Riadh Messaoud",
"Fatma Abid",
"Molka Khairallah",
"Fatma Sakji",
"Hassen Ibn Hadj Amor",
"Hala Attia",
"Sameh Mbarek",
"Riadh Messaoud"
],
"abstract": "Purpose: To report a case of central retinal artery occlusion associated with sildenafil intake and briefly discuss its causative pathogenesis. Methods: A 50-year-old man with no premorbidities presented with symptoms of sudden severe visual field constriction in the left eye (LE). Best-corrected visual acuity in the LE was 20/25. Fundus examination and fluorescein angiography of the LE were suggestive of central retinal artery occlusion (CRAO) with cilioretinal artery sparing. Further investigation revealed that 100 mg of sildenafil had been taken for the first time three hours before the onset of symptoms. Results: The patient was treated promptly with intravenous acetazolamide, sublingual isosorbide dinitrate and ocular massage, but without visual recovery. No other associated systemic or local risk factors were found, and the case was classified as a potential complication of sildenafil. Conclusion: Although no direct link could be established, the aim of this report is to highlight the incidence and to consider this issue when evaluating any case of central retinal artery occlusion.",
"keywords": [
"Central retinal artery occlusion",
"Systemic Drug Retinal Toxicity",
"Sildenafil",
"phosphodiesterase V inhibitor."
],
"content": "Introduction\n\nSildenafil is a specific phosphodiesterase V inhibitor which is a widely used treatment for erectile dysfunction. Many reports have highlighted ischemic ocular side effects associated with sildenafil.1 We report herein a case of central retinal artery occlusion (CRAO), which occurred a few hours after oral sildenafil intake.\n\n\nCase report\n\nA 50-year-old Tunisian man, otherwise healthy and unemployed, presented to the ophthalmology department with sudden severe visual field constriction in the left eye (LE) of 48 hours duration preceded by severe headaches. On ophthalmic examination, visual acuity was 20/20 in the right (RE) eye and 20/25 in the left eye (LE). LE fundus examination revealed diffuse faint retinal whitening, except for central area of normal retinal color along the distribution of a perfused cilioretinal artery (Figure 1: black arrow).\n\nAnterior segment examination of both eyes as well as fundus examination of theRE were unremarkable. LE fluorescein angiography (FA) showed no filling of the central retinal artery, regular filling of the cilioretinal artery and late retrograde filling of the central retinal vein (Figure 2: blue arrowheads).\n\nOCT-A of the left eye at first presentation shows no flow in the microvasculature of the superficial and deep retinal capillary plexuses, except for the territory of the cilioretinal artery (Figure 3).\n\nOnly the flow in cilioretinal artery is visible.\n\nLE central retinal artery occlusion (CRAO) with cilioretinal artery sparing was diagnosed. Echocardiogram, carotid artery imaging and blood tests were unremarkable. Further investigation revealed that a 100 mg dose of sildenafil had been taken for the first time three hours before the onset of symptoms.\n\nOcular massage was performed as well as sublingual isosorbide dinitrate and intravenous acetazolamide were administered. Two weeks later, reduction in retinal oedema was evident on left eye fundus examination, although there was no improvement in either visual acuity or visual field.\n\n\nDiscussion\n\nVarious ischemic ocular events related to sildenafil have been reported. The most notable are branch retinal artery occlusion,2 acute macular neuroretinopathy,3 anterior ischemic optic neuropathy,4,5 central retinal vein occlusion6 and cilioretinal artery occlusion.7\n\nOnly two cases of CRAO with sildenafil have been reported in the literature.8,9\n\nThe patient presented here reported taking sildenafil (100 mg) a few hours before the onset of ocular symptoms and headaches. In fact, ocular side effects are directly proportional to the blood concentration of the drug, which usually appears between 15 and 30 minutes after administration, reaches a peak one to two hours later and clears halfway in 3 to 5 hours.10\n\nAs sildenafil has a high systemic vasodilator effect that reduces systemic blood pressure,11 it may decrease cerebral blood flow leading to severe headaches as experienced by our patient. Similarly, numerous clinical studies have demonstrated that sildenafil induces retinal veinous vasodilatation in vivo.12\n\nBoth the absence of risk factors for retinal vascular occlusion and the timeline of events indicates that oral sildenafil was probably a contributing factor in the development of CRAO, but its pathogenesis remains speculative. We suggest that central retinal artery occlusion occurs in the region of the lamina cribrosa where the central retinal vein and artery share a common adventitia. We speculate that sildenafil-related vasodilation of the central retinal vein causes central retinal artery compression, resulting in secondary changes, including blood flow changes, endothelial damage and platelet thrombi, leading to CRAO. This case underlines the importance of a careful drug intake investigation in cases of CRAO without obvious cause. This incident should not be overlooked by physicians and must be seriously discussed with patients requiring sildenafil, especially since most of them are at risk for ocular ischemic events. Nevertheless, this association remains poorly explained and requires further documented cases.\n\n\nConclusion\n\nIn summary, CRAO secondary to sildenafil is extremely rare and has only been reported in the literature twice previously. Clinicians should be aware of this risk and should avoid prescribing sildenafil in patients with a history of ischemic ocular events.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.",
"appendix": "References\n\nAzzouni F, Abu Samra K: Are phosphodiesterase type 5 inhibitors associated with vision-threatening adverse events? A critical analysis and review of the literature. J. Sex. Med. 2011; 8(10): 2894–2903. PubMed Abstract | Publisher Full Text\n\nTripathi A, O'Donnell NP: Branch retinal artery occlusion; another complication of sildenafil. Br. J. Ophthalmol. 2000; 84(8): 934–935. PubMed Abstract\n\nKolomeyer AM, Kim BJ: High-Dose Sildenafil-associated Acute Macular Neuroretinopathy Variant. Ophthalmol. Retina. 2018; 2(7): 711. PubMed Abstract | Publisher Full Text\n\nThurtell MJ, Tomsak RL: Nonarteritic anterior ischemic optic neuropathy with PDE-5 inhibitors for erectile dysfunction. Int. J. Impot. Res. 2008; 20(6): 537–543. Publisher Full Text\n\nBella AJ, Brant WO, Lue TF, et al.: Non-arteritic anterior ischemic optic neuropathy (NAION) and phosphodiesterase type-5 inhibitors. Can. J. Urol. 2006; 13(5): 3233–3238. PubMed Abstract\n\nGedik S, Yilmaz G, Akova YA: Sildenafil-associated consecutive nonarteritic anterior ischaemic optic neuropathy, cilioretinal artery occlusion, and central retinal vein occlusion in a haemodialysis patient. Eye. 2007; 21(1): 129–130. PubMed Abstract | Publisher Full Text\n\nAkash R, Hrishikesh D, Amith P, et al.: Case report: association of combined nonarteritic anterior ischemic optic neuropathy (NAION) and obstruction of cilioretinal artery with overdose of Viagra. J. Ocul. Pharmacol. Ther. 2005; 21(4): 315–317. PubMed Abstract | Publisher Full Text\n\nAbrishami M, Hosseini SM, Mohseni H, et al.: Central Retinal Artery Occlusion Associated with Sildenafil Overdose. Case Rep. Ophthalmol. Med. 2021; 2021: 1–4. Publisher Full Text\n\nMurthy RK, Perez L, Priluck JC, et al.: Acute, bilateral, concurrent central retinal artery occlusion in sickle cell disease after use of tadalafil (Cialis). JAMA Ophthalmol. 2013; 131(11): 1471–1473. PubMed Abstract | Publisher Full Text\n\nda Cruz NFS , Polizelli MU, Cezar LM, et al.: Effects of phosphodiesterase type 5 inhibitors on choroid and ocular vasculature: a literature review. Int. J. Retina Vitreous. 2020; 6: 38. PubMed Abstract | Publisher Full Text\n\nKrishnappa P, Fernandez-Pascual E, Carballido J, et al.: Sildenafil/Viagra in the treatment of premature ejaculation. Int. J. Impot. Res. 2019; 31(2): 65–70. Publisher Full Text\n\nKrishnappa P, Fernandez-Pascual E, Carballido J, et al.: Sildenafil/Viagra in the treatment of premature ejaculation. Int. J. Impot. Res. 2019; 31(2): 65–70. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "139570",
"date": "21 Jun 2022",
"name": "Yousra Falfoul",
"expertise": [
"Reviewer Expertise retinal imaging",
"peridatric ophthalmology",
"cataract surgery",
"oculogenetics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors report a case of central retinal artery occlusion as a potential complication of Sildenafil. they conclude that Clinicians should take into account this complication while prescribing this treatment.\n\nIn this case, multimodal imaging was well detailed with high quality images. It would be also interesting if the authors could add structural OCT imaging of the posterior pole. On LE fluorescein angiography, are there more earlier phases that could better describe the retrograde filling of the posterior pole vessels? Did the general examination of the patient reveal some characteristics that could be possible markers predicting this potential complication when prescribing this treatment (obesity, sleep apnea syndrome, recent vaccination, COVID...?)\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
},
{
"id": "150351",
"date": "20 Sep 2022",
"name": "Wassim Ben Hadj Salah",
"expertise": [
"Reviewer Expertise Ophtalmology Ocular Surface Disease",
"glaucoma",
"retinal diseases",
"anterior segment surgery",
"contactology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe author reported an original case of a young adult patient with no personal history who presented with a central retinal artery occlusion following the intake of Sildenafil.\nThe retinal imaging is interesting, moreover, it would be necessary to add the early times of the retinal angiography and a B mode OCT, as well as it should be specified that the imaging was not done at an acute stage of the arterial occlusion seen the blood flow recovery exceeding the cilioretinal artery area.\nIt may be relevant to detail the biological radiological and clinical explorations done to rule out other etiologies of retinal arterial occlusion like cardiovascular pathologies, dysimmune diseases with vasculitis, and hematological disorders\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-600
|
https://f1000research.com/articles/11-596/v1
|
01 Jun 22
|
{
"type": "Research Article",
"title": "Bone tissue engineering application on fracture healing with bone defect as assessed through osteocalcin and bone morphogenetic protein-2 (BMP-2) biomarker examination: experimental study on murine models",
"authors": [
"Panji Sananta",
"Respati Suryanto Dradjat",
"Rizqi Daniar Rosandi",
"Muhammad Alwy Sugiarto",
"Respati Suryanto Dradjat",
"Rizqi Daniar Rosandi",
"Muhammad Alwy Sugiarto"
],
"abstract": "Background: Bone is naturally regenerable, with a high ability to repair itself. In massive segmental bone defect, bone cannot be repaired independently. Therefore, it is necessary to give a bone graft to promote the healing process. To date, autografts are the gold standard for bone grafts. However, some of the reported complications reported have led to auto-bone transplants being often disregarded. Both autografts or allografts also have some issues. Therefore, in an effort to develop alternative treatments for correcting bone defects and their consequences, bone tissue engineering (BTE) has gained popularity and is nowadays being researched as a potential alternative in bone defect management. There are three fundamental components in BTE combined: biomaterials (scaffolds), mesenchymal stem cells (MSCs), and growth factors. The combination of these components is believed to help the healing process of bone defects. Methods: This work was an animal study involving twenty Wistar strain Rattus norvegicus. They were divided into five groups: negative group (normal rats), positive group (rats with the bone defect without intervention), K-P1 group (rats with bone defect given SVF and porous carbonated- hydroxyapatite (HA)application), K-P2 group (rats with bone defect given SVF and nanocrystalline-HA application) and K-P3 (rats with bone defect giving SVF a bovine-HA application). After 30 days, the rats were sacrificed, the biomarkers osteocalcin and BMP-2 were evaluated. Biomarkers were quantified using ELISA. Results: Both osteocalcin and BMP-2 biomarker expressions were higher in intervention group (with SVF and scaffolds application) compared to the positive group (with no SVF and scaffolds treatment). The combination of SVF and bovine HA was reported significantly to have the highest osteocalcin and BMP levels when compared with other groups Conclusions: A combined application of SVF and scaffolds could aid the healing process in murine models with bone defect, marked by increasing levels of osteocalcin and BMP-2.",
"keywords": [
"Bone defect",
"SVF",
"Scaffolds",
"Osteocalcin",
"BMP-2",
"In-vivo study"
],
"content": "Introduction\n\nBone is naturally regenerable, with a high ability to repair itself, especially in young individuals; this means that most fractures or bone deformities recover spontaneously without requiring a significant intervention.1,2 Despite bones having some capacity for healing and regeneration, massive segmental bone defects cannot be repaired independently.3 Therefore, for bone defect conditions, it is necessary to give a bone graft to promote the healing process.4 In humans, a bone defect occurs when there is a loss of bone components larger than 1 cm in length which contributes to more than 50% of the circumference of the affected bone.5 In contrast, in animal research objects such as rats, a bone defect is considered when there is a loss of bone components up to 3 mm.5\n\nVarious bone grafts have been employed to correct these defects, including autografts, allografts, and synthetic grafts.6 To date, autografts are the gold standard for bone grafts due to their histocompatibility and low risk of hypersensitivity reactions.7,8 Moreover, autografts also provide the essential parts for osteoconduction (i.e., osteoprogenitor cells, three-dimensional and porous matrix), osteogenesis (i.e., osteoprogenitor cells), and osteoinduction (i.e., bone morphogenetic proteins [BMPs] and other growth factors). Although autografts are a popular graft strategy, they have certain disadvantages, such as donor site morbidity, muscle weakening, risk of infection, bleeding, nerve damage, and function loss.9–11 Another choice for bone substitution is an autologous bone graft.12 However, the availability of suitable bone is restricted; moreover, harvesting a bone graft is challenging, with a high risk of disease transmission and relatively high cost.13,14\n\nTherefore, in an effort to develop alternative treatments for correcting bone defects and their consequences, bone tissue engineering (BTE) has gained popularity and is nowadays being researched as a potential alternative in bone defect management.15,16 BTE approach is perceived as a preferable solution for bone defect condition due to the healing process being facilitated with the patient’s own tissue and provide a good healing process15,17,18 The BTE theory involves the integration of several collaborating elements: stem cells held together by a three-dimensional biomaterial framework that gives shape and initial mechanical strength, and molecular signals that stimulate progenitor cell differentiation into the osteoblastic phenotype.19 It can be concluded that there are three combined fundamental components in BTE: biomaterials (scaffolds), mesenchymal stem cells (MSCs), and growth factors.20,21\n\nIn common tissue engineering procedures, a framework is needed to guide the formation of the tissue formation called a “scaffold”.21,22 Scaffolds are made from synthetic or natural biomaterials that facilitate the proliferation, migration, and differentiation of bone cells for bone repair. Scaffolds themselves are made of a variety of biomaterials and synthetic bone substitutes, including collagen, hydroxyapatite (HA), b-tricalcium phosphate (b-TCP), calcium-phosphate cement, as well as glass-ceramics and bovine HA.23 Other components in BTE include stem cells and growth factors, where both of these components can be found in adipose tissue. Adipose tissue is a multifunctional structure consisting of various cell types, including stromal vascular fraction (SVF) and mature adipocytes. Adult stem cells are abundant and easily extracted from adipose tissue compared to the umbilical cord or bone marrow. The combination of these components is believed to help the healing process of bone defects.24–26 Therefore, this study aimed to observe the effect of bone tissue engineering (SVF and scaffold) in the bone defect healing process based on levels of osteocalcin and BMP-2 in vivo.\n\n\nMethods\n\nThis research was performed from March to December 2020. All protocols were approved by the Ethical Committee of Medical Research Faculty of Medicine Universitas Brawijaya with approval number 160/EC/KEPK – PPDS/09/2020, and all subsequent experimental studies followed the ARRIVE guidelines. All animals were housed in certified vivariums under standard procedures with gentle handling, daily cage cleaning, and regular monitoring to avoid animal suffering.\n\nThis study was an in vivo experimental research with a randomized posttest-only control group design. The parameters measured in this study resulted from the authors’ intervention. The research started by identifying rats that had finally passed the inclusion and exclusion criteria. The inclusion criteria for this study consisted of male Wistar rats aged three months, or twelve weeks, with a body weight of 200-280 grams, who were fit, active, clear of limb abnormalities, and had no history of therapy or chemical administration.\n\nAfter identifying the 20 experimental animals that met the inclusion criteria, we used the Federer formula to determine the sample size. Then, we used simple random sampling for each group. After identifying the 20 experimental animals that met the inclusion criteria, these rats were separated into five groups consisting of four rats. The groups were categorized as follows: (1) was a negative group that consisted of normal rats without critical bone defect and without SVF or scaffold application; (2) was a positive group which were murine models with bone defect and without SVF or scaffold application. These two groups were control groups. Then, for an experimental group, we divided into three groups: group (3) was named K-P1: murine models with bone defect and giving porous-carbonated HA application; group (4) was named K-P2: murine models with bone defect and treated with nanocrystalline HA applications; and group (5) was K-P3: murine models with bone defects and treated with bovine HA application. These five groups were followed for 30 days to evaluate osteocalcin and BMP-2 biomarker levels.\n\nFive 12-week-old male Wistar strain rats were sacrificed by cervical dislocation procedure. We then put the rats in a supine position. A broad and longitudinal skin incision was done to expose the abdomen of rats. Then, the testicles and the fat surrounding the epididymal and perirenal fat pad were extracted. By severing the innervation of the retroperitoneal fat pad, adipose tissue from perirenal fat was harvested from the epididymal and perirenal fat pad for collection.\n\nAfter adipose tissue was obtained, the harvested adipose was washed using a Phosphate-buffered saline (PBS, Sigma-Aldrich, Germany) solution containing a 10% antibiotic-antimycotic solution. The adipose tissue was mashed with a knife. It was then incubated for 30 minutes at 37°C in a 0.075 percent type IA collagenase combination (Sigma-Aldrich) and PBS. After processing the tissue, it was filtered using a 100 mm mesh strainer (Sigma-Aldrich) and centrifuged at 1200 rpm for 10 minutes at 20 °C. The supernatant was removed, leaving a heterogeneous cell suspension with an estimated 2 × 106 cells per gram of adipose tissue\n\nScaffolding is classified into synthetic porous carbonated-HA, nanocrystalline-HA, and bovine xenograft-HA. These three scaffolds are commonly available at Saiful Anwar hospital, making them accessible. In addition, this scaffold is frequently utilized in other research. These three scaffolds were then administered to fractures with bone defects using a measuring spoon to ensure that each mouse model received an equivalent dose.\n\nAfter seven days of acclimatization, rats in the positive and intervention groups received a bone deformity. Rats were sedated with 100 mg/kg ketamine injection and 10 mg/kg xylazine hydrochloride intraperitoneally preoperatively. The authors confirmed that rats were sedated by extending the extremities and pinching the web between the toes using the pedal reflex technique. If the rat retreated or twitched a muscle and made a noise, the anesthetic was insufficient. After that, they were given an antibiotic injection of 20 mg/kg Cefazolin in the right leg. Then, the operating area was shaved and disinfected with chlorhexidine. The murine was positioned prone on the surgical table and incised over 3-4 cm, gradually deepening the incision until the bone was visible. Osteotomy was performed with a 3mm Kerrison, resulting in a 3mm broad bone defect. After that, the intervention was carried out according to the designated groups. Finally, plaster of Paris was put from the proximal femur to the ankle, with the knee in 90 degrees of flexion. Analgesia was supplied every eight hours (IM 5 mg/kg Ketorolac), and antibiotics, i.e., 20 mg/kg cefazoline were administered intramuscularly 24 hours after surgery. Monitoring was conducted on a daily basis for 30 days.\n\nMurine models were sacrificed after 30 days. We collected and then extracted the area of bone defect with callus formation. Osteocalcin and BMP-2 levels were determined using the ELISA technique.27\n\nThe first steps of the hypothetical comparative test are followed by the data normality test and variant homogeneity test. If the data collected was homogenous and normally distributed, we used ANOVA. However, if these two criteria are not fulfilled, we used a non-parametric Kruskal-Wallis test with a confidence interval of 95%. After the hypothesis test was performed, we conducted a post hoc test to evaluate the significant difference in each group. The resulting test was significant when p<0.05\n\n\nResults\n\nIn this research, we used osteocalcin and BMP-2 levels to assess the outcome of using bone tissue engineering (SVF and scaffold) in experimental animals. Osteocalcin and BMP-2 were measured using ELISA, and the results are depicted in Table 1.\n\na Significancy test result using Kruskal-Wallis for osteocalcin.\n\nb Significancy test result using Kruskal-Wallis for BMP-2.\n\nIn this study, we found that the mean level of osteocalcin using bone tissue engineering (SVF and scaffold) was higher when compared to either the positive or negative control groups. The group with the highest osteocalcin level after 30 days was the KP-3 group, which contained SVF and bovine HA, with a mean osteocalcin level of 50.92±2.059 ng/ml while the lowest was KP-1 which contained SVF and porous carbonated-HA (45.998±12.065) ng/ml. Then, we performed a statistical Kruskal-Wallis test; it was found that the significance test result was less than 0.05. Therefore, it can be concluded that applying SVF and scaffolds has a significant effect on osteocalcin levels (Figure 1).\n\nThen, for further comprehension of the difference between in each intervention, the experiment processed to the post hoc test next. From the results of the post hoc test, a significant relationship between positive control and SVF and bovine-HA was found (p=0.006), as well as between negative control and treatment with SVF and bovine HA (p=0.003); therefore, it can be concluded that the use of bone tissue engineering using SVF and bovine HA can significantly increase the level of osteocalcin in experimental animals when compared to the negative and positive groups (Table 2).\n\n+ Significant test result.\n\n* Not significant test result.\n\nFurthermore, we evaluated BMP-2 levels in rats with bone defects using bone tissue engineering. It was found that the outcomes of applying bone tissue engineering using SVF and bovine HA (KP-3) led to a significantly higher BMP level (491,572±88,597) pg/ml, more than the results of the other groups. Moreover, the results of the Kruskal-Wallis test proved that there was a significant difference between groups for this marker (p=0.001). In comparison, the lowest concentration of BMP-2 was found in KP-1, which was treated with SVF and porous carbonated HA (313,337±56,372) pg/mL. This finding was similar to the results obtained in the previous osteocalcin level, which was highest for KP-3 and lowest for KP-1 compared to other experimental groups (Figure 2).\n\nWe also performed a post hoc test to determine the differences between each group. The post hoc test revealed a significant relationship between positive control and SVF and bovine HA (p=0.003) and a relationship between negative control and SVF and bovine HA (p=0.002) (Table 2).\n\n\nDiscussion\n\nOne of the most extraordinary characteristics of bone is its remarkable capability to recover with almost minimal scarring.7 However, when bone defects reach a critical size, disruptions at the fracture site may affect the repair process. This condition results in nonunion healing.19 Because of so many restrictions associated with bone reconstruction using autografts or bank bones, researchers have explored other methods for bone repair. Recent tissue engineering techniques have regenerated bone by putting MSCs and growth factors contained in SVF from adipose tissue onto porous ceramic scaffolds.\n\nAdipose tissue has long been viewed as useless tissue, and for many years, fat tissue has been regarded as “waste material” in surgical treatments.28 Hollenberg initially described SVF in 1960, and in 2001 SVF was discovered to contain a large number of MSCs.28,29 SVF have many benefits promoting bone healing. These advantages include, first, that fat tissue is relatively simple to extract which may minimize patient discomfort. Second, tissue extraction processes from adipose tissue to SVF with significant number of MSCs can be completed quickly; third, the multipotent cells contained in SVF can adhere quickly to the scaffold material, multiply rapidly, and differentiate into osteogenic elements.30,31 Not only does it have the capability to assist the healing process of bone defects, SVF also can prevent bone bridge formation on growth plate injury, which can be useful for growth plate injury cases. This has been evidenced in our previous studies32\n\nScaffolds have been developed over the last few decades; they provide a three-dimensional structure for cell support.33 Thus, they have the potential to dictate cell-specific features via the release of numerous growth factors, as well as surface binding and physicochemical proportions. Furthermore, Scaffolds or bone grafts are used to enhance or induce bone formation for fixing bone fractures or connecting two bones along a diseased joint, to replace and regenerate lost bone as a result of trauma, infection, or disease, or to improve the bone healing response and regeneration of bone tissue surrounding surgically implanted devices, such as artificial joints replacements or plates and screws used to maintain bone alignment.16,34\n\nSeveral studies have reported that SFV and scaffolds lead to promising outcomes for stimulating bone repair in bone defects.13,14,18,19 In this study, we compared the outcome of combining SVF with various types of scaffolds in vivo to assess their effectiveness. We used combinations of SVF and porous carbonated HA, SVF and nanocrystalline HA, last, and SVF and bovine HA. Interestingly, we found the combination of SVF and bovine-HA showed a significantly higher activity of osteocalcin and BMP-2 than other combinations. Moreover, it has been reported previously that bovine HA has a lower toxicity effect than other types; this was confirmed in a study conducted by Kamal et al., who stated that Scaffold IV (bovine HA granule) had the least toxic effect on rat bone marrow.35\n\nIn addition, in this study, we used BMP-2 levels to evaluate bone healing, as BMPs levels are widely considered as the most effective group of growth factors for helping in the healing of major bone lesions. However, only BMP-2 has been demonstrated to be required for the osteogenic process, and both BMP-2 and BMP-7 have been approved for clinical usage in the treatment of significant bone abnormalities.36\n\nBone remodeling is a complex process involving a variety of cellular and molecular events. Bone cells collaborate with other cells to promote the healing process.37 MSCs can be administered in combination with a scaffold to increase bone formation in vivo; autologous MSCs have been effectively used in combination with a HA-based scaffolds to repair critical-sized and bone defects in vivo.38 In another study, Roato, 2018 compared SVF and adipose tissue-derived stem cells (ASCs) combined with bovine scaffold. From the results of the study it was found that the administration of SVF and bovine scaffold had better osteoinductive abilities than ASCs.39 Therefore, the use of SVF in combination with bovine scaffold has a good potential for promoting bone healing in bone defects cases. This theory is relevant to this study, as the combination of SVF and bovine HA scaffold had higher levels of osteocalcin and BMP-2 when compared to the control groups.\n\nThe application of SVF (stem cells) and scaffolds enhances the activity and efficiency of the bone healing process, because SVF containing progenitor cells synergizes with the scaffold, which provides a site for colonization of progenitor cells and growth factors such as transforming growth factor (TGF), insulin-like growth factor 1 (IGF1), and platelet-derived growth factor (PDGF, insulin). In addition to fibroblast growth factor 1 (FGF1), FGF2, and PDGF, scaffolds have a role in filling bone defects. The bone healing process becomes more effective when the procedure described previously is used.\n\nWe suggest further studies to use a different fixation, such as external or internal fixation, to better aim the study towards various modalities used in orthopedics fields. Different biomarkers could also be assessed in future studies, such as alkaline phosphatase (ALP), osteopontin bone marker, type II collagen among others, as well as from a histological standpoint.\n\n\nConclusions\n\nFrom this study, it can be concluded that the application of Bone Tissue Engineering (SVF and scaffolds) could enhance the healing process in murine models with bone defect, marked by increasing levels of osteocalcin and BMP-2 as bone formation markers.\n\n\nData availability\n\nZenodo: Bone Tissue Engineering Application on Fracture Healing with Bone Defect as Assessed Through Osteocalcin and Bone Morphogenetic Protein-2 (BMP-2) Biomarker Examination: Experimental Study on Murine Model, https://doi.org/10.5281/zenodo.6361033.40\n\nThis project contains the following underlying data:\n\n− Raw Data BTE.sav (Osteocalcin and BMP-2 Level)\n\n− Raw Data BTE.xlsx (Osteocalcin and BMP-2 Level)\n\nData are available under the terms of the Creative Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReporting guidelines\n\nZenodo: Bone Tissue Engginering Application on Fracture Healing with Bone Defect as Assessed Through Osteocalcin and Bone Morphogenetic Protein-2 (BMP-2) Biomarker Examination: Experimental Study on Murine Model, https://doi.org/10.5281/zenodo.6361033.40\n\nThis project contains the following reporting guidelines:\n\n- ARRIVE Guidelines Checklist.pdf\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nStevens MM: Biomaterials for bone tissue engineering. Mater. Today. 2008; 11(5): 18–25. Publisher Full Text\n\nRoberts TT, Rosenbaum AJ: Bone grafts, bone substitutes and orthobiologics. Organogenesis. 2012; 8(4): 114–124. Publisher Full Text\n\nQu H: RSC Advances Biomaterials for bone tissue engineering scaffolds. RSC Adv. 2019; 45:26252–26262. Publisher Full Text\n\nLee SS, Huang BJ, Kaltz SR, et al.: Bone regeneration with low dose BMP-2 amplified by biomimetic supramolecular nanofibers within collagen scaffolds. Biomaterials. 2013; 34(2): 452–459. PubMed Abstract | Publisher Full Text\n\nKim JH, Kim HW: Rat defect models for bone grafts and tissue engineered bone constructs. Tissue Eng. Regen. Med. 2013; 10(6): 310–316. Publisher Full Text\n\nSalgado AJ, Coutinho OP, Reis RL: Bone tissue engineering: State of the art and future trends. Macromol. Biosci. 2004; 4(8): 743–765. PubMed Abstract | Publisher Full Text\n\nAmini AR, Laurencin CT, Nukavarapu SP: Bone tissue engineering: recent advances and challenges. Crit. Rev. Biomed. Eng. 2012; 40(5): 363–408. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang J, Liu W, Schnitzler V, et al.: Calcium phosphate cements for bone substitution: Chemistry, handling and mechanical properties. Acta Biomater. 2014; 10(3): 1035–1049. PubMed Abstract | Publisher Full Text\n\nDamien CJ, Parsons JR: Bone Graft and Bone Graft Substitutes: A Review of Current Technology and Applications.\n\nBanwart JC, Asher MA, Hassanein RS: Iliac crest bone graft harvest donor site morbidity: A statistical evaluation. Spine (Phila Pa 1976). 1995; 20(9): 1055–1060. Publisher Full Text\n\nEbraheim NA, Elgafy H, Xu R: Bone-graft harvesting from iliac and fibular donor sites: techniques and complications. J. Am. Acad. Orthop. Surg. 2001; 9(3): 210–218. PubMed Abstract | Publisher Full Text\n\nYounger EM, Chapman MW: Morbidity at bone graft donor sites. J. Orthop. Trauma. 1989; 3(3): 192–195. Publisher Full Text\n\nGunzburg R: The use of bone substitutes in spine surgery: a state of the art review.2002; 129. Accessed February 2, 2022. Reference Source\n\nFernandez de Grado G, Keller L, Idoux-Gillet Y, et al.: Bone substitutes: a review of their characteristics, clinical use, and perspectives for large bone defects management. J. Tissue Eng. 2018; 9: 204173141877681. PubMed Abstract | Publisher Full Text\n\nDimitriou R, Jones E, McGonagle D, et al.: Bone regeneration: Current concepts and future directions. BMC Med. 2011; 9. PubMed Abstract | Publisher Full Text\n\nBose S, Roy M, Bandyopadhyay A: Recent advances in bone tissue engineering scaffolds. Trends Biotechnol. 2012; 30(10): 546–554. PubMed Abstract | Publisher Full Text\n\nLaurencin CT, Ambrosio AMA, Borden MD, et al.: Tissue engineering: Orthopedic applications. Annu. Rev. Biomed. Eng. 1999; 1: 19–46. Publisher Full Text\n\nCowan CM, Soo C, Ting K, et al.: Evolving concepts in bone tissue engineering. Curr. Top. Dev. Biol. 2005; 66: 239–285. Publisher Full Text\n\nPetite H, Viateau V, Bensaïd W, et al.: Tissue-engineered bone regeneration. Nat. Biotechnol. 2000; 18(9): 959–963. Publisher Full Text\n\nPerez JR, Kouroupis D, Li DJ, et al.: Tissue Engineering and Cell-Based Therapies for Fractures and Bone Defects. Front. Bioeng. Biotechnol. 2018; 6(July): 1–23. PubMed Abstract | Publisher Full Text\n\nO’Brien FJ: Biomaterials & scaffolds for tissue engineering. Mater. Today. 2011; 14(3): 88–95. Publisher Full Text\n\nHutmacher DW: Scaffolds in tissue engineering bone and cartilage. Biomater. Silver Jubil. Compend. 2000; 21: 175–189. Publisher Full Text\n\nGiannoudis PV, Dinopoulos H, Tsiridis E: Bone substitutes: an update. Injury. 2005; 36: S20–S27. Publisher Full Text\n\nHuang T, He D, Kleiner G, et al.: Neuron-like differentiation of adipose-derived stem cells from infant piglets in vitro. J. Spinal Cord Med. 2007; 30(SUPPL. 1): S35–S40. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBoquest AC, Noer A, Collas P: Epigenetic programming of mesenchymal stem cells from human adipose tissue. Stem Cell Rev. 2006; 2(4): 319–329. PubMed Abstract | Publisher Full Text\n\nKern S, Eichler H, Stoeve J, et al.: Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow, Umbilical Cord Blood, or Adipose Tissue. Stem Cells. 2006; 24(5): 1294–1301. Publisher Full Text\n\nHidayat R, Wulandari P: Bioscientia Medicina: Journal of Biomedicine & Translational Research Enzyme Linked Immunosorbent Assay (ELISA) Technique Guideline. J. Biomed. Transl. Res. 2021; 5: 352–358. Publisher Full Text\n\nBora P, Majumdar AS: Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation. Stem Cell Res. Ther. 2017; 8(1): 145. PubMed Abstract | Publisher Full Text\n\nLevi B, Longaker MT: Concise review: adipose-derived stromal cells for skeletal regenerative medicine. Stem Cells. 2011; 29(4): 576–582. PubMed Abstract | Publisher Full Text\n\nTodorov A, Kreutz M, Haumer A, et al.: Fat-Derived Stromal Vascular Fraction Cells Enhance the Bone-Forming Capacity of Devitalized Engineered Hypertrophic Cartilage Matrix. Stem Cells Transl. Med. 2016; 5(12): 1684–1694. PubMed Abstract | Publisher Full Text\n\nPrins H-J, Schulten EAJM, Ten Bruggenkate CM, et al.: Bone Regeneration Using the Freshly Isolated Autologous Stromal Vascular Fraction of Adipose Tissue in Combination With Calcium Phosphate Ceramics. Stem Cells Transl. Med. 2016; 5(10): 1362–1374. PubMed Abstract | Publisher Full Text\n\nSananta P, Gede Made Oka I, Suryanto Dradjat PR, et al.: Adipose-derived stromal vascular fraction prevent bone bridge formation on growth plate injury in rat (in vivo studies) an experimental research. Ann. Med. Surg. 2020; 60(September): 211–217. PubMed Abstract | Publisher Full Text\n\nChan BP, Leong KW: Scaffolding in tissue engineering: General approaches and tissue-specific considerations. Eur. Spine J. 2008; 17(SUPPL. 4): 467–479. PubMed Abstract | Publisher Full Text\n\nVelasco MA, Narváez-Tovar CA, Garzón-Alvarado DA: Design, materials, and mechanobiology of biodegradable scaffolds for bone tissue engineering. Biomed. Res. Int. 2015; 2015: 729076. PubMed Abstract | Publisher Full Text\n\nKamal AF, Iskandriati D, Dilogo IH, et al.: Biocompatibility of various hydroxyapatite scaffolds evaluated by proliferation of rat’s bone marrow mesenchymal stem cells: An in vitro study. Med. J. Indones. 2013; 22(4): 202–208. Publisher Full Text\n\nChen G, Deng C, Li Y-P: TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int. J. Biol. Sci. 2012; 8(2): 272–288. PubMed Abstract | Publisher Full Text\n\nDiomede F, D’Aurora M, Gugliandolo A, et al.: Biofunctionalized scaffold in bone tissue repair. Int. J. Mol. Sci. 2018; 19(4): 1–17. PubMed Abstract | Publisher Full Text\n\nVaněček V, Klíma K, Kohout A, et al.: The combination of mesenchymal stem cells and a bone scaffold in the treatment of vertebral body defects. Eur. Spine J. 2013; 22(12): 2777–2786. PubMed Abstract | Publisher Full Text\n\nRoato I, Belisario DC, Compagno M, et al.: Adipose-Derived Stromal Vascular Fraction/Xenohybrid Bone Scaffold: An Alternative Source for Bone Regeneration. Stem Cells Int. 2018; 2018: 1–11. PubMed Abstract | Publisher Full Text\n\nSananta P, Dradjat RS, Rosandi RD, et al.: The Effect of Stromal Vascular Fraction (SVF) & Scaffolds Application on Fracture Healing with Bone Defect as Assessed Through Osteocalcin and Bone Morphogenetic Protein-2 (BMP-2) Biomarker Examination: Experimental Study on Murine Model.March 16, 2022. Publisher Full Text"
}
|
[
{
"id": "151519",
"date": "15 Nov 2022",
"name": "Timo Gaber",
"expertise": [
"Reviewer Expertise Bone tissue engineering",
"tissue regeneration",
"immunometabolism",
"immunology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe research article entitled “Bone tissue engineering application on fracture healing with bone defect as assessed through osteocalcin and bone morphogenetic protein-2 (BMP-2) biomarker examination: experimental study on murine models” by Sananta et al. deals with the analysis of bone fracture healing of critical size defects using Wistar rats (instead of mice!) using bone tissue engineering. Three different approaches have been conducted: (i) porous-carbonated HA, (ii) nanocrystalline HA (iii) bovine HA each combined with a non-defined stromal vascular fraction from adipose tissue compared to (iv) a control group without bone defect (but with surgical intervention? Or not?) and (v) a control group with the bone defect. Readout parameters were osteocalcin (OC) and BMP2 levels. The complete study is poorly described. The diction of the English language is in great need of improvement, as the entire text is difficult, almost incomprehensible. In particular, the wording for mice and rats was mixed-up. Several major concerns have emerged in the scientific work:\nThe basic hypothesis to conduct the animal experiments is missing. What are the primary and secondary outcome parameters? How was bone healing influenced and how was the impact on bone healing measured?\n\nThe power analysis to determine the number of animals needed is missing.\n\nQuality controls and characterization of adipose tissue, stromal vascular fraction and mature adipocytes are missing. How much was added to the fracture gap and what was the frequency of subpopulations?\n\nThe study is poorly designed. The sham control is missing. The SVF-only control and the HA-controls are missing.\n\nThe number of animals used is quite low. A power analysis would have been useful. Sample withdrawal for ELISA of OC and BMP-2 is not explained. Inclusion criteria are poorly defined (What does “fit” mean?). Exclusion and termination criteria are not defined.\n\nStatistical analyses are poorly described (e.g., what kind of post-hoc test?).\nMinor concerns:\nThe requirements for the Arrive guidelines are not sufficiently met or described\n\nThe abbreviation must be explained when used the first time, e.g., SVF in the abstract.\n\nMaterials and methods must be clearly described. In particular, surgical procedures and evaluation of fracture healing.\n\nUnits for OC and BMP-2 are missing in the figures and figure legends.\nAn inadequate study design and lack of controls lead to the assessment that even a revision without large experimental effort is currently not possible and therefore only the rejection of the manuscript comes into account.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "154881",
"date": "15 Nov 2022",
"name": "Kok-Yong Chin",
"expertise": [
"Reviewer Expertise Bone metabolism",
"osteoporosis",
"vitamin E"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors demonstrated that stromal vascular fraction and bovine bone scaffold could increase osteocalcin and BMP2 expression at the bone defect. My major contention for the paper is that the scope is too small and the increase in both biomarkers could not justify enhanced bone healing in the treated animals. Most importantly, physical evidence of healing through microCT or histological techniques is not demonstrated. These data should be available since the bone samples were available for the study. The authors should be well aware that bone defect healing is a multistage process, and the aforementioned markers cannot encapsulate the processes.\n\nI also question the sample size (4 rats/group), which is not justified properly in the methodology. I am not sure which ANOVA test they have chosen but I assumed one-way ANOVA. How did the authors process the post hoc comparison if the KS test were positive?\n\nThe bone protein extraction protocol is not mentioned. I am not sure the results were normalized with total protein concentration. In view of this, I cannot trust the protein level of both markers.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-596
|
https://f1000research.com/articles/11-470/v1
|
28 Apr 22
|
{
"type": "Research Article",
"title": "Presenteeism and associated factors among railway train drivers",
"authors": [
"Asmaa El-Sayed Awaad",
"Sohair El-Bestar",
"Abdel-Hady El-Gilany",
"Adel Al-Wehedy",
"Samah Saleh El-Hadidy",
"Sohair El-Bestar",
"Abdel-Hady El-Gilany",
"Adel Al-Wehedy",
"Samah Saleh El-Hadidy"
],
"abstract": "Background: Presenteeism is an emerging work-related health problem among train drivers. It is more serious than absenteeism, as it accounts for higher productivity losses and may increase the risk of occupational accidents. Train drivers have high rates of mental and physical health conditions that may put them at high risk of presenteeism. Methods: A comparative cross-sectional study was conducted on 100 train drivers working in Mansoura railway station and 100 administrative employees working in the Faculty of Medicine, Mansoura university as a comparison group to estimate the prevalence of presenteeism and its associated factors among train drivers working in Mansoura railway station, Egypt. A questionnaire was used to collect socio-demographic, occupational and medical data. The Kessler Psychological Distress Scale (K10) was used to measure non-specific psychological distress. The Stanford Presenteeism Scale (SPS-6) was used to assess productivity loss related to sickness presenteeism. Results: The prevalence of presenteeism was significantly higher among train drivers (76%) compared to the comparison group (31%). All participants (100%) with psychological distress reported presenteeism. Being a train driver (adjusted odds ratio [AOR]=5.4) and having hypertension (AOR=4.03) are independent predictors for presenteeism. Conclusions: The prevalence of presenteeism and its associated risk factors were significantly higher among train drivers than the comparison group. There is an urgent need for the railway industry to understand the factors that may contribute to presenteeism.",
"keywords": [
"Railway",
"Egyptian train drivers",
"Presenteeism",
"Stanford presenteeism scale-6",
"Psychological distress"
],
"content": "Introduction\n\nPresenteeism is defined as “the phenomenon of people, despite complaints and ill health that should prompt rest and absence from work, still turning up at their jobs”.1 Presenteeism can negatively affect productivity in a way similar to absenteeism. However, presenteeism involves higher productivity losses than absenteeism.2 It can decrease work productivity and working safely and may increase the risk of occupational accidents.3 Presenteeism is more costly to employers than absenteeism, since employers pay the employees for their attendance at work and prolonged work time to complete a task. They also pay them for any compensation as a result of errors done by sick employees.4\n\nCertain difficulties in work can increase the risk of presenteeism such as; the fear of un employment or losing a job, staff replacement, and financial difficulties.1,5 Lack of control over tasks and inadequate support from coworkers are also risk factors associated with higher risk of presenteeism.6,7\n\nPresenteeism has been linked to stress at work.8 Stress and subsequently psychological distress are considered to be significant contributors to presenteeism.9–11\n\nIn the railway industry, presenteeism is a common problem among train drivers as they have to deal with a high level of job demands and responsibilities.12 Train driving is a high-strain job which needs complex skills. A healthy physical and mental condition of train drivers is also very important since, their vigilance and attention are crucial to their job. The work-place environment and its different hazards increase the work load among train drivers.13 They are exposed to several psychosocial risk factors such as; working in shifts, lone working and irregular working hours, long hours of duty with rigid protocols and little options for taking rest. These factors are considered a source of stress and mental suffering among train drivers affecting their health, interfering with their attention and concentration and directly influence the prevalence of presenteeism.14–16\n\nThe presence of chronic conditions is also a major risk factor for presenteeism. Chronic conditions can lead to inadequate work performance as a result of poor physical and psychological well-being of workers.17,18 Cardiovascular risk factors such as obesity, hypertension and dyslipidemia were the most prevalent health conditions in train drivers and also have the greatest impact on their fitness for duty.19 Several studies have found that health risks such as obesity, physical inactivity, poor diet, hypertension, hypercholesterolemia and musculoskeletal pain are directly related to productivity loss if the workers continue to work while ill.10,20 Furthermore, presenteeism may exacerbate the existing health conditions and impair the quality of life of sick employees.20 To the best of the authors’ knowledge, this work is the first attempt to study the problem of presenteeism and its association with physical and psychological health status among railway train drivers in Egypt.\n\nThis study aims to estimate the prevalence of presenteeism and determine its possible associated factors among train drivers working at Mansoura railway station.\n\n\nMethods\n\nThis manuscript is abstracted from an MD thesis (not published yet) that was approved by Institutional Research Board (IRB) of Faculty of Medicine, Mansoura University, code number: MD.18.12.108. Approval of all responsible authorities was obtained. Written informed consent was obtained from participants with assurance of confidentiality. The questionnaire was anonymous. A copy from laboratory investigation was given to each participant with suitable advice in case of abnormal findings for further management.\n\nThe study was conducted on train drivers working at Mansoura railway station located in the Central Delta Region of the Egyptian National Railways (ENR) during the period from February to November 2019.\n\nCross-sectional comparative study.\n\nThis study included all train drivers and their assistants working in Mansoura railway station. They were requested personally by the investigator and asked to participate voluntarily in the study. All eligible train drivers and their assistants who accepted to participate in the study and had the following inclusion criteria were recruited; working for at least one year, in both day and night shifts and in both passenger and freight (goods) transport. Train drivers who were away from train driving and shifted to administrative work due to medical or non-medical causes were not included in the study. The total workforce in the group was 100, including; 58 train drivers and 42 train driver assistants. An equal number of 100 participants were chosen from the administrative staff working in the Faculty of Medicine, Mansoura university as a comparison group. Both groups were matched in their socio-demographic characteristics.\n\nTrain drivers were interviewed and examined at 8 am in the off days or either before or after shift in a specific room at a nearby hospital (Mogamaa Al-Eyman Hospital), near to Mansoura railway station; while for the comparison group, the study was carried out at Public Health and Community Medicine Department, Faculty of Medicine, Mansoura university, during the work day. The interview and examination of study participants were carried out in the same session personally by the investigator and lasted for 20-30 minutes for each participant, including filling in the questionnaire; clinical examination and withdrawing blood samples for laboratory investigation. The blood samples were collected between 8-9 am in a sitting position after 10-12 hours of fasting to assess lipid profile then the samples were transferred in an icebox to the laboratory of Clinical Pathology Department, Faculty of Medicine where biochemical evaluation was carried out. The research work was carried out 2-3 times weekly, at times suitable to the study participants, with an average of 8-10 participants per setting.\n\nParticipants in both groups were subjected to:\n\n1) A pre-designed questionnaire to collect the following data; sociodemographic characteristics and personal history, occupational history and physical complaints in the last 12 months.53 No preliminary testing was done as sociodemographics, occupational and clinical data have no scoring to create latent variable. Physical complaints were arranged according to international classification of diseases ICD-10, World health Organization version 201621 and included; ocular, auditory, respiratory, dermatological, musculoskeletal, cardiovascular and neurological complaints. Cardiovascular complaints included; chest pain, chest tightness, shortness of breath and palpitation. Neurological complaints included; difficulty in concentration, tingling and/or numbness in toes or fingers and pain and/or weakness in distal muscles.\n\n2) Kessler Psychological Distress Scale (K10): a widely-known measure of non-specific psychological distress based on behavioral, emotional, cognitive, and psychophysiological manifestations.22 The questionnaire (K10) measures the frequency with which the individual developed anxiety and depression symptoms in the past month. The questionnaire consists of 10 questions, each of which has five possible response choices ranging from “none of the time” to “all of the time” with scores from 1 to 5. The highest score is 50, which indicate severe distress, and the lowest score is 10 indicating no distress. Scores of 11-19 indicates low level of distress, 20–24 indicates mild level of distress, 25–29 moderate level of distress and scores of 30–50 indicates severe or very high psychological distress. Psychological distress is determined with a score higher than 19 (>19).23 Arabic translation of questions was derived from the Arabic version of the ten-item version of Kessler Psychological Distress Scale (K10).24\n\n3) Stanford Presenteeism Scale (SPS-6): a well-known measure of productivity loss related to sickness presenteeism. It has two parts; in the first part, prevalence of sickness presenteeism is determined using the following question; ‘During the last month have you shown up for work despite feeling sick or having a health problem that prevented you from carrying out your tasks in a normal manner?’.25 If presenteeism is detected in the first part, the second part of the questionnaire should be completed, it consists of six-items with a five-point scale of responses ranging from strongly disagree to strongly agree and scored from 1 to 5 translated in to Arabic. Questions 1, 3 and 4 evaluate the ability of the respondents to concentrate during work performance; while the questions 2, 5 and 6 assess the interference of the reported health problems with the ability to complete work.26 Scores can range from 6-30, with lower scores (≤18) indicting presenteeism (decreased productivity and below-normal work quality due to an illness), and higher scores (>18) indicating a greater ability to concentrate on and accomplish work despite health problem(s).26\n\n4) Blood pressure measurement: a mercury sphygmomanometer (Alpk2 300-V, Japan) was used to measure blood pressure on the right arm supported at heart level in the seated position after five minutes of rest. It was measured twice at five-minute intervals and the average of both readings was used to estimate the individual’s blood pressure.27 Hypertension is considered when systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg; or current use of antihypertensive treatment.28\n\n5) Anthropometric measurements: body weight was measured in kilograms with a portable mechanical weighing scale (Laica LC02/e-11/2013, China). Height was measured in centimeters. Body mass index: was derived by dividing the weight in kilograms by the square of the height in meters (kg/m2). According to BMI, the subject is classified as: underweight (BMI <18.5) normal weight (BMI ≥ 18.5 to < 25), overweight (BMI ≥ 25 to < 30) and obese (BMI ≥ 30).29,30\n\n6) Laboratory investigation: a 2 ml peripheral blood sample was obtained from the antecubital vein of each participant after 10-12 hours of fasting for biochemical testing (lipid profile). Blood samples were collected in glass tubes and transferred immediately to the laboratory of Clinical Pathology Department, Faculty of Medicine where total cholesterol, low-density lipoprotein (LDL-cholesterol), high-density lipoprotein (HDL-cholesterol), and triglycerides serum levels were measured (Roche copus c111 analyzer, Switzerland). Dyslipidemia was defined as abnormalities in the plasma lipids occurring either singly or in combinations measured in milligrams (mg) per deciliter (dl) of blood and converted in to SI units (mmol/L), including; total cholesterol ≥200 mg/dL (≥5.18 mmol/L), LDL ≥130 mg/dl (≥3.36 mmol/L), triglycerides ≥150 mg/dl (≥1.69 mmol/L) and HDL <40 mg/dl (<1.03 mmol/L) and/or using lipid-lowering medications.31,32\n\nData were entered and statistically analyzed using (SPSS version 16.0, RRID:SCR_016479). Qualitative variables were expressed as numbers and percentages. Chi-square test (χ2) was used for significance testing of categorical data; as appropriate. Crude odds ratios (COR) and their 95% confidence intervals (CI) were calculated. Quantitative data were described as means ±SD (standard deviation) after testing for normality using Shapiro test and for comparison between groups, independent sample t-test was used. Significant predictors of presenteeism in bivariate analysis were entered into binary stepwise logistic regression for prediction of independent predictors of presenteeism. Adjusted odds ratios (AOR) and their 95% confidence intervals (CI) were calculated. A statistically significant difference was considered at P value ≤0.05.\n\n\nResults\n\nThe number of participants at each stage of the study was 200 (100 train drivers and 100 comparison group) except for the stage of laboratory investigation where the number of participants was 185 (92 train drivers and 93 comparison group) indicating those who accepted to give blood sample for laboratory investigation.52\n\nTable 1 reveals that train drivers matched the comparison group in all sociodemographic characteristics with no statistically significant differences (P>0.05). There is no statistically significant difference (P>0.05) between duration of employment in both groups. However, the mean working hours per week is statistically significantly higher (P≤0.001) among train drivers (65.52±8.7 hours) compared to the comparison group (35.88±0.8 hours). Most of the train drivers (72%) worked alternating day and night shifts while all the comparison group (100%) worked only day shifts with a highly statistically significant difference (P≤0.001).\n\na Day shift (6:00 a.m. to 6:00 p.m.); and night shift (6:00 p.m. to 6:00 a.m.). SD=standard deviation.\n\nTable 2 shows that the most frequent physical complaints among train drivers during the last 12 months were musculoskeletal complaints (60%), followed by neurological (47%), then cardiovascular complaints (33%). In the comparison group, the musculoskeletal complaints (36%) ranked the first, followed by ocular (17%) and neurological complaints (17%). Almost all physical complaints were more frequent among train drivers compared to the comparison group with a statistically significant difference (P≤0.05) except for auditory and dermatological complaints where the difference was statistically not significant (P>0.05)\n\nTable 3 shows that the prevalence of obesity, hypertension, dyslipidemia and psychological distress are statistically significantly higher among train drivers compared to the comparison group (P≤0.001).\n\nb Hypertension cases (46 vs. 16) = previously diagnosed cases of HTN (26 vs. 11) - in addition to newly discovered cases of HTN (20 vs. 5).\n\nc Participants who accepted to give a blood sample for laboratory investigation - train drivers (n=92) & comparison group (n=93).\n\nTable 4 shows that there is a higher prevalence of presenteeism among train drivers compared to the comparison group (76% and 31%, respectively) with a highly statistically significant difference (P≤0.001). In total, 54 persons out of 76 (71.1%) train drivers with presenteeism have lower scores (≤18) of the Stanford Presenteeism Scale and reduced performance at work compared to 13 persons out of 31 (41.9%) among the comparison group. The mean score of SPS-6 is significantly (P≤0.001) lower among train drivers (15.7±3.7) compared to the comparison group (19.2±2.9).\n\nd Percentage within presenteeism. SD=standard deviation.\n\nThe bivariate analysis (Table 5) shows that all participants (100%) with psychological distress reported presenteeism. Furthermore, logistic regression analysis shows that being a train driver (AOR=5.4) and having hypertension (AOR=4.03) are independently associated with the likelihood of having presenteeism.\n\n*, ** and *** = significant difference at P≤0.05, P≤0.01 and P≤0.001 respectively.\n\ne Total for dyslipidemia =185 (15 subjects are missed).\n\n\nDiscussion\n\nPresenteeism is a term used when employees come into work despite physical or psychological health problems. So, they may not be able to fully perform their duties and are more likely to make mistakes on their job. In the present study, almost all physical complaints and morbidities were more frequent among train drivers compared to the comparison group with a statistically significant difference (P≤0.05) (Tables 2, 3). Train driving is a high-level job where the workers’ ill health may lead directly to a serious incident affecting the rail network and public safety since, the vigilance and attention of train drivers are crucial to their job. They are also responsible for people’s lives. So, going to work despite physical or psychological health problems (presenteeism) may increase the risk of occupational injuries and train accidents.\n\nThe number of existing studies on presenteeism among train drivers is scant, and most studies on presenteeism have analyzed healthcare workers especially nurses.33–36\n\nIn the current study, there is a higher prevalence of presenteeism among train drivers (76%) compared to the comparison group (31%) with a high statistically significant difference (P≤0.001) (Table 4). Logistic regression analysis shows that being a train driver (AOR=5.4) is an independent predictor of presenteeism (Table 5).\n\nThe prevalence of presenteeism among Egyptian train drivers in the current study (76%) is shown to be similar to that of nurses (76.2%) working in hospitals of Croatia.34 However, a lower prevalence of presenteeism (52%) was detected among railroad workers in Korea.12 Also, a lower prevalence was detected in other occupations such as police officers in Sweden (46.5%),37 workers at a food industrial company in Brazil (50.9%)5 and employees in South Korea (41.2%).38\n\nPresenteeism is usually common among workers whose occupations involve high job demands and relatively large individual responsibility, where the personnel are required to be in place, with minimal chance for temporary replacement such as; train drivers and health care providers. In such occupations, inadequate physical and psychological status of the affected workers can interfere with maintaining vigilance and concentration.35,37 Presenteeism is common among train drivers than other railway occupations due to higher job strain among train drivers.12\n\nIn the present work, bivariate analysis shows that all participants (100%) with psychological distress reported presenteeism (Table 5). Similarly, several studies support the positive association between psychological distress and presenteeism.11,39–41 Psychological health problems may be more linked to presenteeism than absenteeism because it may be more difficult to ensure that absence is due to this reason.2\n\nTrain drivers were exposed to several psychosocial risk factors in the workplace affecting their mental and psychological wellbeing and may result in mental and psychological health problems, such as; shift work, high job demands, limited decisional latitude and job insecurity which can adversely affect their health and directly influence the prevalence of presenteeism.14–16 Working night and/or alternating day and night shifts was shown to be associated with presenteeism in our study in bivariate analysis (Table 5). This was compliant with a study conducted upon Korean workers in which a higher presenteeism was reported among shift workers than non-shift workers.42 Shift workers are particularly vulnerable to long hours of duty and insufficient rest elevating their risk to develop presenteeism.\n\nThe current study revealed a positive association between different health conditions and presenteeism, logistic regression analysis shows that hypertension was an independent predictor for presenteeism (AOR=4.03) (Table 5). This was in agreement with a study conducted among Chinese workers where a higher prevalence of presenteeism was found among workers with high blood pressure.20 Similarly in the United States, all individuals with hypertension were more likely to report lost productive time (LPT) while at work (presenteeism) compared to normotensive individuals.43 However, there was no significant association between lost productivity and hypertension in a study conducted to assess the effect of different cardio-metabolic risk factors including hypertension on productivity.44 The greater impact of hypertension on LPT and presenteeism can be explained by hypertension being largely undertreated despite its high prevalence rates,45 probably due to late access to health care and poor compliance to medication regimens resulting in inadequate control of hypertension, so, the workers may go to work while ill (hypertensive).46,47\n\nA significant association between presenteeism and obesity was detected in bivariate analysis (Table 5) which was similarly found in workers in Petrochemical industry in China20 and workers at a food industrial company in Brazil.5 This could be attributed to sedentary work of train drivers and its negative impact on their health. Sedentary work with insufficient movement and muscle activity, low energy expenditure and lack of changes in posture may result in low physical activity and obesity.48 Also, the high job demands among train drivers can cause stress and unhealthy dietary behaviors that may result in obesity and increase its negative impact on health and consequently greater adverse workplace effects such as presenteeism.49 Furthermore, obesity is considered an important risk factor for cardiovascular disease, as it can increase the prevalence and severity of cardiovascular risk factors such as; diabetes mellitus (type II), dyslipidemia and hypertension.50 So, it can significantly exacerbate the adverse effects of these conditions on productivity.44\n\nMoreover, the present findings revealed a significant association between musculoskeletal complaints and presenteeism among train drivers (Table 5). Correspondingly in Brazil, a positive association was found between presenteeism and occurrence of musculoskeletal symptoms.5 Musculoskeletal problems may interfere with work and daily life activities as a result of functional limitations. They also arouse feelings of ineffectiveness and uselessness resulting in a lack of productivity.51 So, targeting and assessment of the underlying health risks that might lead to presenteeism in the workplace is a critical issue for its control and management.\n\n\nConclusions\n\nIn the present study, the prevalence of presenteeism and its associated risk factors are significantly higher among train drivers than the comparison group. All participants with psychological distress reported presenteeism. Being a train driver and having hypertension are independently associated with the likelihood of having presenteeism. There is an urgent need for the railway industry to understand the factors that contribute to presenteeism. Of particular interest are, the use of effective health promotion programs and effective physical and psychological assessment that may play a role in increasing worker productivity and reduction in presenteeism. Provision of enough rest periods after shifts, and regulation of work to facilitate sick leaves when needed are recommended to ameliorate presenteeism. A large scale national study including all train drivers is recommended.\n\nThe study was conducted in single locality with a relatively small sample size. So, the results can’t be generalized to all train drivers. There is a possibility of recall bias in physical complaints such as; musculoskeletal, cardiovascular and neurological complaints.\n\n\nData availability\n\nHarvard Dataverse: Presenteeism and associated factors among railway train drivers. https://doi.org/10.7910/DVN/CG8Z1K.52\n\nHarvard Dataverse: questionnaire and informed consent form for “Presenteeism and associated factors among railway train drivers”. https://doi.org/10.7910/DVN/ZGY5UB.53\n\nThis project contains the following extended data:\n\n- informed written consent.doc\n\n- questionnaire.docx\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgements\n\nThe authors would like to acknowledge Mansoura railway station administration for their help and support. Also, we thank the participants for their participation in the study.\n\n\nReferences\n\nAronsson G, Gustafsson K: Sickness Presenteeism: Prevalence, Attendance-Pressure Factors, and an Outline of a Model for Research. J. Occup. Environ. Med. 2005 Sep; 47(9): 958–966. PubMed Abstract | Publisher Full Text Reference Source\n\nJohns G: Presenteeism in the workplace: A review and research agenda. J. Organ. Behav. 2010 May; 31(4): 519–542. Publisher Full Text\n\nQueiroz-Lima ME, Serranheira F: Absenteeism and presenteeism costs from occupational accidents with WRMSDs in a Portuguese hospital. Dyna. 2016 Apr; 83(196): 27–30. Publisher Full Text\n\nHui SK, Grandner MA: Trouble sleeping associated with lower work performance and greater healthcare costs: longitudinal data from Kansas state employee wellness program. Journal of Occupational and Environmental Medicine/American College of Occupational and Environmental Medicine. 2015 Oct; 57(10): 1031–1038. PubMed Abstract | Publisher Full Text\n\nSilva BM, Zanatta AB, de Lucca SR : Prevalence of presenteeism among workers of an industrial company. Revista brasileira de medicina do trabalho. 2017; 15(3): 236–243. PubMed Abstract | Publisher Full Text\n\nDew K, Keefe V, Small K: ‘Choosing’to work when sick: workplace presenteeism. Soc. Sci. Med. 2005 May 1; 60(10): 2273–2282. Publisher Full Text\n\nGosselin E, Lemyre L, Corneil W: Presenteeism and absenteeism: differentiated understanding of related phenomena. J. Occup. Health Psychol. 2013 Jan; 18(1): 75–86. PubMed Abstract | Publisher Full Text\n\nBaldonedo-Mosteiro M, Sánchez-Zaballos M, Rodríguez-Díaz FJ, et al.: Adaptation and validation of the Stanford Presenteeism Scale-6 in healthcare professionals. Int. Nurs. Rev. 2020 Mar; 67(1): 109–117. PubMed Abstract | Publisher Full Text\n\nHilton MF, Whiteford HA: Interacting with the public as a risk factor for employee psychological distress. BMC Public Health. 2010 Dec; 10(1): 1–7. PubMed Abstract | Publisher Full Text\n\nCallen BL, Lindley LC, Niederhauser VP: Health risk factors associated with presenteeism in the workplace. J. Occup. Environ. Med. 2013 Nov 1; 55(11): 1312–1317. Publisher Full Text Reference Source\n\nCoutu MF, Corbiere M, Durand MJ, et al.: Factors associated with presenteeism and psychological distress using a theory-driven approach. J. Occup. Environ. Med. 2015 Jun 1; 57(6): 617–626. PubMed Abstract | Publisher Full Text Reference Source\n\nRyu IS, Jeong DS, Kim IA, et al.: Association between job stress, psychosocial well-being and presenteeism, absenteeism: focusing on railroad workers. Korean Journal of Occupational and Environmental Medicine. 2012 Sep 1; 24(3): 263–273. Publisher Full Text\n\nLoukzadeh Z, Zare ZO, Mehrparvar AH, et al.: Fitness-for-work assessment of train drivers of Yazd railway, central Iran. Int. J. Occup. Environ. Med. 2013 Jul 1; 4(3): 157–163. PubMed Abstract | Publisher Full Text\n\nHertz RP, Unger AN, McDonald M, et al.: The impact of obesity on work limitations and cardiovascular risk factors in the US workforce. J. Occup. Environ. Med. 2004 Dec 1; 46: 1196–1203. PubMed Abstract Reference Source\n\nSelligmann-Silva E: Presenteísmo em diferentes países. Rev Proteção. 2011. Reference Source\n\nde Lucca SR : Application of an instrument for diagnosis of psychosocial risk factors in organizations/Aplicacao de instrumento para o diagnostico dos fatores de risco psicossociais nas organizacoes. Revista Brasileira de Medicina do Trabalho. 2017 Jan 1; 15(1): 63–72. Publisher Full Text Reference Source\n\nSchultz AB, Edington DW: Employee health and presenteeism: a systematic review. J. Occup. Rehabil. 2007 Sep; 17(3): 547–579. Publisher Full Text\n\nSteultjens E, Baker N, Aas RW: Organizational leadership, health risk screening, individually tailored programs, and supportive workplace culture might reduce presenteeism. Aust. Occup. Ther. J. 2012; 59(3): 247–248. PubMed Abstract | Publisher Full Text\n\nMina R, Casolin A: National standard for health assessment of rail safety workers: the first year. Med. J. Aust. 2007 Oct; 187(7): 394–397. PubMed Abstract | Publisher Full Text\n\nYu J, Wang S, Yu X: Health risk factors associated with presenteeism in a Chinese enterprise. Occup. Med. 2015 Dec 1; 65(9): kqv115–kqv738. Publisher Full Text\n\nWorld Health Organization: International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)-WHO Version for 2016. Geneva: WHO; 2016. Reference Source\n\nKessler RC, Andrews G, Colpe LJ, et al.: Short screening scales to monitor population prevalences and trends in non-specific psychological distress. Psychol. Med. 2002 Aug; 32(6): 959–976. PubMed Abstract | Publisher Full Text\n\nYiengprugsawan V, Kelly M, Tawatsupa B: Kessler Psychological Distress Scale. Michalos AC, editors. Encyclopedia of Quality of Life and Well-Being Research. Dordrecht: Springer; 2014; 1–3. Publisher Full Text\n\nEaston SD, Safadi NS, Wang Y, et al.: The Kessler psychological distress scale: translation and validation of an Arabic version. Health Qual. Life Outcomes. 2017 Dec; 15(1): 215. PubMed Abstract | Publisher Full Text\n\nAronsson G, Gustafsson K, Dallner M: Sick but yet at work. An empirical study of sickness presenteeism. J. Epidemiol. Community Health. 2000 Jul 1; 54(7): 502–509. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKoopman C, Pelletier KR, Murray JF, et al.: Stanford presenteeism scale: health status and employee productivity. J. Occup. Environ. Med. 2002 Jan 1; 44: 14–20. PubMed Abstract | Publisher Full Text Reference Source\n\nMuntner P, Shimbo D, Carey RM, et al.: Measurement of blood pressure in humans: a scientific statement from the American Heart Association. Hypertension. 2019 May; 73(5): e35–e66. PubMed Abstract | Publisher Full Text\n\nChobanian AV, Bakris GL, Black HR, et al.: The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003 May 21; 289(19): 2560–2572. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: Obesity: preventing and managing the global epidemic. Geneva: World Health Organization; 2000.\n\nConsultation WE: Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet (London, England). 2004 Jan 10; 363(9403): 157–163. PubMed Abstract | Publisher Full Text\n\nNielsen TR, Lausten-Thomsen U, Fonvig CE, et al.: Dyslipidemia and reference values for fasting plasma lipid concentrations in Danish/North-European White children and adolescents. BMC Pediatr. 2017 Dec; 17(1): 111–116. PubMed Abstract | Publisher Full Text\n\nRhee EJ, Kim HC, Kim JH, et al.: 2018 Guidelines for the management of dyslipidemia in Korea. Journal of Lipid and Atherosclerosis. 2019 Sep 1; 8(2): 78–131. PubMed Abstract | Publisher Full Text\n\nMartinez LF, Ferreira AI: Sick at work: presenteeism among nurses in a Portuguese public hospital. Stress. Health. 2012 Oct; 28(4): 297–304. PubMed Abstract | Publisher Full Text\n\nBrborović H, Brborović O, Brumen V, et al.: Are nurse presenteeism and patient safety culture associated: a cross-sectional study. Arh. Hig. Rada Toksikol. 2014 Jun 11; 65(2): 149–156. PubMed Abstract | Publisher Full Text\n\nHomrich PH, Dantas-Filho FF, Martins LL, et al.: Presenteeism among health care workers: literature review. Revista Brasileira de Medicina do Trabalho. 2020; 18(1): 97–102. PubMed Abstract | Publisher Full Text\n\nImai C, Hall L, Lambert SB, et al.: Presenteeism among health care workers with laboratory-confirmed influenza infection: A retrospective cohort study in Queensland, Australia. Am. J. Infect. Control. 2020 Apr 1; 48(4): 355–360. PubMed Abstract | Publisher Full Text\n\nLeineweber C, Westerlund H, Hagberg J, et al.: Sickness presenteeism among Swedish police officers. J. Occup. Rehabil. 2011 Mar; 21(1): 17–22. PubMed Abstract | Publisher Full Text\n\nYi JS, Kim H: Factors related to presenteeism among South Korean workers exposed to workplace psychological adverse social behavior. Int. J. Environ. Res. Public Health. 2020 Jan; 17(10): 3472. PubMed Abstract | Publisher Full Text\n\nMiraglia M, Johns G: Going to work ill: A meta-analysis of the correlates of presenteeism and a dual-path model. J. Occup. Health Psychol. 2016 Jul; 21(3): 261–283. PubMed Abstract | Publisher Full Text\n\nYang T, Shen YM, Zhu M, et al.: Effects of co-worker and supervisor support on job stress and presenteeism in an aging workforce: a structural equation modelling approach. Int. J. Environ. Res. Public Health. 2016 Jan; 13(1): 72. PubMed Abstract | Publisher Full Text\n\nSkela-Savič B, Pesjak K, Hvalič-Touzery S: Low back pain among nurses in Slovenian hospitals: cross-sectional study. Int. Nurs. Rev. 2017 Dec; 64(4): 544–551. PubMed Abstract | Publisher Full Text\n\nJeon SH, Leem JH, Park SG, et al.: Association among working hours, occupational stress, and presenteeism among wage workers: results from the Second Korean Working Conditions Survey. Ann. Occup. Environ. Med. 2014 Dec; 26(1): 6. PubMed Abstract | Publisher Full Text\n\nUnmuessig V, Fishman PA, Vrijhoef HJ, et al.: Association of controlled and uncontrolled hypertension with workplace productivity. J. Clin. Hypertens. 2016 Mar; 18(3): 217–222. PubMed Abstract | Publisher Full Text\n\nSullivan PW, Ghushchyan V, Ben-Joseph RH: The effect of obesity and cardiometabolic risk factors on expenditures and productivity in the United States. Obesity. 2008 Sep; 16(9): 2155–2162. PubMed Abstract | Publisher Full Text\n\nGoldstein LB, Bushnell CD, Adams RJ, et al.: Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011 Feb; 42(2): 517–584. Publisher Full Text\n\nCenters for Disease Control and Prevention (CDC: Vital signs: prevalence, treatment, and control of hypertension--United States, 1999-2002 and 2005-2008. MMWR Morb. Mortal. Wkly Rep. 2011 Feb 4; 60(4): 103–108.\n\nMitchell RJ, Bates P: Measuring health-related productivity loss. Popul. Health Manag. 2011 Apr 1; 14(2): 93–98. PubMed Abstract | Publisher Full Text\n\nStraker L, Dunstan D, Gilson N, et al.: Sedentary work. Evidence on an emergent work health and safety issue – Final Report. Canberra: Safe Work Australia; 2016.\n\nBorak J: Obesity and the workplace. Occup. Med. 2011 Jun 1; 61(4): 220–222. Publisher Full Text\n\nProspective Studies Collaboration: Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009 Mar 28; 373(9669): 1083–1096. PubMed Abstract | Publisher Full Text\n\nSantos HE, Marziale MH, Felli VE: Presentismo y síntomas musculoesqueléticos entre trabajadores de enfermería. Rev. Lat. Am. Enfermagem. 2018 May 7; 26: e3006. PubMed Abstract | Publisher Full Text\n\nAwaad A: Presenteeism and associated factors among railway train drivers. [Dataset] Harvard Dataverse, 2022, V2, UNF:6:QiDsEfG9lEVvgZ4c6lQi1A== [fileUNF]. Publisher Full Text\n\nAwaad A: Replication Data for: questionnaire and informed consent for Presenteeism and associated factors among railway train drivers. Harvard Dataverse. 2022; V1. Publisher Full Text"
}
|
[
{
"id": "136241",
"date": "25 May 2022",
"name": "Alisha McGregor",
"expertise": [
"Reviewer Expertise Presenteeism"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThanks for giving me the opportunity to review this article on presenteeism amongst train drivers in Egypt.\n\nI have some comments for consideration below.\n\nIn the intro, the author says that presenteeism results in greater productivity losses than absenteeism, which is correct over the long term; However, on any given day that a worker chooses presenteeism over absenteeism they are going to be more productive. In that even if they are only 20% productive when they come into work ill this is still more than if they chose to take the day off (i.e., 0% productivity). I think this should be considered when talking about productivity losses associated with presenteeism compared to absenteeism.\n\nThe author has used Aronsson and Gustafsson definition of presenteeism in the intro but then measures the construct using the SPS-6 scale which incorporates productivity into the measure. The author could consider modifying their definition of the construct to be consistent with the way they have measured presenteeism in the study.\n\nVery limited discussion of the predictors of presenteeism in the intro, this could be expanded upon.\n\nIn the methods section - the use of the heading 'flow of work' seems odd. I have never seen the study procedure described in this way. Please review.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8290",
"date": "01 Jun 2022",
"name": "Asmaa Awaad",
"role": "Author Response",
"response": "We thank Dr. McGregor for reviewing our manuscript. We present our responses below each comment as well as a new version of our manuscript (Version #2) In the intro, the author says that presenteeism results in greater productivity losses than absenteeism, which is correct over the long term; However, on any given day that a worker chooses presenteeism over absenteeism they are going to be more productive. In that even if they are only 20% productive when they come into work ill this is still more than if they chose to take the day off (i.e., 0% productivity). I think this should be considered when talking about productivity losses associated with presenteeism compared to absenteeism. Response: Thank you, the term \"over the long term\" is added to the sentence (presenteeism involves higher productivity losses than absenteeism over the long term) The author has used Aronsson and Gustafsson definition of presenteeism in the intro but then measures the construct using the SPS-6 scale which incorporates productivity into the measure. The author could consider modifying their definition of the construct to be consistent with the way they have measured presenteeism in the study. Response: Thank you, the definition is modified to be consistent with the way we have measured presenteeism in the study. Very limited discussion of the predictors of presenteeism in the intro, this could be expanded upon. Response: Thank you, pain including; musculoskeletal and neurological pain are added to the predictors of presenteeism in the intro. In the methods section - the use of the heading 'flow of work' seems odd. I have never seen the study procedure described in this way. Please review. Response: Thank you, the heading 'flow of work' is replaced by \"study procedure\""
}
]
}
] | 1
|
https://f1000research.com/articles/11-470
|
https://f1000research.com/articles/11-595/v1
|
01 Jun 22
|
{
"type": "Research Article",
"title": "The role of technology capability in supporting firm performance in the high-tech manufacturing industry",
"authors": [
"Noerlina Noerlina",
"Christie Nugroho",
"Tirta Nugraha Mursitama",
"Boto Simatupang",
"Agustinus Bandur",
"Noerlina Noerlina",
"Tirta Nugraha Mursitama",
"Boto Simatupang",
"Agustinus Bandur"
],
"abstract": "Background: Technology has influenced many aspects of life, particularly in the digital era of today. Companies that are closely related to technology are also challenged to keep innovating to stay competitive in the market, especially the higher their technology intensity their products and services are related. This study focuses on examining the technology capability of high-tech manufacturing firms in Indonesia. According to the International Standard Industrial Classification, high-tech manufacturing firms are firms that manufacture computer, electronic, and optical products. The aim of this study is to identify the role of technology capability that influences a firm’s performance and identify whether the value chain mediates the relationship between technology capability to firm performance. Methods: The method used in this study is descriptive quantitative analysis, using multi-linear regression and path analysis to test the hypothesis. The data used in this study is secondary data that came from Badan Pusat Statistik (BPS), Indonesia's official statistics agency. The survey data used in this study comes from Indonesia's annual survey of manufacturing firms in 2017. Result: Technology capability and value chain have significant effects on firm performance. Nonetheless, the value chain as an intervening variable has no significant effect on firm performance. In other words, with or without technology utilization of the value chain, both produce similar results. Conclusion: Firms in the high-tech manufacturing industry are expected to have sufficient knowledge and capability in utilizing their technology resources to ensure the firm's long-term viability and to enable them to continuously create innovations, which leads to improved firm performance and thus to their competitive market survival. By identifying the effect of the value chain as an intervening variable and identifying the difference between direct and indirect effects, this study also adds to previous research on the effects of technology capability and value chain on firm performance.",
"keywords": [
"Technology capability",
"value chain",
"firm performance",
"business process",
"high-tech manufacturing industry",
"technology resources"
],
"content": "Introduction\n\nAdvancing technology has inevitably affected almost every life aspect, from simplest things we often encounter in everyday lives to most advanced ones that affects the lives of many (Fatimah et al., 2021). Along with the times, not only the way of our lives is becoming more dynamic and complex, technology also has changed the way businesses do business. In this fast-evolving technology era, business processes are also becoming even more complex and due to that, companies need to have the ability to survive in their respective sectors of industry without being kicked out from the competition (Ahmadi, n.d.). The firm will be able to survive if it is able to constantly make efforts in creating innovations and able to maintain good firm performance. A firm’s performance can be considered good when the firm is able to run its business processes effectively and able to utilize its resources effectively and efficiently to reach its strategic goals (Rais et al., n.d.). To maintain firm performance, it is also important to keep updated and take advantage of the current trends that may affect the business. This way, the firm will be able to gain more profits and earn trust from the stakeholders, also from other interest groups (Benková et al., 2020). In present time, technology has played a major role in almost every sector of industry (Zahra & Covin, 1994). Technology has become a very important asset for firms, even considered valuable. When utilized effectively, technology can help the firm in various aspects, from strategic decision-making to managing the firm’s resources (Ahmadi, n.d.). Previous studies also proved that the capability of a firm in utilizing their technology resources can help the firm to increase their productivity and gain competitive advantages, which results in better firm performance (Ahmadi, n.d.; Daya et al., n.d.; Marfuah & Silvianti Rosyadi, 2021). However, the measure of technology intensity among each industry are different. According to OECD Taxonomy of Economic Activities Based on R&D Intensity, the industries are classified into five groups of technology intensity level: high, medium-high, medium, medium-low, and low. The R&D intensity is measured from the ratio of R&D expenditures to the gross value added to the industry (Galindo-Rueda & Verger, n.d.). Industries with 5 or more percent of R&D intensity are classified as high-tech, meanwhile industries with R&D intensity below 0.9 percent are classified as low-tech (Hirsch-Kreinsen, 2008). Office equipment, accounting, computers and machinery, medical tools, precision and optical instruments, and pharmaceuticals are some of the industries classified in high-tech industry sector meanwhile industries such as metal, rubber, and plastic manufacturers, food and beverages, tobacco, furniture, wood, and paper products are classified in low-tech industry sector (Hartmut & Kirner, 2015). In Indonesia, one of the high-tech industry sector that has been one of the government’s focus on growing is computer industry, since the demand of technology products, especially computers, has become even higher each day (Cholid & Robiani, 2020) and the involvement of computer products in people’s lives has also become more intense. However, as high-tech industries are highly reliant in innovations, high-tech industries are encouraged to continuously create new innovations in order to support the industrial growth and maintain the sustainability of the industry (Rahma Saphyra et al., n.d.). This has emerged the awareness of the importance of tech involvement in the industry. In today’s world of business where the markets have grown even more competitive and fast-changing, technology should become an important asset that needs to be owned and properly utilized by companies to create a distinctive competitive advantage, which leads to better firm performance, and help the company survive in the competitive environment (Sawng et al., 2018; Syailendra, 2019). Therefore, this paper aims to analyze and identify how the involvement of technology takes role in supporting a firm’s performance, specifically in high-tech manufacturing industry sectors of Indonesia. This paper also aims to identify and measure the impact given by technology capability to a firm’s value chain and performance level.\n\n\nTheoretical background\n\nNowadays, we have witnessed how technology has in various ways and create improvements in many aspects within the firm. There are some previous studies existed regarding on how technology capability strongly affects firm performance According to Dosi et al. (1992), technology capability can be defined as the ability to create innovations in products and processes, and the ability to utilize technological resources effectively (Weinstein & Azoulay, 1999). Technology capability also refers to the ability of a firm in utilizing their human resources to maximize the role of their technology resources regarding internal communications with suppliers, and also maximizing the firm’s internet capability (Aral & Weill, 2007). Meanwhile Zhang et al. (2008) defines technology capability as a firm’s ability to diffuse their technological resources in supporting other resources and capabilities within the firm (Ekonomi & Manajemen, 2017).\n\nAccording to Porter (1994), value chain analysis is a process of examining the activities that runs in a firm and how each activity corresponds to deliver the end output (products or services) (Porter, 2008). The value chain model presents particular sets of activities needed in order to create valuable products and services and since each model can be different for each product and services, value chain model helps the firm to identify the uniqueness of the value produced by each particular sets of activities (Ensign, 2001). In the world of business that keeps growing even more competitive, there are reasons why value chain analysis is important to be done: (1) In the era of advancing technology where businesses has become more dynamic and complex, systemic competitiveness is highly needed, (2) In order to enter the global market, a firm needs to rely heavily on efficiency, (3) and the ability of a firm to understand the dynamic factors of their whole value chain is highly required in order to maintain the firm’s position in the global market (Kaplinsky & Morris, 2001). Therefore, value chain is a powerful tool to help firms gain competitive advantages (Ensign, 2001).\n\nHelfert (1996) defines firm performance as a condition of a firm in a particular range of time as a result of the firm’s achievements, which depends on the firm’s ability to utilize their resources effectively (Nuswandari, 2009). Verboncu and Zalman (2005) states that a firm’s performance is a result of a firm’s competence in various sectors that are done effectively and efficiently (Taouab & Issor, 2019). According to a study by Teng (2002), Venegas and Alarcon (2007), and Sudarto (2011), a firm’s performance mainly depends on 3 factors, namely: (1) internal factors, (2) external factors, and (3) market conditions. Internal factors that may affect a firm’s performance can come from human resources, customer relationships and resource managements while the external factors are usually from politics and governance. Aside of that, a highly competitive industry environment may also affect a firm’s performance (Tumelap et al., 2014). In conclusion, a firm’s performance relies heavily on effectiveness and efficiency of the activities and resource management within the firm.\n\nA study conducted by Bhadarwaj (2000) identified that technology capability contributes to creating competitive advantages for the firm and measured by profit and cost, helps maintaining good firm performance (Syailendra, 2019). 3 years after, Santhanam and Hartono (2003) conducted a follow-up research departing from Bhadarwaj’s findings and from their research, they concluded that firms with sufficient technology capability have better firm performance compared to the average level of firm performance in the industry (Riset & Terpadu, 2020; Syailendra, 2019). Therefore, from the previous statements, there is a known relation between tech capability to firm performance.\n\nH1: Tech capability has a significant effect to firm performance.\n\nAs technology advances, firms face tougher competition and due to that, agility has become an important trait for companies to own. Kidd (2000) defines that an agile enterprise is fast-moving and able to quickly adapt to uncertain situations, quickly responds to opportunities, and understands customers (Swafford et al., 2006). Technology era has inevitably brought us a lot of changes in many ways, including the way business processes are carried out nowadays. In order to survive in the competitive and turbulent business environment, a company also have to produce greater values. A study by Edwards et al. (2004) has pointed out 3 kinds of strategic options in order to help the company to carry out greater values, namely: (1) Adoption of better practices, (2) create innovations to streamline the business process, and (3) configure the activity sets in the value chain model so that the output will deliver greater values, in other words, remodelling the value chain model (Noke & Hughes, 2010). In terms of better practices, technological capability is needed to be able to identify and manage linkages and relationships between each activity within the firm (Eriksson et al., 2016).\n\nH2: Tech capability has a significant impact to firm’s value chain.\n\nValue chain itself is a great tool in helping companies to discover their competitive advantages (Ensign, 2001). Prior studies done by various researchers proved that there is a positive relation between competitive advantages and company performance. For example, a study by Raduan et al. (2009) proves that unique edge contributes to organizational success, in particular, competitive advantage is able to predict the measure of a company’s performance (Majeed, 2011). According to a study by Moran (1981), having a competitive advantage may help the company to improve their economic performance and maintain customer relationship, which also validates that there is a positive relation between competitive advantage and company performance (Lakhal, 2009), which then can be concluded that a company’s value chain takes role in improving company performance.\n\nH3: Value chain has a significant effect to firm performance.\n\nA firm that has adequate technology capability will be more likely to survive the competition in the fast-changing business world today through adequate knowledge of technological resources management, which encourages firms to improve the effectiveness and efficiency of the activities carried out in their business processes, referred as the firm’s value chain. This has shown that the technology capability contributes to the value chain model of the firm, resulting in improvement in overall business processes within the firm. A new and improved business process will help firms to gain competitive advantage, thus maintaining the firm’s overall performance.\n\nH4: There is a mediating effect of value chain between the relationship of technology capacity and firm performance.\n\n\nMethods\n\nQuantitative method is a framework commonly used in researches that involves statistics and mathematics to test a theory or to verify hypotheses (Basias & Pollalis, n.d.). Quantitative research relies heavily on numerical data interpretation in order to obtain the result (Kilani & Kobziev, 2016). A research can be considered suitable of using quantitative method when the research questions aims to achieve one or more of these objectives: (1) obtain quantitative answer, (2) study numerical changes, (3) conduct audience segmentation, (4) quantify and/or find out how the whole population feels regarding the issue carried in the research, (5) explain some occurrence, and (6) testing hypotheses (Sukamolson, n.d.). In quantitative research, there are 3 main approaches of how the research can be conducted: descriptive, experimental, and casual comparative. Descriptive research aims to identify a correlation between two or more variables, experimental research aims to measure an outcome of a research based on manipulation of an independent variable measured to a dependent variable, while casual comparative research aims to discover the relationship between independent and dependent variables from an event that has already happened (Habib & Habib, 2021).\n\nThe type of data used in this research is secondary data obtained from the survey of Indonesia’s medium to large manufacturing industries in 2017, provided by Badan Pusat Statistik (BPS) as Indonesia’s official institution of statistics. The survey is conducted by Badan Pusat Statistik (BPS) annually by collecting each related firms’ data through a questionnaire of manufacturing industries survey starting from the basic information of the firm, the firm’s characteristics such as the research and development intensity, the firm’s employee and materials used, the revenue and expenditures carried out in a year, and the details of the production in a year. To represent the three variables used in this research, the royalty value is used to determine the technology capability of the firm. Second, the total of local and international services value is used to determine the value chain of the firm. And last, the firm’s performance is determined by the total value added. The population of this research are 267 firms in Indonesia which are classified in the computer, electronic, and optical products manufacturing industry according to International Standard Industrial Classification (United Nations Statistical Division, 2008).\n\nThis research uses descriptive quantitative analysis with path analysis. Path analysis is a developed model of multiple linear regression, which used to investigate not only direct effects, but also indirect effects between the variables in the model (Lima et al., 2020). Based on the research model, there are 2 equations that will be examined, (1) Technology capability effects on value chain, and (2) Technology capability and value chain effects on firm performance. Testing the hypotheses will be done using a Sobel test to identify the coefficients of the indirect effect, and a t-test using SPSS (Statistical Package for Social Sciences) version 26.0. There are 2 path analysis that will be examined in this research, based on the model below:\n\nThe first path analysis is to identify the direct effect of technology capability on firm performance while the second path analysis is to identify the indirect effect of technology capability on firm performance through value chain as an intervening variable.\n\nPrior to performing a regression analysis, normally, a classic assumption test consisting of normality test, autocorrelation test, multicollinearity test, and heteroscedasticity test is done in order to assure that such issues don’t exist in the regression models. The most basic test usually done within the set of the classic assumption test is the normality test. This test basically examines whether the sample in the research is distributed normally. The Central Limit Theorem is used in this research to determine the normality of the sample distribution. This theorem states that if the sample size is 30 or greater, the sample distribution is considered normal (Ahad et al., 2011). Since the sample size of this research is 267, the distribution is considered normal as the amount of the sample is greater than 30. However, there are some situations in which a classic assumption test is not required. Basically, a classic assumption test is only required if the regression model is meant to be used as a predictive tool. Besides that, a classic assumption test isn’t needed if the regression model involves intervening variable(s). Also when proving a hypothesis, the normality of the samples will not affect the outcome. With or without a classic assumption test, the effect of the independent variable(s) to the dependent variable can still be identified (Hadi, n.d.). As a result, the normality test was not performed on the sample based on the conditions of the sample analyzed in this study, departing from the theoretical basis previously mentioned.\n\nFirst, a regression is done to the relationship between technology capability and value chain to determine and prove that the technology capability has a significant effect on value chain, as shown in the table below.\n\na Dependent Variable: Value Chain.\n\na Predictors: (Constant), Tech capability.\n\nBased on Table 2, it shows that the adjusted R square value is 0,049, indicating that technology capability is able to affect the value chain for 4,9% of the time, aside from external factors. Then, Table 1 shows that the unstandardized beta value is 0,181, with a significance value of 0,000 ≤ 0,05. It demonstrates that technology capability has a significant effect on value chain. Next, the relationship between value chain and technology capability on firm performance is examined in order to determine and prove that both value chain and technology capability simultaneously have a significant impact on firm performance, and to determine whether technology capability can have a significant impact on firm performance through the value chain as an intervening variable.\n\na Dependent Variable: Firm Performance.\n\na Predictors: (Constant), Tech Capability, Value Chain.\n\nAs seen on Table 4, the adjusted R square value is 0,574, indicating that, aside from the external factors, value chain and technology capability can affect firm performance simultaneously for 57,4% of the time. And then, Table 3 shows the unstandardized beta value of value chain and technology capability respectively are 0,438 and 0,081, with a significance value of 0,000 ≤ 0,05 for both. It demonstrates that value chain and technology capability both has a significant effect on firm performance.\n\nThe next step is to identify the direct and indirect effects. The effects are determined using the following equations:\n\nSince the unstandardized beta value of technology capability to firm performance is 0,081 as shown on Table 3, the direct effect of technology capability on firm performance can be identified directly. The next step is to identify the indirect effect of technology capability on firm performance using the value chain as an intervening variable. The indirect effect is calculated by multiplying the value of the unstandardized beta value of technology capability to value chain (0,181) by the value of the unstandardized beta value of value chain to firm performance (0,438). And last, the total value of the effects is obtained by adding the direct effect value and the indirect effect value. The approximate values of the effects are summarized in the table below:\n\nAs seen on Table 5, the direct effect and the indirect effect has the same value. As a result, it is possible to conclude that the effect of technology capability on firm performance can mediate the effect of technology capability on firm performance, despite the fact that there is no significance of the effect.\n\nTesting the hypothesis will be done using a t-test with the t-table value of 1,96 according to the sample size, which is greater than 120 and the significance level of 0,05. As for the indirect effect, a Sobel test is done beforehand to obtain the t-count value.\n\nFirst, because the t value of technology capability to firm performance as shown in Table 3 is 4,021 ≥ 1,96 and the significance value is 0,000 ≤ 0,05, then it can be concluded that H1 is accepted, which means that there is a significant effect from technology capability to firm performance. This demonstrates that the better a firm's technological capability, the better the firm's capability in creating competitive advantages, which may help the firm to maintain their performance. This research confirmed Bharadwaj (2000)’s and Santhanam and Hartono (2003)’s study regarding on how technology capability contributes in creating competitive advantages which may lead to better firm performance (Riset & Terpadu, 2020; Syailendra, 2019). Then, because the t value of technology capability to value chain as shown on Table 1 is 3,844 ≥ 1,96 and the significance value is 0,000 ≤ 0,05, then it can be concluded that H2 is accepted, which means that there is a significant effect from technology capability to value chain. This proves that a firm with an adequate technology capability will be more likely capable in creating a better improvement to the firm’s value chain model to streamline the business processes. Next, from Table 3 above, we can see that the t value of value chain to firm performance is 17,148 ≥ 1,96 and the significance value is 0,000 ≤ 0,05, then it can be concluded that H3 is accepted, which means that there is a significant effect from value chain to firm performance. This result proves that a better utilization of value chain model, it can help firms to improve their overall performance. Corresponds with the study by Moran (1981) which states that having a competitive advantage may help the firm to improve their economic performance and maintain customer relationship, which also validates that there is a positive relation between competitive advantage and firm performance (Lakhal, 2009), which then can be concluded that a firm’s value chain takes role in improving firm performance.\n\na Dependent Variable: Firm Performance.\n\nTo obtain the results of Table 6 above, first, a Sobel test is used to determine the value of the unstandardized error value, and the t-count value can then be calculated.\n\nFirst, the unstandardized error value is calculated with the following formula:\n\nAs seen on the Table 6 above, the unstandardized error value is 3,754. After that, it is possible to calculate the t-count value with the following formula:\n\nAfter the t-count value is obtained, it can also be seen on Table 6 that the t-count value of the indirect effect is 0,021 ≤ 1,96, with the significance value of 0,000 ≤ 0,05. From this result, it can be concluded that H4 is rejected since the t-count value is smaller than the t-table value, which means that the value chain as an intervening variable in the relationship between technology capacity and firm performance has no significant effect.\n\n\nConclusion\n\nTechnology has become a crucial asset for today’s businesses. A firm’s capability of utilizing its technology resources expands the firm’s ability for carrying out various activities and opens the opportunity of innovation, allowing it to survive in the industry. The ability to carry out various activities within the firm also emerges, as does an understanding of the value chain's importance to the firm. Firms in the high-tech manufacturing industry, which rely heavily on innovation to maintain their performance and sustainability, must have sufficient knowledge and capability in utilizing their technology resources in order to compete in the market. Prior studies also have demonstrated a positive result regarding the effect of technology capability and value chain on firm performance. The findings of this study support previous research that both technology capability and value chain have a significant impact on firm performance in high-tech manufacturing firms. Despite having an equivalent value to the direct effect, the value chain as an intervening variable between technology capability and firm performance has no significant effect in this case. As a result, it can be concluded that whether a firm decides to build its technology utilization through its value chain model or not, both options produced similar results.\n\n\nData availability\n\nDue to the agreement of use with Indonesia’s official institution of statistics, the dataset used in this study which consists of the royalty value, the local and international services value, and the total value added is limited for research purposes only and not for public viewing.\n\nThe survey data consisting of the quantity and the total production value can be accessed here with the requirement of the user’s email and are prohibited to be used for commercial purposes.\n\nThe complete list of the required information for the survey can be viewed through the survey questionnaire which can be accessed here.",
"appendix": "References\n\nAhad NA, Yaacob CR, Rahman Othman A, et al.: Central Limit Theorem in a Skewed Leptokurtic Distribution Teoram Had Memusat dalam Taburan Kepencongan Leptokurtic. Jurnal Sains Dan Matematik. 2011; 3(1): 64–71.\n\nAhmadi J: Journal of Science, Management and Tourism Letter The Impact of IT Capability on Company Performance: The Mediating Role of Business Process Management Capability and Supply Chain Integration Capability. n.d.; 2021.Reference Source\n\nAral S, Weill P: IT assets, organizational capabilities, and firm performance: How resource allocations and organizational differences explain performance variation. Organ. Sci. 2007; 18(5): 763–780. Publisher Full Text\n\nBasias N, Pollalis Y: Quantitative and Qualitative Research in Business & Technology: Justifying a Suitable Research Methodology.n.d.Reference Source\n\nBenková E, Gallo P, Balogová B, et al.: Factors affecting the use of balanced scorecard in measuring company performance. Sustainability (Switzerland). 2020; 12(3). Publisher Full Text\n\nCholid I, Robiani B: Analysis in Productivity and Efficiency on Computer and/or Assembly in Electronic Computer and Computer Device Industries in Indonesia 2011-2015 (ISIC 26210 and 26210).2020. Publisher Full Text\n\nDaya PS, Meningkatkan D, Teknologi P, et al.: Peran Sumber Daya Dalam Meningkatkan Pengaruh Teknologi Terhadap Produkvitas.n.d.Reference Source\n\nEkonomi M, Manajemen D: Analisis Kapabilitas Teknologi Informasi Terhadap Kinerja Bisnis UKM Sebagai Variabel Intervening (Studi pada UKM Sektor Manufaktur di Wilayah Solo Raya).2017; 32(1).\n\nEnsign PC: Value Chain Analysis and Competitive Advantage. J. Gen. Manag. 2001; 27(1): 18–42. Publisher Full Text\n\nEriksson T, Nummela N, Sainio LM, Saarenketo S:Value chain management capability in international SMEs. Value Creation in International Business: Volume 2: An SME Perspective. Springer International Publishing;2016; (pp. 171–193). Publisher Full Text\n\nFatimah S, Azlina N, Akuntansi J, et al.: Pengaruh Teknologi Informasi dan Inovasi Terhadap Kinerja Usaha Kecil dan Menengah (UKM) (Studi Pada UKM Berbasis Online di Kota Dumai). Jurnal Riset Akuntansi Dan Perbankan. 2021; 15: 444–459.\n\nGalindo-Rueda F, Verger F: OECD Taxonomy of Economic Activities Based on R&D Intensity.n.d.Publisher Full Text\n\nHabib M, Habib MS: Analyze Quantitative and Qualitative Research Qualitative and Quantitative Research Approaches.2021.\n\nHadi SM: Aplikasi dan Interpretasi Regresi OLS (Beginikah Aplikasi dan Interpretasi Regresi OLS.n.d.\n\nHartmut HK, Kirner E:Innovation in low-tech industries: Current conditions and future prospects. Low-Tech Innovation: Competitiveness of the German Manufacturing Sector. Springer International Publishing;2015; (pp. 17–32). Publisher Full Text\n\nHirsch-Kreinsen H: Low-Tech Innovations. Ind. Innov. 2008; 15(1): 19–43. Publisher Full Text\n\nKaplinsky R, Morris M: A Handbook for Value Chain Research Global Value Chains and Global Innovation Networks View project Tendering sustainable energy transitions (TENTRANS) View project.2001.Reference Source\n\nal Kilani M , Kobziev V: An Overview of Research Methodology in Information System (IS). OALib. 2016; 03(11): 1–9. Publisher Full Text\n\nLakhal L: Impact of quality on competitive advantage and organizational performance. J. Oper. Res. Soc. 2009; 60(5): 637–645. Publisher Full Text\n\nLima S, Teixeira L, Esteves R, et al.: Spirituality and quality of life in older adults: A path analysis model. BMC Geriatr. 2020; 20(1): 259. PubMed Abstract | Publisher Full Text\n\nMajeed S: The Impact of Competitive Advantage on Organizational Performance.2011; 3(4).Reference Source\n\nMarfuah U, Silvianti Rosyadi L: Penerapan Metode Teknometrik untuk Mengukur Kontribusi Komponen Teknologi dalam Proses Produksi Industri Kecil dan Menengah. JISI: Jurnal Integrasi Sistem Industri. 2021; 8. Publisher Full Text\n\nNoke H, Hughes M: Climbing the value chain: Strategies to create a new product development capability in mature SMEs. Int. J. Oper. Prod. Manag. 2010; 30(2): 132–154. Publisher Full Text\n\nNuswandari CPengaruh Corporate Governance Perception Index Terhadap Kinerja Perusahaan Pada Perusahaan yang Terdaftar di Bursa Efek Jakarta.2009; 16(2): 70–84.\n\nPorter ME: Competitive Advantage - Creating and Sustaining Superior Performance.2008; 36–40.\n\nRahma Saphyra A, Dewi K, Nugraha Mursitama T: The role and impact of Value Chain on Sustainable Firm Performance: A Literature Review in High-Tech Industries.n.d.\n\nRais M, Dewi K, Nugraha Mursitama T: Determinant of Sustainable Firm Performance: A Literature Review of Technology Intensity Industries Comparison.n.d.Reference Source\n\nRiset J, Terpadu A: Kapabilitas Teknologi Informasi, Kinerja Perusahaan dan Nilai Perusahaan.2020; Vol. 13(Issue 1).\n\nSawng YW, Park Y, Jo SH, et al.: Technology adoption and company performance: Correlation analysis with the evidence of Korean export companies’ case. Journal of Korea Trade. 2018; 22(2): 143–161. Publisher Full Text\n\nSukamolson S: Fundamentals of quantitative research.n.d.\n\nSwafford PM, Ghosh S, Murthy NN: A framework for assessing value chain agility. Int. J. Oper. Prod. Manag. 2006; 26(2): 118–140. Publisher Full Text\n\nSyailendra GD: Influence of Information Technology Governance to Company Performance with Mediation of Information Technology Capabilities in Indonesia. American Journal of Humanities and Social Sciences Research. 2019; (Issue 5). AJHSSR.Reference Source\n\nTaouab O, Issor Z: Firm Performance: Definition and Measurement Models. Eur. Sci. J. ESJ. 2019; 15(1). Publisher Full Text\n\nTumelap J, Sumajouw MDJ, Waney EVY: Analisis Kinerja Perusahaan Jasa Pelaksana Konstruksi (Studi Kasus di Kabupaten Sarmi). Jurnal Ilmiah Media Engineering. 2014; 4(2): 135–142.\n\nUnited Nations Statistical Division: International Standard industrial classification of all economic activities (ISIC). United Nations;2008.\n\nWeinstein O, Azoulay N: Firms’ Capabilities and Organizational Learning - A critical survey of some literature.1999.\n\nZahra SA, Covin JG: Domestic and International Competitive Focus, Technology Strategy and Company Performance: An Empirical Analysis. Tech. Anal. Strat. Manag. 1994; 6(1): 39–54. Publisher Full Text"
}
|
[
{
"id": "157394",
"date": "04 Jan 2023",
"name": "Irwan Trinugroho",
"expertise": [
"Reviewer Expertise finance",
"strategic management",
"banking",
"digital innovation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThere are some problems in this paper:\nDescriptive statistics of variables are not provided; therefore, it is difficult for readers to clearly understand the data, and the methodology as a whole.\n\nI assume that even though data was gathered from a survey, the variables are not latent variables. For instance, technology capability is measured by royalty. The measure of variables should be clearer.\n\nThere are no control variables even though it is obvious that firm performance is not only affected by the three explanatory variables in this study.\n\nThe number of observations is relatively small.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "176049",
"date": "30 Jun 2023",
"name": "Jun Jin",
"expertise": [
"Reviewer Expertise Technological innovation management"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper analyses the impact of technological capabilities and value chain on firm’s performance based on the survey data of Indonesia manufacturing industry. It is interesting to integrate the value chain into the research on technological capabilities and performance. However, the measurement of all variables in the research is not introduced, which makes the reliability and variability of data is not confirmed. In addition, the theoretical contributions of paper could be improved to make the paper novelty. Therefore, the paper is not ready for indexing, needing more revision.\nHere are some comments to the further improvement of paper.\nMore detail literature review is needed to support the proposition of hypotheses. For instance, it is not clear why the value chain has a mediate role in the research. In addition, please combine the H2 to H4 as one hypothesis about the mediate role of advantages in value chain. H2 and H3 seems the process to test H4.\n\nValue chain is a tool to analyse the advantages of a firm. It could not be as a variable directly. The results of value chain analyses perhaps be used as a variable to measure the competitiveness of firm. Please explain why the value chain could be used as variable in this research.\n\nPlease introduce how to measure all variables in this research. Now there is only a data source. Please give a detail information of DV and IV. For instance, which results of value chain analyses will be used in the research, The position in the value chain or the shares in the value chain or anything? Patents, new products, and any other data will be used as the variable of technological capabilities in this research?\n\nPlease improve the novelty of the research? All hypotheses are normal, not new to existed theories and research. What are contributions of this research?\n\nPlease add discussion of hypotheses results and response to the existed theories and research.\n\nPlease do the robust test.\n\nPlease give an introduction of questions of the survey which refer to all variables used in the research.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "167588",
"date": "24 Dec 2024",
"name": "Nurazwa Ahmad",
"expertise": [
"Reviewer Expertise Technological capability",
"firm performance",
"manufacturing performance",
"technology transfer"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMost of the literature referenced for the theoretical background are old references.\n\nIt did not have a clear operational definition for all the variables.\n\nThe theoretical background discussion did not provide sound discussions on all of the variables and relationships.\n\nUnclear theoretical discussion on TC towards firm performance, the past evidence on the relationship is absent.\n\nThe descriptive analysis of demographic profiles is absent.\n\nHow can royalty value can represent technological capability? There is no discussion on this.\n\nHow the data was gathered and measured, what type of data used are somewhat ambiguous. The population and sampling techniques can be described in better ways.\n\nThere was no discussion part after the data analysis and finding. The paper ends abruptly. How can royalty values, local & international values and total values added be explained in the whole idea?\n\nThe authors should consider the resource-based view theory to support most of the discussion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-595
|
https://f1000research.com/articles/10-1047/v1
|
15 Oct 21
|
{
"type": "Research Article",
"title": "Thermal comfort optimization through bioclimatic design in Mediterranean cities",
"authors": [
"Nermine Hany",
"Hala Alaa",
"Hala Alaa"
],
"abstract": "Background: Bioclimatic design is an approach based on local climate which improves thermal qualities and indoor comfort. Buildings follow this process to minimize negative effects on the environment. However, this approach is still not suitable in developed countries. This study aims to investigate Mediterranean local bioclimatic strategies’ impact on thermal comfort efficiency in housing, by examining architectural elements and treatments. Methods: We adopted a descriptive, analytical, and comparative methodology, complemented with a software simulation, within a qualitative and quantitative approach. Investigation and methodological tools were based on technical information including plans, elevations, photos, and documentation. The approach consisted of multiple stages: a literature review interpreting the concept of bioclimatic design, as well as thermal comfort variables and common Mediterranean building features. Moreover, the paper showcases three examples of successful Mediterranean passive houses. Furthermore, the paper presents a case- studyhouse in Alex West, Alexandria, designed in the Mediterranean Revival style. Results: The results showed that the most influencing building features on thermal comfort were the low-pitched roofs and the top chimney, which achieved 12.6% and 5% improvement in the summer and 13% and 6.8% in winter, respectively. The pergola and porch elements barely had an effect when placed on the northern façade. However, on the southern façade, a positive contribution in the summer by 1.4% and 3.4% respectively were reported, but a slight negative impact in winter by 0.5% and 2% respectively. Conclusions: We examined the impact of common Mediterranean building features , and compared thermal comfort results between case-study houses. Features focusing on passive design for cooling rather than heating, allowing wind flow for maximized natural ventilation, using ventilated pitched roof spaces, using sun shading elements in the proper facades and angles, help passive thermal regulation. The study proposes recommendations for optimizing thermal comfort in residential buildings in Alexandria, Egypt.",
"keywords": [
"bioclimatic design",
"thermal comfort",
"energy-efficient house",
"energy performance simulation",
"Mediterranean architecture",
"Alexandria"
],
"content": "Introduction\n\nFor many years, architecture has been influenced by context and societies. People in different regions had different construction methods depending on their culture, weather, geography, geology…etc. Scientists around the world are developing strategies for reducing a building’s overall energy consumption, in order to minimize negative effects on the environment, while maintaining the desired environmental conditions such as better indoor temperature and thermal comfort. However, this approach is still lacking and not suitable in many regions around the world, especially developing countries such as Jordan Egypt.11 The study aims to investigate the impact of Mediterranean local bioclimatic strategies on thermal comfort efficiency in housing, by examining the architectural elements and treatments that accompanied the Mediterranean building style. The study adopted a descriptive, analytical, and comparative methodology, along with a simulation using DesignBuilder V.6.1 software20 and accompanied with Energyplus core calculations, for the examined case study, within a set of qualitative and quantitative approaches. Investigation and methodological tools were based on technical information including plans, elevations, photos, and documentation.\n\nPrevious studies focused on developing a model to be used as a tool by architects, to predict the energy efficiency for buildings in the design phase, as well as describing the architectural strategies employed and analyze the existing trends in bioclimatic architecture.1,3 The main novelty of this paper is to analyze the impact of Mediterranean local bioclimatic strategies on thermal comfort efficiency in the housing sector, with more specific information was collected on the examined building case study.\n\nThe paper consists of multiple sections: first, the concept of bioclimatic design, as well as thermal comfort variables and common Mediterranean local building features in the region are introduced. The rest of this paper is structured as follows. The Methods showcase three examples of successful Mediterranean passive houses. A case study of a house in Alex West, Alexandria, which is designed in the Mediterranean Revival Architectural Style is adopted in the Results. Simulation results are explained in the Discussion depending on the evaluation of scaling parameters. Finally, the last section concludes this work.\n\n\nMethods\n\nThe concept of bioclimatic architecture is based on taking maximum benefits from the surrounding climate conditions and building placement, to meet indoor thermal comfort needs with minimum energy consumption.1 Bioclimatic architecture is occasionally based on vernacular architecture, and attempts to analyze traditional architecture based on the climate and culture of a place, and to study the architectural and construction solutions. This type of architecture adapts to the local climate without using additional devices that consume energy and leave an ecological footprint.2\n\nTo apply bioclimatic architecture, it is necessary to consider the building's location, climate and microclimate; the next step would include the architectural skin, as one of the main elements to consider when striving for comfortable conditions.3\n\nDifferent bioclimatic diagrams are used as tools with which to determine comfort levels.3 One of the most widely used tools includes the diagram developed by Baruch Givoni (Figure 1). The Givoni bioclimatic chart is mainly applied for residential scale construction, and it provides more alternatives in building design to enable thermal comfort, including natural ventilation, evaporative cooling, thermal mass, passive heating, conventional air conditioning or dehumidification.4\n\nThermal comfort design variables\n\nAs per ASHRAE 55, thermal comfort is defined as “that condition of mind that expresses satisfaction with the thermal environment and is assessed by subjective evaluation.” The human body is in the constant process of heat exchange with the environment. This heat balance of the human body governs the thermal comfort experience of individuals. As such, many variables affect human thermal comfort.5\n\nResearch on thermal comfort focuses on two main factors, namely, the thermal environment factor (including air temperature, relative humidity, air velocity, and mean radiant temperature) and the individual factor (including clothing and metabolic rate).6 Although people could achieve thermal comfort through self-adjustments, such as clothing, activity level, and psychological preference, the thermal environment still plays an essential role in research on thermal comfort. Improving the thermal environment by adjusting architectural forms is one of the most effective methods to achieve thermal comfort.7\n\nThe predicted mean vote (PMV) scale is often used to measure thermal comfort (Figure 2). The PMV, which was developed by Ole Fanger, is a seven-point scale ranging from −3 to +3 and is the most commonly used thermal comfort index.8 PMV is the mean vote that one would expect to obtain from averaging the thermal sensation votes of a large group of people in a given environment.\n\nThe PMV is a complex mathematical expression that involves the individual as well as the four environmental parameters. On the same lines, the predicted percentage dissatisfied (PPD) gives the percentage of people who are dissatisfied with the thermal environment. When PMV is zero, the PPD is of five percent, which means that when the sensational level of cold or hot is zero, five percentage votes are for discomfort.9\n\nThe Mediterranean area is a distinct geographical entity, which has been inhabited since the origins of human history, with particular geomorphologic and climatic features. From Antiquity to the present, cultural trends of East and West intersect and influence each other, and in combination with the natural environment, the climate, the light and the sea, the previous natural elements have defined a very special way of life and consequently, a unique architectural style.11\n\nMediterranean climate refers to the typical climate of the Mediterranean Basin, and is a particular variety of subtropical climate.11 To state it simply, it usually consists of hot dry summers and mildly cold, wet winters with high daily thermal excursions characterize the Mediterranean climate. Traditional Mediterranean architecture evolved to produce buildings that would be in harmony with the harsh climates of its various regions. In the traditional architecture, the mechanism of indoor thermal regulation was incorporated in the building itself.12\n\nIn the Mediterranean region, ventilation and sun protection measures, together with appropriate materials and construction, represent the main issues of bioclimatic efficiency. Ventilation is necessary for comfort and hygiene; even on hot summer days when the outdoors are warmer than the building interior. In traditional buildings, attention was given to ventilation, especially to the pre-treatment of air. Solar shading is important, as well, to control the penetration of the sun in the summer.12\n\nThe paper summarizes the most common design features in Mediterranean Residential Architecture Style in Table 1, and a graphical summary in Figure 3, based on literature describing Architectural Design Guidelines and its codes; specifically, the Mediterranean Revival Style, as the style incorporated references from various Mediterranean regions such as the Spanish Renaissance, Italian Renaissance, and Arabic Andalusian Architecture.\n\nIn this section, the study analyzes three examples of good practice regarding passive and bioclimatic design in Mediterranean cities. The selection criteria of the examples were based on their successful bioclimatic house design approach, their diversity in geographic location, their diversity in passive techniques, and their similarity with the case study. These examples include: Lamaca, Oroklini, Cyprus; Casa Pineda, Barcelona, Spain; and Umbertide, Umbria, Italy.\n\nLamaca, Oroklini, Cyprus\n\nClimate and location\n\nCyprus has an intense Mediterranean climate with a typical seasonal rhythm concerning temperature, rainfall and weather in general. The predominantly clear blue skies and intense sunshine periods give large seasonal and daily variations between the temperature of the coast and that at the interior of the island, that also is considerably affected by climate change, especially near the coasts. Its average hottest peak reaches 41°C in the summer and drops to an approximate of 5°C in the winter. Relative humidity ranges from 40-60%, and a large daily temperature range is noted with up to 18°C difference between day and night. Thus, Cyprus's climate calls for the need for cooling in the summer, and the large amount of solar radiation during the summer may easily be used for heating in winter. The house is located in the Larnaca District, in the Oroklini village.15 The land is located on a small hill, where neighboring buildings are located at a distance. On the eastern side, there is a road, while to the south, the plot borders a green space, which grants it more privacy.\n\nBuilding description\n\nThe building houses a family of four. It consists of three levels (Figure 4). The ground floor is divided into two individual departments, one of them being accommodated with the entrance, the living room and dining area, while the other department is accommodated with another living room with a dining area and kitchen. The first floor consists of four bedrooms and an office. The mezzanine directly communicates with these areas through an internal staircase (Figure 5). Situated in a central point on the north with southern clerestory windows which, when opened, give the advantage of direct sunlight gain and contribute to the natural ventilation and stack effect of all spaces on all floors.15\n\n(a) South façade; (b) North and East façade.\n\n(From left to right): Ground floor plan. First floor plan. Mezzanine floor plan.\n\nThe building frame is reinforced concrete. The external walls are 25cm-thick masonry brick, 5cm-thick thermal insulation, plaster, and stone cladding. The internal walls are 10cm-thick masonry brick wall, plaster, and paint. The roof is inclined reinforced concrete, with 10cm-thick thermal insulation, water barrier, and ceramic roofing tiles. The windows are aluminium profile, double glazed, have low emissivity, and argon filled. Also, the floors are composed of ceramic tiles.15\n\nBioclimatic Approach\n\nThe bioclimatic approach is applied in; orientation as most spaces are South-oriented, thermal mass in floors, walls, and staircase; passive solar heating as direct gain (glass openings and clerestory windows). Solar control is achieved with external shading devices with regards to East and West. Moreover, the shading of openings is achieved with the use of overhangs, with the extension of the floors on the southern and northern sections and extension of the roof and the balcony on the southern section. There is also anticipation at the time of writing to plant trees around the building shell, but this has not been developed to a satisfactory level yet. The natural ventilation relies on night ventilation (in the summer nights all openings can be opened manually, except the clerestory windows which are electrical), cross ventilation (provisions had been made so that most spaces have openings on two sides), and stack effect (Figure 6) (At the top point of the staircase as well as in the mezzanine area, clerestory windows have been placed and are opened during the summer months).15\n\nCasa Pineda, Barcelona, Spain\n\nClimate and location\n\nThe Mediterranean coast of Spain is in the warm climate zone, where average temperatures in July and August are about 26°C. Recent results indicate that summer temperatures may be 3°C to 4°C lower. Winters are moderately cold and humid, so active heating is still necessary for residential buildings. The weather in Palau Plegamans (province of Barcelona) is similar to Barcelona, but the daily temperature oscillation in the summer is more pronounced, with typical temperatures of 14°C in the early morning hours. Located at 41° North, high solar radiation is available during the winter months.16\n\nBuilding description\n\nThe detached family house “Casa Pineda” in Palau Plegamans has one story and no basement floor. The user of the building is a two-person family (Figure 7). It is a lightweight building with a wooden beam structure; the roof is covered with rear-ventilated roof tiles. In Catalonia, it is common to combine passive houses with wood structure, which is not more expensive than the ‘traditional’ construction system, based on burnt bricks.16 The building is located in a suburban district. The L-shaped building is oriented towards the south, defining a homely open space in the garden.\n\n(a) The southern façade; (b) The eastern façade showing L-shaped structure and open garden.\n\nBioclimatic approach\n\nThe building is a lightweight construction with low thermal inertia and there is no active cooling system. An EIFS with EPS insulation was applied to the exterior walls on the northern and eastern side; the other façades are finished with a wooden ventilated structure. The main openings are towards the South (50% of all windows) (Figure 8), so in winter, the solar gains due to windows are about 40% higher than the transmission losses of the windows. Windows were installed on the inner side of the walls. This solution has a high thermal bridge effect. Summer comfort is achieved by appropriate user behavior: during daytime, closing exterior blinds which reduces mechanical ventilation; during night times, tilting windows and wide opening in the early morning hours. All windows have efficient sun shading blinds.16\n\nUmbertide, Umbria, Italy\n\nClimate and location\n\nThe project is a development of bioclimatic housing for a housing development in Umbertide, Umbria, in Italy. Umbertide lies in a Mediterranean temperate climate with rainy winters and hot summers. The local climate creates a significant requirement for energy for heating and cooling. During the summer months, light breezes (under five to 10 metres per second) from the South, East or West enter the city from the surrounding hills and are caught by the streets that separate the buildings, providing them with natural air conditioning. During the remaining seasonal periods, the prevalent direction of the wind is North-West. The most comfortable months are in the spring (May) and in autumn (September and October); the central months (from June to August) are hot and humid with light breezes.17\n\nBuilding description\n\nThe alternation of the form and function of this external space is organized according to the position of the site, in correspondence with the main pedestrian wind axis or with the secondary edible garden lines. The apartment buildings range from two to five floors, depending upon different typologies (Figure 9), and each floor is composed of four rooms (bedrooms, kitchen and living room) and two bathrooms. The construction system is as follows; a structural system for row houses and detached houses consisting of load-bearing walls of traditional brick masonry; apartments are made from reinforced concrete frames with traditional brick cladding; external walls comprising ventilated cavities, with traditional brick masonry; roofs comprising a concrete structural system, sealer, air space and traditional roof tiles.17\n\n(a) Building typology showing the shading screens on the external façade; (b) The housing courtyard.\n\nBioclimatic approach\n\nAt the building level, the use of the stack effect (integrated with a convective loop system and with a chimney) to realize a system of cooling and ventilation resulted in a good microclimate and adequate indoor conditions during summertime. The development of this system has been progressive and has been tested and improved by continuous fluent simulations. Incoming air is transported through the building by different chimneys, either for admission or for expulsion functions, which work by stack effect (Figure 10). In the admission chimney, during winter, the air flows into the glazed section, becomes warmer as a result of the passive greenhouse effect and is then distributed to each room. In summer, the air flows into an insulated section and provides cooling due to its speed and continuous circulation; moreover, shading systems at the windows and at the glazed chimney prevent overheating. Part of the south façade is completely glazed in order to increase direct heat gain. Sun protection in summer is provided through selective shading, which allows winter direct heat gain from the sun, but screens out summer sun.17\n\n(a) Cross section showing predicted ventilation system; (b) Typical Floor plan.\n\nExamples of mediterranean muilding features\n\nThe study analyzed three examples of passive housing in Mediterranean cities, which have managed to achieve sustainable design and improved building performance, along with maintaining the Mediterranean architecture style. The study concluded that the most common Mediterranean local building features utilized in passive building design based on these examples are low-pitched roofs and large sized windows, followed by a projected front porch, red clay roofs, pergolas and screens, top chimneys, open floor plan and high ceiling, as well as two-story buildings. Table 2 summarizes the achieved features in the examples, to present a framework for the selection of the examined building features in section 4.\n\n\nResults\n\nThe paper investigates the impact of local Mediterranean building features on the thermal comfort of a house in Alexandria. First, it discusses the climatic characteristics of the location, and analyzes the bioclimatic chart. Furthermore, it examines the performance of the house of the case study, with and without the tested building features.\n\nThe approach considered here included performing a preliminary analysis of the bioclimatic chart to formulate the general design strategies that are most adapted to the climate of Alexandria. A didactical software named Climate Consultant v. 6.021 was used for this purpose. This tool, based on the Milne and Givoni bioclimatic chart,18 plots the climatic data (i.e., dry bulb temperature and relative humidity data) on the psychrometric graph. The distribution of the hourly climatic data on the psychrometric graph provides the relative potential of the application of each bioclimatic design strategy (passive and active) to improve indoor thermal comfort.\n\nAmong the different thermal comfort models proposed by this tool, the ASHRAE Handbook of Fundamentals 2005 Comfort Model was chosen. For people dressed in normal winter clothes (relatively thicker with warmer materials), at effective temperatures of 20°C to 23.3°C (measured at 50% relative humidity), the temperature decreases slightly as humidity rises. The upper humidity limit was a 17.8°C wet bulb and a lower dew point of 2.2°C. If people are dressed in light weight summer clothes, then this comfort zone shifts 2.8°C warmer.\n\nThe bioclimatic chart of Alexandria city, obtained using Climate Consultant, is presented in Figure 11, displaying only the passive design strategies. It is noticeable that the percentage of the comfort zone did not exceed 20.7% of the year. The exploitation of the internal heat gains should extend the number of thermal hours of about 36.8% primarily during the cold season. On the second level, sun shading from windows could represent an enhancement of about 17.70%, in particular in the hot season. The natural ventilation cooling contributed to 14%, as well as high thermal mass night flushing by 6.9%. The passive solar gain contributed to about 8.2% when combined with high thermal mass, allowing the comfort level to reach 76%. However, the previous outcomes only provided general recommendations for design enhancement, given that it was based solely on the analysis of the climatic data and did not take into account the specificities of each building case. Thus, design parameters would be further specified for the given case study in the following analysis.\n\nGreen represents ‘comfortable’ hours by 76%. Red represents ‘not comfortable’ hours by 24%.\n\nFor the purpose of this paper, a case study of a detached family house was considered. The house is located in the Alex West compound, in Alexandria. The chosen prototype was V4, which is located in the St. Catherine zone. It consists of two floors, four bedrooms, a living room, a dining room, a kitchen, four bathrooms, and is occupied by five people (Figure 12). The total built-up area is 312 m2 with a 3-metre height. The building design follows the Mediterranean Revival architectural style (Figure 13).\n\n(a) Ground floor plan; (b) First floor plan.\n\n(a) Southern façade shot; (b) Northern façade shot.\n\nThe software used for analysis was DesignBuilder v. 6.120 (Figure 14). The building was constructed and analyzed, and the boundary conditions were imported as output data of EnergyPlus dynamic thermal simulation.22 Furthermore, the paper set specific local building features for investigation, based on the literature review, as well as the most common features drawn from the analysis of the successful passive building examples. These features include the low-pitched roof, the pergola, the projected porch/veranda, and the top chimney (Figure 14).\n\n(a) DesignBuilder view; (b) Mediterranean building features subject to investigation.\n\nThe dynamic simulation tool was used to estimate the occupant thermal comfort PMV levels, as it incorporates an AUTOCAD interface for the EnergyPlus core calculations.22 Site data is based on WMO meteorological measurements for the egyptian typical meteorological year (ETMY) reported by the Alexandria station number 623180. The project file settings specified in the software are summarized in Table 3 including heating, ventilation and air conditioning (HVAC), environment, and activity settings. As the research focuses on passive design techniques, the system was set to natural ventilation only, avoiding any active heating, cooling, mechanical cooling, or ventilation control to take effect. Furthermore, the materials specified in the project are showed in Table 4. The top chimney feature is made of the material type ‘solid brick 125 mm, uninsulated’, the low-pitched roof feature of ‘clay tiles 25 mm on concrete 150 mm, reinforced with 2% steel’, the porch/veranda feature of ‘solid brick 250 mm, uninsulated’, and finally the pergola feature is made of the material type ‘2”×6” timber wooden stringers’.\n\nHVAC: heating, ventilation and air conditioning.\n\n* An operation schedule for ventilation assigned in DesignBuilder and set for residential spaces common areas.\n\nThe simulation period was assigned for the entire year from 1 January to 31 December, within hourly output intervals. Seven simulations were conducted; one for the base case, while the other six were modified scenarios for the same building aimed at testing the specified Mediterranean building features. Table 5 summarizes the simulation scenarios. Scenarios 1-5 (S1-5) included removing the examined building features (low-pitched roofs, top chimney, pergola, and porch/veranda) which already existed in the building. However, S4 and S5 results had barely shifted from the base case result, due to the position of the pergola and porch on the northern façade. Therefore, S6 and S7 were tested as well, which consisted in examining the cases of moving the same pergola and porch elements to the southern façade. Figure 15 shows the graphical and numerical representation of the resulting hourly simulation outputs for Fanger PPD percentage as a function of PMV, in the whole thermal zones of the examined building.\n\nw/o = without.\n\n\nDiscussion\n\nThermal comfort was examined for the previous building scenarios, using Fanger PPD and PMV values, to indicate the percentage of dissatisfaction of users in the building for these conditions. Table 6 demonstrates the PMV scaling parameters ranging from −3 to 3; a PMV of −3 represents the cold perception, while a PMV of 3 represents the hot perception. The simulation we carried out showed that the examined building features have made some considerable alleviation in both summer and winter.\n\nThe first scenario examined the thermal comfort for the base case, which included all the villa’s existing building features. The PMV reached a maximum output value of 2.51 on the hot scale, and a value of −1.10 on the cold scale. On the other hand, the second scenario, which examined thermal comfort in the case the low-pitched roofs element was removed, and replacing them with flat roofs, showed the greatest alleviation among all the scenarios on both the hot and cold scales. The result reported a maximum output value of 3 on the hot scale, which represents a 12.6% increase, and a value of −1.58 on the cold scale, which represents a 13% increase from the base case. The third scenario, which examined thermal comfort in the case the top chimney element was removed, had reported a maximum PMV output value of 2.71 on the hot scale with a 5% increase, and a value of −1.63 on the cold scale with a 6.8% increase. This scenario was the second greatest alleviation among the other ones.\n\nScenarios 4 and 5 barely showed any alleviation due to the northern façade position of the pergola and porch elements, which barely caused any auxiliary shading effect nor impacted thermal comfort. Therefore, this research examined the impact of the same pergola and porch elements in the southern façade respectively. Both techniques caused a slight alleviation in the summer, but also a slight aggravation in the winter. Scenario 6 included adding the pergola element in the southern façade, and results reported a maximum PMV output value of 2.49 on the hot scale with a 1.4% reduction from the base case, and a value of −1.11 on the cold scale with a 0.5% increase from the base case. Scenario 7, which examined moving the porch element to the southern façade, had reported a maximum PMV output value of 2.39 on the hot scale with a 3.4% reduction from the base case, and a value of −1.16 on the cold scale with a 2% increase from the base case. Figure 16 shows the graphical shift of results from the base case for the various scenarios.\n\nThe green dashed lines represent the maximum PMV values of the base case on both the hot and cold scale. The red dashed lines represent the shift of results in the other scenarios.\n\nTable 7 compares the maximum resulting PMV for the seven tested scenarios for both the hot and cold scales. Moreover, Figures 17 and 18 illustrate the maximum PMV from best to least convenient bioclimatic design, for hot and cold scales respectively.\n\nOverall, for a yearly thermal comfort outcome, the best bioclimatic design alternative was determined to be S7. The Flow Design software was used to generate the natural ventilation flow for the building’s cross sections, showing the impact of the tested Mediterranean features in the best design scenario alternative concluded from the simulation (Figures 19 and 20).\n\n\nConclusion\n\nThe bioclimatic design concept aims to improve building thermal performance with a perfect adaptation to the local climate specificities. The PMV scale, which was developed by Ole Fanger, is a seven-point scale ranging from −3 to +3 and is the most commonly used thermal comfort index. Moreover, this paper summarizes the most common design features in the Mediterranean Residential Architecture Style. The analytical section included analyzing three examples from Lamaca, Oroklini, Cyprus; Casa Pineda, Barcelona, Spain; and Umbertide, Umbria, Italy. Consequently, the paper concluded the most common design features from the literature and examples examined in the case study, were low-pitched roofs, top chimney, pergola, and porch/veranda.\n\nFor the paper’s case study, a bioclimatic chart was analyzed to highlight the passive design strategies which are the most adapted to the climate in Alexandria, Egypt. The bioclimatic chart showed that the internal heat gain, sun shading of windows, and natural ventilation were the most optimal passive design strategies to increase thermal comfort range in the city of Alexandria. The building adopted for case study analysis was a single family detached house in Alex West, Alexandria, Egypt; it was designed in the Revival Mediterranean architectural style, consisted of two floors, and was occupied by five people. Simulations were carried out on the building’s thermal zones following seven different scenarios, to examine the impact of removing each building feature on thermal comfort.\n\nThe overall building thermal comfort in all scenarios yielded better results in the winter than in the summer. The results showed that the most influencial building features on thermal comfort of the building were the low-pitched roofs and top chimney elements, which achieved 12.6% and 5% improvement in the summer and 13% and 6.8% in winter, respectively. The pergola and porch elements barely had an effect when placed on the northern façade. However, replacing their position to the southern façade resulted in a positive contribution in the summer by 1.4% and 3.4% respectively, but also a slight negative impact in the winter by 0.5% and 2% respectively.\n\nIt was clear that the such pre-existing local building features had an overall positive impact on the thermal comfort and performance of the building. This paper proposes some recommendations for improving thermal comfort for similar housing projects in Alexandria, including: putting more focus on the passive design for cooling than heating; allowing wind flow for maximized natural ventilation cooling, using chimneys and other similar elements; using ventilated pitched roof spaces which allow to cool the house; using sun shading elements such as pergolas and projected porches in the proper facades and angles, to take advantage of the sun protection elements as well as the architectural style aesthetics, preferably moveable and interchangeable shading elements to function in both summer and winter.\n\n\nData availability\n\nData supporting reported results are available online at https://doi.org/10.5281/zenodo.4814710.23\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nTzikopoulos A, Karatza M, Paravantis J: Modeling energy efficiency of bioclimatic buildings. Energy and Building. 2005; 37: 529–544. Publisher Full Text\n\nPereira I, Aleixo J, Correia Guedes M: Low-cost sustainable building solutions: case studies: Angola and guinea-bissau. Louvain-la-Neuve, Belgium:PLEA;July 2011; 13–15.\n\nManzano-Agugliaro F, Montoya FG, Sabio-Ortega A, et al.: Review of bioclimatic architecture strategies for achieving thermal comfort. Renew. Sust. Energ. Rev. 2015; 49: 736–755. Publisher Full Text\n\nEl Harrouni K, Filali M, Kharmich H, et al.: Energy Efficient Houses Meeting both Bioclimatic Architecture Principles and Moroccan Thermal Regulation. 6th International Renewable and Sustainable Energy Conference (IRSEC), Rabat, Morocco, 2018; Publisher: IEEE. 1–8.\n\nRAA-C.E: ANSI/ASHRAE Standard 55—Thermal environmental conditions for human occupancy. American Society of Heating, Refrigerating and Air conditioning Engineer. 1992; 145.\n\nASHRAE: Thermal environmental conditions for human occupancy. American Society of Heating, Refrigerating and Air conditioning Engineer. 2017.\n\nHuang X, Ma X, Zhang Q: Effect of building interface form on thermal comfort in gymnasiums in hot and humid climates. Frontiers of Architectural Res. 2019; 37: 529–544. Publisher Full Text\n\nFanger PO: Thermal comfort: Analysis and applications in environmental engineering. Copenhagen, Denmark:Danish Technical Press;1970.\n\nAnand P, Deb C, Alur R: A simplified tool for building layout design based on thermal comfort simulations. Frontiers Architectural Res. 2017; 6: 218–230. Publisher Full Text\n\nHegger M, Fuchs M, Stark T, et al.: Energy Manual: Sustainable Architecture. Birkhäusers;2008. Publisher Full Text\n\nAtiyat D: Architecture Building Treatments in the Mediterranean Climate From an Environmental Perspective: Case Study of Amman Jordan. J Archit Eng Tec. 2015; 04: 2. Publisher Full Text\n\nSerghides DK: The wisdom of Mediterranean traditional architecture versus contemporary architecture–the energy challenge. The Open Construction and Building Technology Journal. 2010; 4: 29–38. Publisher Full Text\n\nPlatt J: Glendale Design Guidelines for Residential Buildings in Adopted Historic Districts.2012.\n\nGlendora Municipal Code: Architectural styles defined. (accessed on 31 May 2020). Reference Source\n\nLapithis P: Bioclimatic Architecture and Cyprus. Nicosia, Cyprus:Pantheon Cultural Association;2018.\n\nSchnieders J, Eian TD, Filippi M, et al.: Design and realisation of the Passive House concept in different climate zones. Energ. Effic. 2019; 13: 1561–1604. Publisher Full Text\n\nHyde R: Bioclimatic housing: innovative designs for warm climate. London:Routledge;2012. Publisher Full Text\n\nMilne M, Givoni B: Architectural design based on climate. Energy conservation through building design. 1979; 96–113.\n\nAlex West Egypt. (accessed on 21 June 2020).Reference Source\n\nDesign Builder Software V.6.1 (accessed on 1 April 2020).Reference Source\n\nClimate Consultant V. 6.0. Reference Source\n\nEnergy Plus Software. Reference Source\n\nHany N: Thermal Comfort Optimization through Bioclimatic Design in Mediterranean Cities.2021. Publisher Full Text"
}
|
[
{
"id": "99740",
"date": "01 Dec 2021",
"name": "Hassan Abdel-Salam",
"expertise": [
"Reviewer Expertise Architecture and Environmental Design"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDeveloping strategies for reducing the overall energy consumption of buildings constitutes a core concern in the field of Architecture. Minimizing negative effects on the environment, while maintaining the desired indoor qualities / favorable conditions (such as thermal comfort) is a subject worthy of investigation.\nThe study purpose and objectives are clear and targeted at enhancing the environmental performance of residential buildings, promoting the thermal comfort in indoor spaces, in addition to achieving optimization of economics in the built environment.\nThe hybrid methodology adopted in the experiment is clear and helps establish then assess qualitative attributes based on clear/simple action-taking, measurement and inference of results.\nThe paper has introductory theoretical reviews on the Bioclimatic Approach and the Mediterranean climatic context. The linkage of the two topics is used as a basis for adopting an environmentally driven thinking process.\nThe section in pp. 5-10 has an analysis of three selected examples of good practice regarding passive and bioclimatic design in Mediterranean cities. This is followed by a case study of one relevant example in Alexandria, Egypt.\nBased on the review of the manuscript and its contents, the following issues are revealed:\nThe paper could benefit from an overall re-arrangement under specific numbered headings or bulleted points in order to better present the research discourse and to follow the build-up of argument leading to findings and recommendations deduced from this study.\n\nThe Conclusion Section on p.18 could also benefit from minor re-structuring under specific bulleted points in order to better present the research findings and to provide clearer guidance and / or specific recommendations addressed to designers.\n(Note: it would be useful if the author(s) can add concise statements about the validity of results and possibility of generalizing upon the findings across the broader Mediterranean zone).\n\nThe text needs careful and thorough revision, and editing of language.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8297",
"date": "01 Jun 2022",
"name": "Nermine Hany",
"role": "Author Response",
"response": "Thank you for your very informative and important review. The authors worked on the points mentioned from your side and uploaded the updated version on the journal website. 1. The paper could benefit from an overall re-arrangement under specific numbered headings or bulleted points in order to better present the research discourse and to follow the build-up of argument leading to findings and recommendations deduced from this study. The authors updated the headings arrangement and added more detailed headings (in red) 2. The Conclusion Section on p.18 could also benefit from minor re-structuring under specific bulleted points in order to better present the research findings and to provide clearer guidance and / or specific recommendations addressed to designers. The authors restructured the findings under 2 major bullet points and presented the recommendations in a more specific form. (In red) 3. It would be useful if the author(s) can add concise statements about the validity of results and possibility of generalizing upon the findings across the broader Mediterranean zone. The authors discussed the possibility of generalizing the findings at the conclusion and recommendations section. 4.The text needs careful and thorough revision, and editing of language. The authors generated a careful revision for language."
}
]
},
{
"id": "97059",
"date": "01 Dec 2021",
"name": "Amin Habibi",
"expertise": [
"Reviewer Expertise -"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI have some comments regarding this manuscript as follows:\nA language revision is recommended.\n\nThe authors are strongly recommended to address more accurate references in the literature review to satisfy the previous works and establish the method. For example, see Ozarisoy & Altan (2021) for the latest review study on this area.\n\nThe data used as input in Designbuilder are not fully described.\n\nThere are no valid data regarding the simulation and it would be a lack of methodology, meanwhile, you do not validate your data by dataloggers it could not be reasonable.\n\nThe conclusion should be further developed, a simple repetition of results should be avoided.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8298",
"date": "01 Jun 2022",
"name": "Nermine Hany",
"role": "Author Response",
"response": "Thank you for your important review. The authors worked on the points mentioned from your side and uploaded the updated version on the journal website. 1. The authors are strongly recommended to address more accurate references in the literature review to satisfy the previous works and establish the method. For example, see Ozarisoy & Altan (2021) for the latest review study on this area. The authors are grateful for the advice to refer to this reference. We referred to the reference and added more specific parts in the literature review to address Previous Studies on Modern Mediterranean ( in Methods Section) 2. The data used as input in Designbuilder are not fully described. The authors included a brief description of the case study project file settings assigned in DesignBuilder as the focus and the scale of the research was to give a generalized idea of the impact of local Mediterranean building features on the thermal comfort. All the Data supporting reported results are available online at https://doi.org/10.5281/zenodo.4814710. 3. There are no valid data regarding the simulation and it would be a lack of methodology, meanwhile, you do not validate your data by dataloggers it could not be reasonable. Concerning data loggers, the authors believes that this is out of research scope due to unavailability of dataloggers and on-site field equipment. 4. The conclusion should be further developed, a simple repetition of results should be avoided. The authors updated the conclusion according to the first reviewer comments. The conclusion included a quick compacted summary of results, to be easier for quick reading."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1047
|
https://f1000research.com/articles/11-214/v1
|
22 Feb 22
|
{
"type": "Research Article",
"title": "Association between the body mass index, waist circumference, and body fat percentage with erosive esophagitis in adults with obesity after sleeve gastrectomy",
"authors": [
"Alba S. Zevallos-Ventura",
"Gabriel de la Cruz-Ku",
"Fernando M. Runzer-Colmenares",
"Jesús Pinto-Elera",
"Carlos J. Toro-Huamanchumo",
"Gabriel de la Cruz-Ku",
"Fernando M. Runzer-Colmenares",
"Jesús Pinto-Elera",
"Carlos J. Toro-Huamanchumo"
],
"abstract": "Background: High anthropometric indexes before sleeve gastrectomy (SG) are associated with an increased risk of erosive esophagitis (EE) in bariatric surgery candidates. Reasons that explain how these indexes influence the development of esophageal pathology after surgery remains unclear. Objectives: To assess the association between the body mass index (BMI), waist circumference (WC), and body fat percentage (BFP) with the development of EE in adults with obesity three months after SG. Setting: Clínica Avendaño, Lima, Peru. Methods: Retrospective cohort using a database including adults with obesity who underwent SG during 2017-2020. All the patients included had an endoscopy before and after the surgery. Sociodemographic, clinical and laboratory characteristics were compared according to BMI, WC and BFP, as well as by the development of de novo esophagitis. The association was evaluated by crude and adjusted generalized linear models with the log-Poisson family. Results: From a total of 106 patients, 23 (21.7%) developed EE. We did not find significant differences in sociodemographic, clinical and laboratory characteristics between patients with de novo EE compared to those who did not develop EE. After adjustment, BMI (aRR = 0.59, 95% CI = 0.18-1.40), BFP (aRR = 0.41, 95% CI = 0.15-1.19) and WC (aRR = 0.91, 95% CI = 0.69-1.16) were not associated with the development of EE three months post SG. Conclusions: We found no association between preoperative anthropometric indexes and the development of de novo EE; therefore, morbid obesity should not be a criterion to exclude the patients to undergo SG as primary surgery because of the risk of developing EE.",
"keywords": [
"Obesity",
"Esophagitis Peptic",
"Abdominal fat",
"Body mass index",
"Waist circumference"
],
"content": "Introduction\n\nObesity is currently considered as a chronic and multifactorial metabolic-related disease, of which prevalence has been increasing along the decades,1 and has an important impact on morbidity and mortality worldwide.2,3 Surgical treatment is available and is managed with different techniques by bariatric and minimally invasive procedures. To date, sleeve gastrectomy (SG) is the most commonly used technique (American Society for Metabolic and Bariatric Surgery).4,5\n\nThere is a direct relationship between obesity and the development of gastroesophageal reflux disease (GERD). In fact, the elevated intra-abdominal pressure and the increased transient lower esophageal sphincter (LES) relaxation6 in patients with obesity has been described as a pathophysiological mechanism of GERD, and, consequently, esophageal mucosal damage7 which leads to erosive esophagitis (EE).8 Moreover, there are several studies that associate high values of body mass index (BMI),9 waist circumference (WC), abdominal subcutaneous fat, and visceral fat10–12 with the esophageal pathology. However, in a Swedish community-based study, Lagergren J et al. concluded that this parameter is not a sufficient indicator and would even qualify as inaccurate as a predisposing factor for EE.13 Furthermore, a study among an Iranian population showed that the symptoms of GERD occur independently of the BMI.14\n\nThere is scarce literature that explores the association between anthropometric indexes and the development of de novo EE in gastrectomized patients in a short-term period; Jan S. Burgerhart showed that esophageal acid exposure increased significantly when comparing 24-h pH measurements before and three months after sleeve gastrectomy.15 Furthermore, because the rate of de novo EE is higher after SG compared to gastric bypass16,17 evaluating the effect of BMI, WC and body fat percentage (BFP) on the development of de novo EE might be invaluable to predict whether patients with high anthropometric indexes can undergo this type of procedure. Hence, we sought to determine the association between BMI, WC and BFP with de novo EE three months after undergoing sleeve gastrectomy.\n\n\nMethods\n\nWe conducted a retrospective cohort study, analyzing a secondary database to which we had access between January and March 2021. The database was recorded in an Excel 2016 spreadsheet of the Clínica Avendaño that was collected between 2017 and 2020 from patient medical records. The study population consisted of 176 adults with obesity that underwent sleeve gastrectomy as primary surgery during 2017-2020 at the Clínica Avendaño, a specialized bariatric center located in Lima, Perú\n\nThe inclusion criteria were: age ≥18 years old, BMI ≥30kg/m2, sleeve gastrectomy as primary surgery, and endoscopy performed preoperatively and three months post SG. The exclusion criteria were: esophagitis at preoperative endoscopy, diagnosis of hiatal hernia, excessive alcohol consumption (chronic and periodic alcohol consumption of more than three times per week) and heavy smoking (15 cigarettes or more per day). In addition, we excluded patients with missing data, as well as those who were lost to follow-up, which took place in the third postoperative month at Clínica Avendaño where a control endoscopy was performed. (Figure 1).\n\nWe considered demographic variables (age, sex), comorbidities (type 2 diabetes mellitus (T2DM), hypertension), clinical and laboratory variables (systolic blood pressure (SBP), diastolic blood pressure (DBP), cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), anthropometric variables (BMI, WC, percentage of BFP) and endoscopic variables (presence of Helicobacter pylori and de novo esophagitis at three months)). Blood analyses after fasting for 8 to 12 hours were performed for preoperative control in all patients at approximately 2 to 4 weeks before surgery (COBAS 60000 module C501).\n\nAge was categorized into two groups (18-29 and 30-59 years) while the sex variable was defined as \"male\" or \"female\". The BMI was calculated as weight (in kg) /height (in meters)2 and was categorized into non-morbid (<40.00 kg/m2) and morbid obesity (≥40.00 kg/m2). WC was measured between the lowest ribs and the iliac crest, and the measurements were recorded in centimeters.18 BFP was recorded as a percentage using the ¨TANITA¨ bioelectrical impedance scale (Body Composition Analyzer TBF-310GS) with cut-off points of 25% for men and 35% for women categorized as normal and elevated.19 The HOMA-IR was calculated as follows: [fasting insulin (μU/ml) × fasting glucose (mg/dl)] /405. A cut-off ≥ 2.5 was considered as insulin resistance.20\n\nEsophagitis was endoscopically evaluated prior to surgery and at three months after the procedure for each patient. The degree of esophagitis was classified according to the Los Angeles classification system and subsequently categorized as presence or absence of esophagitis.21 The endoscopies were performed after preparation of the patient with a standardized technique using a flexible endoscope (OLYMPUS EXERA 180). The presence of H. pylori was considered if at least 1+ was observed in the preoperative gastric biopsy report. All surgical procedures were performed by the same physicians using a standardized technique that consists of dissection of the greater omentum until the complete visualization of the left pillar of the diaphragm, liberation of the posterior gastric wall, and dissection of the diaphragmatic crura. In case of finding hiatal hernia the correction of the hernia is performed intraoperatively, a 34F calibration bougie is used, the section is 4 cm from the pylorus until 1 cm from his angle. In all patients, reinforcement is performed with absorbable monofilament suture or with staples with polyglycolic acid reinforcement material.\n\nWe calculated the statistical power with Epidat v4.2 according to the studies of Tai et al22 and Matar et al.23 For all scenarios the statistical power exceeded 90%.\n\nStata version 16.0 (StataCorp, TX, US) was used for data processing. Numerical variables were presented as mean and standard deviation or median and interquartile range. Categorical variables were presented as frequencies and percentages. The chi-square test was used to compare frequencies between groups; if more than 20% of the expected values were ≤5, the Fisher exact test was used instead.\n\nWe performed a first bivariate analysis using the Student’s t-test or Mann Whitney U test to evaluate the presence of significant differences between the anthropometric indexes and categorical variables depending on the normal and abnormal distribution of the variable, respectively. Moreover, Spearman correlation was used for assessing the relation between the anthropometric indexes and numerical variables. In addition, a second bivariate analysis was performed between numerical and categorical variables according to the presence of EE.\n\nFinally, in order to assess the association between each index and de novo EE, individual generalized linear models (GLM) with the Poisson family, logarithmic link function, and robust variances were used. The WC variable was modeled by adding a quadratic term. Nonparametric bias-corrected and accelerated bootstrap estimation of confidence intervals with 1000 replications were performed for all the models. Crude relative risks (cRR) and adjusted relative risks (aRR) were calculated for the bivariate and multivariable analyses. In addition, these models were adjusted by age and sex. All models were presented with their respective 95% confidence intervals (95% CI), and a p-value <0.05 was considered significant.\n\nThe present study was approved by the Ethics Committee of the Universidad Científica del Sur on December 1st, 2020 (N°405-2020-PRE15). We downloaded deidentified information from the database and used codes for each patient, maintaining the confidentiality of the patients.\n\n\nResults\n\nA total of 106 patients were included in our study (Figure 1), of which 74 (69.8%) were women, 76 (71.7%) were between 30 and 59 years of age and 32 (30.2%) had morbid obesity. A higher mean of BMI was observed in males (40.28 kg/m2 vs. 36.85 kg/m2; p < 0.001) and patients with insulin resistance (38.7 kg/m2 vs. 33.87 kg/m2; p < 0.001). Regarding BMI, a negative monotonic correlation was found with HDL (r= -0.35; p < 0.001); on the other hand, a positive monotonic correlation was found with insulin (r= +0.59; p<0.001), and HOMA-IR (r= +0.61; p<0.001). Regarding the BFP, males presented a higher median value compared to females (50% vs. 43%; p<0.001), as well as a positive correlation with SBP (r= +0.36; p<0.001), insulin (r= +0.47; p<0.001) and HOMA-IR (r= +0.48; p<0.001). Regarding WC, we found higher median values in male patients compared to females (126cm vs. 104cm; p<0.001), and in patients with T2DM (134.33cm vs. 111.51cm; p<0.001), presence of H. pylori (119.61cm vs. 109.29cm; p<0.001) and insulin resistance (115.31cm vs. 100.52cm; p<0.001). In addition, there was a negative monotonic correlation with HDL (r= -0.44; p<0.001), and a positive monotonic correlation with glucose levels (r= +0.31; p < 0.001), insulin (r= +0.58; p < 0.001) and HOMA-IR (r= +0.61; p<0.001) (Table 1 and 2).\n\n† Student's t-test\n\n†† Mann Whitney U\n\n‡ Spearman's correlation coefficient\n\nWe found that 23 patients (21.7%) developed esophagitis (grade A: 14, grade B: 9, grade C:0, grade D:0). There were no significant differences for the sociodemographic, clinic and laboratory characteristics according to the development of EE after SG. In spite of these results, the group which did not develop EE had a higher median BMI (38 kg/m2 vs. 36 kg/m2, p=0.26), WC (113cm vs. 107cm, p=0.12), and BFP (46% vs. 44%, p=0.18) compared to the group who developed EE (Table 3).\n\n† Student's t-test\n\n†† Mann Whitney U\n\nǂ Chí2 test\n\nǂǂ Fisher's exact test\n\nOn the multivariable analyses, after adjusting for age and sex, we found that a BMI ≥ 40 kg/m2 (aRR = 0.59, 95% CI = 0.18-1.40), an elevated BFP (aRR = 0.41, 95% CI = 0.15-1.19) and the WC (aRR = 0.91, 95% CI = 0.69-1.16) were not associated with a higher risk of developing EE at three months after sleeve gastrectomy. Conversely, these high anthropometric indexes seemed to reduce the risk of de novo EE, but these results were not significant (Table 4).\n\n* It was modeled by adding a quadratic variable.\n\n** Non-parametric bias-corrected and accelerated bootstrap confidence interval estimation with 1000 replications for generalized linear models with Poisson link-log family and robust standard errors.\n\n† Adjusted by age and sex\n\n\nDiscussion\n\nIn this study, we assessed the association between BMI, WC, and BFP and the development of de novo EE in adults with obesity three months after undergoing sleeve gastrectomy. Although none of the variables showed significant differences according to the development of de novo EE, we found that the female patients more frequently developed EE and patients without EE had higher anthropometric indexes. We did not find any association in crude and adjusted models between BMI, WC and BFP with the development of de novo EE.\n\nOur study showed that male patients presented a higher BMI, WC, and BFP compared to women, results that are similar to previous literature.24–26 The BMI represents the overall body mass that includes visceral and subcutaneous fat, muscle, bone, and major organs, among others. Due to genetic, environmental, and behavioral factors men tend to have a greater fat amount and distribution.27 In addition, the sexual hormonal responses lead to obesogenic changes28 and sexual dimorphism with a high impact in the WC.27,29 However, Lihua Hu et al. found that women present a greater proportion of visceral fat than men, being the only anthropometric measurement that prevails between the two sexes, and this tends to increase over time.30 High adiposity values in the abdominal circumference stimulates the release of fatty acids, thereby increasing the availability of glucose and hyperinsulinism31,32 and favoring the development of T2DM due to low sensitivity of the glucose transporter receptors of the organs to insulin,33 which may explain and correlate with the results described in our study.\n\nCurrently, there are several parameters for measuring obesity, and among these, the measurement of visceral body fat percentage by computed tomography is considered one of the best predictors of GERD.34 However, the BMI, WC and the percentage of BFP are more accessible and less costly parameters to obtain. Several studies reported that an elevation of these anthropometric indexes was associated with the development of EE in bariatric surgery candidates.7,9,35,36 In fact, previous studies have shown that men with higher obesity values37 and the presence of hiatal hernia38 are more likely to develop EE. However, in our study, firstly we excluded the patients with preoperative hiatal hernia in order to avoid this as a confounder, and regarding the anthropometric indexes, we did not find a significant association with de novo esophagitis, which could be explained by the fact that the EE group was composed of a higher proportion of women with lower-than-expected anthropometric indexes.\n\nThere are different pathophysiological mechanisms to explain how obesity can cause GERD. Previous studies have indicated that obesity may cause EE by mechanical factors such as high intra-abdominal and intragastric pressure,39 an increased LES relaxation, a high gastroesophageal pressure gradient40; as well as physiological factors such as increased bile and pepsin composition of gastric contents41 and high leptin levels.42 Sleeve gastrectomy is currently leading up to 80% of weight loss in a long-term setting.43 A recent study demonstrated that a substantial reduction in BMI is required to induce the resolution of esophagitis, especially in individuals with obesity. Moreover, a study reported that the resolution rate was twice as high in subjects who achieved a BMI reduction of more than 2 kg/m2.44 Nevertheless, in our study, we found that higher anthropometric indexes were not associated with the development of EE after sleeve gastrectomy. This could be explained by the fact that patients with higher levels of obesity tend to have a greater and more rapid weight loss compared to those with a lower BMI who tend to achieve a more sustained weight loss. Indeed, this suggests that a controlled reduction of the BMI by sleeve gastrectomy may constitute an effective measure to prevent the development of esophagitis by the alleviation and control of the pathophysiologic factors involved in this outcome.\n\nTo our knowledge, this is the first study to show that having a higher obesity index is not a risk factor for the development of de novo EE at three months post sleeve gastrectomy. However, the present study has some limitations. First, external validity is limited because the results come from a single center and are limited to adult patients with obesity. Second, the patients were followed for only three months, and thus, long-term results were not available. Third we could not include the assessment of proton bump inhibitor (PPI) use within the period of evaluation, however, according to clinic protocol, lansoprazole 30 mg is indicated for the first postoperative month and omeprazole 20 mg for the following two months, and depending on the reflux symptoms after three months of treatment, the use of PPIs can be postponed. Finally, in spite of the usage of the bioelectrical impedance scale for the measurement of BFP, a computed tomography would have been better to measure the visceral BFP as it has been reported to be more accurate as a predictor of EE according to the literature.\n\n\nConclusion\n\nIn conclusion, there were no significant differences between anthropometric indexes and the development of de novo EE esophagitis at three months post sleeve gastrectomy. Based on these results, we consider that morbid obesity should not be an excluding factor for undergoing sleeve gastrectomy as the surgery of choice for weight loss because of the risk of developing EE. Nonetheless, further studies are needed to evaluate this association in gastrectomized patients over a longer follow-up period.\n\n\nData availability statement\n\nHarvard Database: Association between the body mass index, waist circumference, and body fat percentage with erosive esophagitis in adults with obesity after sleeve gastrectomy. https://doi.org/10.7910/DVN/ZBVTY4\n\nThis project contains the following files:\n\n• Association between the body mass index, waist circumference, and body fat percentage with erosive esophagitis in adults with obesity after sleeve gastrectomy.tab (raw data file)\n\n• README_Association between the body mass index, waist circumference, and body fat percentage with erosive esophagitis in adults with obesity after sleeve gastrectomy.txt (data key)\n\nData are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nHales CM, Carroll MD, Fryar CD, et al.: Prevalence of Obesity and Severe Obesity Among Adults: United States, 2017-2018. NCHS Data Brief. 2020 Feb; 360: 1–8.\n\nZhou Y, Chi J, Lv W, et al.: Obesity and diabetes as high-risk factors for severe coronavirus disease 2019 (Covid-19). Diabetes Metab. Res. Rev. 2021 Feb; 37(2): e3377. PubMed Abstract | Publisher Full Text\n\nHruby A, Manson JE, Qi L, et al.: Determinants and Consequences of Obesity. Am. J. Public Health. 2016 Sep; 106(9): 1656–1662. PubMed Abstract | Publisher Full Text\n\nOzsoy Z, Demir E: Which Bariatric Procedure Is the Most Popular in the World? A Bibliometric Comparison. Obes. Surg. 2018 Aug; 28(8): 2339–2352. PubMed Abstract | Publisher Full Text\n\nKhorgami Z, Shoar S, Andalib A, et al.: Trends in utilization of bariatric surgery, 2010-2014: sleeve gastrectomy dominates. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2017 May; 13(5): 774–778. PubMed Abstract | Publisher Full Text\n\nRichter JE, Rubenstein JH: Presentation and Epidemiology of Gastroesophageal Reflux Disease. Gastroenterology. 2018 Jan; 154(2): 267–276. PubMed Abstract | Publisher Full Text\n\nSingh S, Sharma AN, Murad MH, et al.: Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2013 Nov; 11(11): 1399–1412.e7. Publisher Full Text\n\nKim TJ, Lee H, Baek S-Y, et al.: Metabolically Healthy Obesity and the Risk of Erosive Esophagitis: A Cohort Study. Clin. Transl. Gastroenterol. 2019 Sep; 10(9): e00077. PubMed Abstract | Publisher Full Text\n\nCai N, Ji G-Z, Fan Z-N, et al.: Association between body mass index and erosive esophagitis: a meta-analysis. World J. Gastroenterol. 2012 May 28; 18(20): 2545–2553. PubMed Abstract | Publisher Full Text\n\nKang MS, Park DI, Oh SY, et al.: Abdominal obesity is an independent risk factor for erosive esophagitis in a Korean population. J. Gastroenterol. Hepatol. 2007 Oct; 22(10): 1656–1661. PubMed Abstract | Publisher Full Text\n\nMatsuzaki J, Suzuki H, Kobayakawa M, et al.: Association of Visceral Fat Area, Smoking, and Alcohol Consumption with Reflux Esophagitis and Barrett’s Esophagus in Japan. Maeda N, editor. PLoS One. 2015 Jul 30; 10(7): e0133865. PubMed Abstract | Publisher Full Text\n\nMazzoleni F, Mazzoleni LE, de Magalhães Francesconi CF , et al.: Potential roles of Helicobacter pylori treatment, body mass index and waist circumference in the causation of erosive esophagitis: a randomized clinical trial (HEROES-GERD). Int J Obes 2005. 2020 Jan; 44(1): 147–158. Publisher Full Text\n\nLagergren J, Bergström R, Nyrén O: No relation between body mass and gastro-oesophageal reflux symptoms in a Swedish population based study. Gut. 2000 Jul; 47(1): 26–29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSolhpour A, Pourhoseingholi MA, Soltani F, et al.: Gastro-esophageal reflux symptoms and body mass index: no relation among the Iranian population. Indian J Gastroenterol Off J Indian Soc Gastroenterol. 2008 Aug; 27(4): 153–155.\n\nBurgerhart JS, Schotborgh CAI, Schoon EJ, et al.: Effect of sleeve gastrectomy on gastroesophageal reflux. Obes. Surg. 2014 Sep; 24(9): 1436–1441. Publisher Full Text\n\nTai C-M, Huang C-K, Lee Y-C, et al.: Increase in gastroesophageal reflux disease symptoms and erosive esophagitis 1 year after laparoscopic sleeve gastrectomy among obese adults. Surg. Endosc. 2013 Apr; 27(4): 1260–1266. PubMed Abstract | Publisher Full Text\n\nSignorini F, Olguín S, Viscido G, et al.: Esophagitis evolution after sleeve gastrectomy or gastric bypass in consecutive cases. Surg. Endosc. 2020 Oct; 34(10): 4330–4335. Publisher Full Text\n\nOrces CH, Montalvan M, Tettamanti D: Optimal waist circumference cutoff values for predicting metabolic syndrome among older adults in Ecuador. Diabetes Metab. Syndr. 2019 Apr; 13(2): 1015–1020. PubMed Abstract | Publisher Full Text\n\nSnitker S: Use of body fatness cutoff points. Mayo Clin. Proc. 2010 Nov; 85(11): 1057; author reply 1057-1058. PubMed Abstract | Publisher Full Text\n\nMotamed N, Miresmail SJH, Rabiee B, et al.: Optimal cutoff points for HOMA-IR and QUICKI in the diagnosis of metabolic syndrome and non-alcoholic fatty liver disease: A population based study. J. Diabetes Complicat. 2016 Mar; 30(2): 269–274. PubMed Abstract | Publisher Full Text\n\nLundell LR, Dent J, Bennett JR, et al.: Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999 Aug 1; 45(2): 172–180. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTai C-M, Lee Y-C, Tu H-P, et al.: The Relationship Between Visceral Adiposity and the Risk of Erosive Esophagitis in Severely Obese Chinese Patients. Obesity. 2010 Nov; 18(11): 2165–2169. PubMed Abstract | Publisher Full Text\n\nMatar R, Maselli D, Vargas E, et al.: Esophagitis After Bariatric Surgery: Large Cross-sectional Assessment of an Endoscopic Database. Obes. Surg. 2020 Jan; 30(1): 161–168. PubMed Abstract | Publisher Full Text\n\nXi B, Liang Y, He T, et al.: Secular trends in the prevalence of general and abdominal obesity among Chinese adults, 1993-2009. Obes Rev Off J Int Assoc Study Obes. 2012 Mar; 13(3): 287–296. PubMed Abstract | Publisher Full Text\n\nWu Y, Ma G, Hu Y, et al.: The current prevalence status of body overweight and obesity in China: data from the China National Nutrition and Health Survey. Zhonghua Yu Fang Yi Xue Za Zhi. 2005 Sep; 39(5): 316–320. PubMed Abstract\n\nCai L, Han X, Qi Z, et al.: Prevalence of overweight and obesity and weight loss practice among Beijing adults, 2011. PLoS One. 2014; 9(9): e98744. PubMed Abstract | Publisher Full Text\n\nTchernof A, Després J-P: Pathophysiology of human visceral obesity: an update. Physiol. Rev. 2013 Jan; 93(1): 359–404. PubMed Abstract | Publisher Full Text\n\nYoo S, Cho H-J, Khang Y-H: General and abdominal obesity in South Korea, 1998-2007: gender and socioeconomic differences. Prev. Med. 2010 Dec; 51(6): 460–465. PubMed Abstract | Publisher Full Text\n\nDesprés J-P: Body fat distribution and risk of cardiovascular disease: an update. Circulation. 2012 Sep 4; 126(10): 1301–1313. Publisher Full Text\n\nHu L, Huang X, You C, et al.: Prevalence of overweight, obesity, abdominal obesity and obesity-related risk factors in southern China. PLoS One. 2017; 12(9): e0183934. PubMed Abstract | Publisher Full Text\n\nVasques AC, Rosado L, Rosado G, et al.: Indicadores antropométricos de resistência à insulina. Arq. Bras. Cardiol. 2010 Jul; 95(1): e14–e23. Publisher Full Text\n\nAguilar-Roa P, Echavarría-Sánchez M: Relación circunferencia abdominal e insulinorresistencia y su impacto en parámetros seminales. Perinatol Reprod Humana. 2016 Jun; 30(2): 75–81. Publisher Full Text\n\nCarrera Boada CA, Martínez-Moreno JM: Pathophysiology of diabetes mellitus type 2: beyond the duo “insulin resistance-secretion deficit.”. Nutr. Hosp. 2013 Mar; 28 Suppl 2: 78–87. PubMed Abstract | Publisher Full Text\n\nGreen HD, Beaumont RN, Wood AR, et al.: Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study. Int. J. Epidemiol. 2020 Aug 1; 49(4): 1270–1281. PubMed Abstract | Publisher Full Text\n\nPandolfino JE, El-Serag HB, Zhang Q, et al.: Obesity: a challenge to esophagogastric junction integrity. Gastroenterology. 2006 Mar; 130(3): 639–649. Publisher Full Text\n\nZe EY, Kim BJ, Kang H, et al.: Abdominal Visceral to Subcutaneous Adipose Tissue Ratio Is Associated with Increased Risk of Erosive Esophagitis. Dig. Dis. Sci. 2017 May; 62(5): 1265–1271. PubMed Abstract | Publisher Full Text\n\nFass R: Erosive esophagitis and nonerosive reflux disease (NERD): comparison of epidemiologic, physiologic, and therapeutic characteristics. J. Clin. Gastroenterol. 2007 Feb; 41(2): 131–137. Publisher Full Text\n\nYu H-X, Han C-S, Xue J-R, et al.: Esophageal hiatal hernia: risk, diagnosis and management. Expert Rev. Gastroenterol. Hepatol. 2018 Apr; 12(4): 319–329. Publisher Full Text\n\nEl-Serag HB, Tran T, Richardson P, et al.: Anthropometric correlates of intragastric pressure. Scand. J. Gastroenterol. 2006 Aug; 41(8): 887–891. Publisher Full Text\n\nWu JC-Y, Mui L-M, Cheung CM-Y, et al.: Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology. 2007 Mar; 132(3): 883–889. PubMed Abstract | Publisher Full Text\n\nAnand G, Katz PO: Gastroesophageal reflux disease and obesity. Gastroenterol. Clin. N. Am. 2010 Mar; 39(1): 39–46. Publisher Full Text\n\nAbdelkader NA, Montasser IF, Bioumy EE, et al.: Impact of anthropometric measures and serum leptin on severity of gastroesophageal reflux disease. Dis Esophagus Off J Int Soc Dis Esophagus. 2015 Oct; 28(7): 691–698. PubMed Abstract | Publisher Full Text\n\nKheirvari M, Dadkhah Nikroo N, Jaafarinejad H, et al.: The advantages and disadvantages of sleeve gastrectomy; clinical laboratory to bedside review. Heliyon. 2020 Feb; 6(2): e03496. PubMed Abstract | Publisher Full Text\n\nBang KB, Park JH: Weight Loss as a Nonpharmacologic Strategy for Erosive Esophagitis: A 5-Year Follow-up Study. Gut Liver. 2018 Nov 15; 12(6): 633–640. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "124758",
"date": "11 Mar 2022",
"name": "Sergio Goicochea-Lugo",
"expertise": [
"Reviewer Expertise evidence based medicine"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nCongratulations for the article, it is important to be able to identify potential risk factors associated with erosive esophagitis, even more so, using a design that can estimate relative risks.\nI would also like to make the following comments that I hope will be useful.\nRegarding the methods section: I would recommend specifying the moment in which the data of the body mass index, waist circumference, and body fat percentage were obtained since it was not clear to me if these values were obtained before performing the gastrectomy (and at what time) or were obtained after performing the gastrectomy (and at what time).\nThis seemed important to clarify the discussion since you mention that not finding statistical differences could be due to the fact that the patients have a rapid and progressive weight loss. If it is possible to show the data of these variables three months after surgery in a table or as a narrative part, it would support this hypothesis.\nRegarding the statistical analyses: In the bivariate analyses, you found statistical differences between men and women. Have you raised the possibility that sex is an effect modifier rather than a confounder? It could be important to carry out an analysis with the regression model for men and women separately, taking into account the statistical and biological basis that you comment on in the discussion.\nOther than that, I found the limitations mentioned and how they were dealt with to be correct.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8295",
"date": "30 May 2022",
"name": "Alba Zevallos",
"role": "Author Response",
"response": "Thank you for the review of our manuscript. We would like to express our gratitude for your time invested in reading the paper. We are also thankful for the comments. Please, find our point-by-point response to the comments provided below. All changes made are included in the new version of the manuscript. R1C1: I would recommend specifying the moment in which the data of the body mass index, waist circumference, and body fat percentage were obtained since it was not clear to me if these values were obtained before performing the gastrectomy (and at what time) or were obtained after performing the gastrectomy (and at what time). This seemed important to clarify the discussion since you mention that not finding statistical differences could be due to the fact that the patients have a rapid and progressive weight loss. If it is possible to show the data of these variables three months after surgery in a table or as a narrative part, it would support this hypothesis. AR1: Thank you very much for the comment. We have added the time the anthropometric indexes were measured in the methods section: “All three anthropometric indexes were measured on the day of surgery.” Moreover, added information about the weight loss in the results section: “A higher mean of weight loss at 3 months postoperatively was observed in patients with morbid obesity (26.78 kg vs 19.50 kg).” R1C2: In the bivariate analyses, you found statistical differences between men and women. Have you raised the possibility that sex is an effect modifier rather than a confounder? It could be important to carry out an analysis with the regression model for men and women separately, taking into account the statistical and biological basis that you comment on in the discussion. AR2: Thank you for your comment. We agree that a sex-stratified analysis would have been interesting. Unfortunately, due to our limited sample size, we consider that this would have affected our estimates (and our confidence intervals). However, we hope to consider these analyses in further studies."
}
]
},
{
"id": "135643",
"date": "25 Apr 2022",
"name": "Kei Nakajima",
"expertise": [
"Reviewer Expertise Obesity",
"diabetes",
"nutrition",
"cardiovascular risk factors"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study aims to assess the association between the body mass index (BMI), waist circumference (WC), and body fat percentage (BFP) with the development of EE in adults with obesity three months after SG in a retrospective cohort of 106 obese patients. In conclusion, the authors found no association between preoperative anthropometric indexes and the development of de novo EE. This article is well written and of clinical interest. However, I have some concerns.\nMajor comments:\nIt is unclear why the authors selected the time point of three months after the surgery. I wonder if gastric function does not reach full recovery at the time point.\n\nThe primary purpose of sleeve gastrectomy is for weight loss. However, such data is not provided in this study. It may be interesting if weight loss is associated (inversely?) with the incidence of erosive esophagitis.\n\nI suggest that the reference of BMI should be less than 30 or 35 in the regression model. In addition, I would like to know whether a dose effect association exists after classification into three or four groups, for instance, <30, 30-35, 35-40, > 40 BMI.\n\nIt may be better to include helicobacter pylori infection as a confounding factor in the logistic regression model.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8296",
"date": "30 May 2022",
"name": "Alba Zevallos",
"role": "Author Response",
"response": "Thank you for the review of our manuscript. We would like to express our gratitude for your time invested in reading the paper. We are also thankful for the comments. Please, find our point-by-point response to the comments provided below. All changes made are included in the new version of the manuscript. R2C1: It is unclear why the authors selected the time point of three months after the surgery. I wonder if gastric function does not reach full recovery at the time point. AR1: Thank you so much for the comment. We would have liked to evaluate a longer follow-up; however, we have limited data to perform this analysis. Furthermore, we considered evaluating erosive esophagitis at three months cause the study by Jan.S Burgerhart showed an increase in acid exposure time at 3 months post sleeve gastrectomy measured by manometry, which is why we consider that there could be endoscopic signs of erosive esophagitis as early as 3 months post sleeve gastrectomy. We have added this information in the introduction: “Jan S. Burgerhart showed that esophageal acid exposure increased significantly when comparing 24-h pH measurements before and 3 months after sleeve gastrectomy.[15] ” R2C2: The primary purpose of sleeve gastrectomy is for weight loss. However, such data is not provided in this study. It may be interesting if weight loss is associated (inversely?) with the incidence of erosive esophagitis. AR2: Thank you very much for the comment. We have added information about the weight loss in the results section: “A higher mean of weight loss at 3 months postoperatively was observed in morbidly obese patients (26.78 kg vs. 19.50 kg).” We agree that it would be interesting to evaluate whether weight loss is associated with the development of erosive esophagitis, however, that is beyond the scope of our study. R2C3: I suggest that the reference of BMI should be less than 30 or 35 in the regression model. In addition, I would like to know whether a dose effect association exists after classification into three or four groups, for instance, <30, 30-35, 35-40, > 40 BMI. AR3: Thank you very much for your suggestion, we will consider the new cut-off point for BMI for future studies. On the other hand, we believe that polytomizing the BMI variable would result in a loss of statistical power since the number of patients enrolled is not very large. R2C4: It may be better to include helicobacter pylori infection as a confounding factor in the logistic regression model. AR4: Thank you for the suggestion. According to our DAG (directed acyclic graph), the H. pylori infection was not considered as a confounder. We do believe that H. pylori is associated with obesity; however, it is important to mention that all our study participants had obesity. In addition, we had to mention that, since we only had 23 events, adding one more variable to our regression model could have generated overfitting."
}
]
}
] | 1
|
https://f1000research.com/articles/11-214
|
https://f1000research.com/articles/11-30/v1
|
11 Jan 22
|
{
"type": "Research Article",
"title": "Bacterial and fungal co-infections among ICU COVID-19 hospitalized patients in a Palestinian hospital: a retrospective cross-sectional study",
"authors": [
"Hani A. Naseef",
"Ula Mohammad",
"Nimeh Al-Shami",
"Yousef Sahoury",
"Abdallah D. Abukhalil",
"Mutaz Dreidi",
"Ibrahim Alsahouri",
"Mohammad Farraj",
"Ula Mohammad",
"Nimeh Al-Shami",
"Yousef Sahoury",
"Abdallah D. Abukhalil",
"Mutaz Dreidi",
"Ibrahim Alsahouri",
"Mohammad Farraj"
],
"abstract": "Background: Diagnosis of co-infections with multiple pathogens among hospitalized coronavirus disease 2019 (COVID-19) patients can be jointly challenging and essential for appropriate treatment, shortening hospital stays and preventing antimicrobial resistance. This study proposes to investigate the burden of bacterial and fungal co-infections outcomes on COVID-19 patients. It is a single center cross-sectional study of hospitalized COVID-19 patients at Beit-Jala hospital in Palestine. Methods: The study included 321 hospitalized patients admitted to the ICU between June 2020 and March 2021 aged ≥20 years, with a confirmed diagnosis of COVID-19 via reverse transcriptase-polymerase chain reaction assay conducted on a nasopharyngeal swab. The patient's information was gathered using graded data forms from electronic medical reports. Results: The diagnosis of bacterial and fungal infection was proved through the patient’s clinical presentation and positive blood or sputum culture results. All cases had received empirical antimicrobial therapy before the intensive care unit (ICU) admission, and different regimens during the ICU stay. The rate of bacterial co-infection was 51.1%, mainly from gram-negative isolates (Enterobacter species and K.pneumoniae). The rate of fungal co-infection caused by A.fumigatus was 48.9%, and the mortality rate was 8.1%. However, it is unclear if it had been attributed to SARS-CoV-2 or coincidental. Conclusions: Bacterial and fungal co-infection is common among COVID-19 patients at the ICU in Palestine, but it is not obvious if these cases are attributed to SARS-CoV-2 or coincidental, because little data is available to compare it with the rates of secondary infection in local ICU departments before the pandemic. Comprehensively, those conclusions present data supporting a conservative antibiotic administration for severely unwell COVID-19 infected patients. Our examination regarding the impacts of employing antifungals to manage COVID-19 patients can work as a successful reference for future COVID-19 therapy.",
"keywords": [
"COVID 19",
"Co-infection",
"Palestine",
"Iron supplements",
"ICU"
],
"content": "Introduction\n\nSevere Acute Respiratory Syndrome Coronavirus 2 (SAR-CoV-2) is a highly contagious novel viral pathogen that provokes an immediate spread among hospitalized patients with Community-Acquired Pneumonia (CAP)1; extending from mild symptoms in approximately 84% of patients to life-threatening hypoxic conditions necessitating admittance into the Intensive Care Unit (ICU) and oxygen support.2 Additionally, it causes multi-organ failure that involves sepsis and thromboembolic complications, which progresses into an acute kidney and cardiac injury.3 On March 11th, 2020, the World Health Organization (WHO) deemed coronavirus disease 2019 (COVID-19) a pandemic disease, due to its unusual transmission speed and the wide-scale of infection.4\n\nThe bacterial and fungal co-infections are frequently recurring due to respiratory viral diseases. For example, most deaths in the Spanish flu pandemic in 1918 were due to subsequent bacterial infection.5 The possibility for co-infections raises concerns as it hinders COVID-19 management, worsens prognosis, and might increase the fatality rate. The reported prevalence of bacterial co-infection varies between studies. Previous studies showed low prevalence of early bacterial coinfection.6,7 On the other hand, data from France pointed to a high prevalence of early bacterial coinfection during severe COVID-19 pneumonia.8\n\nThroughout the pandemic, evaluation of gathered specimens from hospitalized COVID-19 patients reported the following as the most prevalent organisms that induce co-bacterial infection: S. aureus, S. epidermidis, H. influenzae, Streptococcus spp., E. coli, K. pneumoniae and P. aeruginosa.9 Therefore, many COVID-19 treatment protocols include empirical antibiotic therapy to cover suspected organisms. Relatively, in a systematic review, 30 studies were summarized including 3834 COVID-19 patients. Overall, only 7% of the hospitalized patients were confirmed to have bacterial co-infection with one or more pathogens, primarily in seriously ill patients.10 On the contrary, diagnosis and/or treatment of fungus infections in COVID-19 patients are neglected or delayed and the actual prevalence of fungal co-infection is yet to be established. Few studies were conducted in this regard; one systematic review meta-analysis research was carried out in China on 2780 confirmed SAR-CoV-2 participants from nine relevant articles. After fungal culturing at admission, 0.12%- 0.15% of the cases were positive for fungal infection and Asian patients were more likely to acquire fungal co-infection compared to the patients in the studies from the U.K. The infecting fungi include Aspergillus, Candida, Cryptococcus neoformans, and Pneumocystis.11\n\nThe exact mechanism of microbial co-infection is inadequately understood. Virologists assumed that the viruses attach and penetrate the host's airway epithelial cells creating an inflammatory response, desensitizing Toll-like receptors and leading to cellular apoptosis in numerous mechanisms.12 In addition, it debilitates the body's defense, induces cellular dysfunction and death.12\n\nViruses aid in proliferation, colonization, and invasive infection of opportunistic nosocomial pathogens or respiratory tract normal flora, via hindering the innate immune response, compressing airway mucus, and disrupting the cilia. This will then allow for the virus to spread and adhere to more sites.3 Furthermore, various researchers13,14 highlighted the synergy regulations among viruses and bacteria; both are jointly advantageous, aggravating clinical outcomes. If this cooperation is confirmed, then the management of some viral infections with antibiotics becomes further necessary.15\n\nCOVID-19 has been chiefly linked to high levels of inflammatory markers, such as elevated levels of C-reactive protein and procalcitonin. Accordingly, the similarity between Sar-CoV-2 and bacterial infections in radiological infiltrates and laboratory findings makes it challenging in daily medical practice to provide a precise diagnosis.16 However, according to current studies, most COVID-19 patients did not have bacterial or fungal co-infections upon admission or through the hospital stay, even though they received antibiotics upon admission or before diagnosis.17 Furthermore, many factors advocated escalation of antimicrobial consumption in the pandemic: lack of specific antiviral agents, the overload to the health services’ capacities, saturated laboratories, and diagnosis uncertainty.18 As a result, clinicians are obliged to prescribe broad-spectrum multi-antibiotic regimens in order to treat all the possible infected pathogens. Therefore, this study aimed to investigate and evaluate bacterial and fungal co-infection burden and prevalence among COVID-19 patients admitted to a treatment facility at Beit-Jala hospital in Palestine. In addition, it reveals the etiology of the infection, provides the antimicrobial stewardship that was used in the hospital and gives insight into the association of clinical outcomes with several factors and comorbidities.\n\n\nMethods\n\nThe current research is based on data extraction from electronic medical reports and as such it is not considered human subject research. Neither patients nor the public were involved in the design, conduct, or reporting of this research. The research was done retrospectively and without patient involvement. The study was approved by the Scientific Research Ethics Committee of Birzeit University on 27-2-2021 and by Beit-Jala hospital on 10-3-2021. The permission to use the generated data was obtained from Beit Jala Governmental Hospital laboratory administration.\n\nThis single-center cross-sectional study was conducted on patients aged 20 years and older in Beit-Jala hospital (as patients under 20 are not admitted to this hospital), one of the central institutes for treating SAR-CoV-2 patients in Palestine. A total of 458 records were screened. The records were for critically ill patients, admitted to the ICU between June 2020 and March 2021, with a confirmed diagnosis of COVID-19 via reverse transcriptase-polymerase chain reaction assay (RT-PCR) conducted on nasopharyngeal swab specimens. 321 patients with positive cultures for bacteria or fungi were included in the study, and patients with negative cultures were excluded.\n\nData extraction was done manually by one researcher between the 15th-29th of March 2021, and verified by a second researcher, using graded data forms from electronic medical reports. The obtained data were socio-demographics, chronic comorbidities, laboratory findings (CRP, leukocytes, blood oxygen saturation), duration of the ICU stay and if they had taken an iron supplement. The bacterial or fungal co-infection was proved through clinical presentation and positive blood or sputum testing via Laboratory Information System. Before and during the ICU admission, antimicrobial utilization was recorded, and the reports were double-checked for accuracy and completeness.\n\nData was analyzed and socio-demographic and clinical characteristics were summarized using relevant descriptive statistics, and categorical variables as percentages and frequencies. Pearson’s Chi-square test was performed to determine the association between the main parameters, which were the ICU residency duration and the other factors such as age, gender, iron supplements, antibiotics administration before and during the ICU admission, smoking habits, and comorbidities. Data was analyzed and presented using SPSS version 22.0.\n\nCo-infection is a sequela that occurs during or after the primary causative pathogen or its treatment. The isolated bacteria or fungi obtained from COVID-19 patients should be clinically relevant and not microbiota or contaminants. All the microbiological samplings were conducted upon the hospital`s entry and before the ICU admittance, and only patients holding positive bacterial or fungal outcomes were admitted into the unit. In combination with decision-making, a scope of tests should be met to provide permission on who necessitates access, including computerized tomography (CT) scans to reveal ground-glass opacification, which correlated with pneumonia. In addition, supplementary laboratory outcomes were crucial in making the diagnosis, such as C-reactive protein (CRP) level, Oxygen saturation (SpO2), Leukocyte numbers and body temperature. Patients were immediately admitted to the ICU if two or more of the above matched positive isolates test and their CT-scan showed pneumonia.\n\nTo determine the status of each patient, laboratory findings must be evaluated. For example, CRP values that ranged between 4.5-8.5 mg/dL were rated as moderate and ≥8.5 mg/dL was rated as severe. Leukocytes results in the 4.6-8 g/L range were considered mild, while >8 g/L indicated seriously ill patients. Normal oxygen saturation was considered ≥95%, but in COVID-19 patients, an oximeter reading at rest of 90% or lower was classed as a severe case. The body temperature was deemed high if it was between 38-39 °C and very high if it was >39 °C.\n\n\nResults\n\nA total of 458 moderate-severe ill patients were screened and evaluated, and of those 321 participants were included in this study. The patients’ demographics and clinical characteristics are presented in Table 1. Overall, 48.9% (170) were 41-64 years of age and 50.5% (162) were males. Prevailing chronic medical conditions included diabetes mellitus at 77.9% (250), atrial hypertension at 66.4% (213), obesity at 36.8% (118), cancer at 20.6% (66), and coronary heart disease at 23.1% (74). 3.7% of patients did not have past medical history of any comorbidity. 58.6% were not smokers, and 62.6% were supplemented with Iron 376 mg/day intravenously for three days. Additionally, all the participants in this study had received N-acetyl-cystine at 1200 mg/day, which began when they were admitted and continued until they left.\n\n(N 321; ICU: intensive care unit; SpO2: oxygen saturation).\n\nThe overall mortality rate in this study was 8.1%,26 while 72.9% (234) of the patients remained in the ICU for 1-6 days. Each patient was infected with one type of bacteria or fungi, which presented as a respiratory infection, bacteremia, and skin infections. A total of six different pathogens were detected in the samplings and considered as the infecting organisms. The most abundant types were Aspergillus fumigatus 48.9% and Enterobacter 24.9%, as shown in Table 1.\n\nIn terms of antibiotic prescription patterns, through the first 24 hours of hospital admission and based on per case specificity, the proper liver or kidney function tests had been conducted in all cases, in order to determine the appropriate regimen for treating bacterial or fungal infections. Before the ICU access, the treatment span was six days on average; 69.5% (223) received ceftriaxone 2 g/day, and 30.5% (98) patients had received ampicillin and sulbactam 12 g/day; both regimens were administered intravenously (IV). Upon ICU admission, every patient had been given one kind of IV antibiotic regimen throughout the stay; 43.0% (138) took meropenem 2 g/day and vancomycin 1 g/day and 35.5% (114) were given piperacillin/tazobactam 13.5 g/day and levofloxacin 500 mg/day. By January and after getting financial support from the Ministry of Health, patients infected with A. fumigatus started therapy with fluconazole 200 mg/day. Since then, 100% of the patients with fungal infection were successfully treated. Considering different regimens had notable distinct outcomes, analysis was performed to determine the association linking antimicrobial therapy class and the ICU stay or death (Table 2). After hospital discharge, patients taking antibacterial medications were switched to oral azithromycin. Patients treated with Fluconazole IV for two days switched to oral Fluconazole 150 mg/week.\n\n(N 321; ICU: intensive care unit; SpO2: oxygen saturation).\n\n* The percentages indicate proportion of patients within each category in any duration.\n\nTable 2 reports no significant association between the ICU stay duration with age, laboratory test results or having a chronic disease. A significant association was found between the residency duration and SpO2 (P=0.032): patients whose SpO2 levels were <90% (188; 75.2%) were admitted in the ICU for a shorter duration (1-6 days) compared to patients whose SpO2 read >90% (46; 64.8%).\n\nTable 3 shows a significant association between the ICU residency duration and the infecting isolates (P=0.008). The patients suffering from fungal co-infection (126; 80.3%) spent fewer days in the ICU than patients with bacterial co-infection (108; 65.9%).\n\n** The percentages indicate proportion of patients within each category in any duration.\n\nRegarding the hospital`s therapy strategy, there was a significant association between ICU residency duration and the empirical antibiotics (P<0.001); patients administered ceftriaxone (182; 81.6% of the patients given ceftriaxone) were more likely to stay in the ICU for fewer days compared with patients administered ampicillin/sulbactam (52; 53.1%). In addition, patients who took fluconazole (69; 100%) were significantly more likely to stay for fewer days in the ICU compared to those administered piperacillin and tazobactam with levofloxacin (57; 50%) or meropenem with vancomycin (108; 78.3%) respectively (P<0.001).\n\nMoreover, patients that were administered iron supplements as part of their therapy regimen (199; 99%) were significantly more likely to stay for a shorter duration of time compared with those who were not administered iron (35; 29.2%, P<0.001).\n\n\nDiscussion\n\nIn this research, the characteristics of co-infection in 321 severely ill COVID-19 patients were evaluated. This research found a mortality rate of 8.1% in the ICU, compared to a 25.7% mortality rate that was obtained from a systematic review of the emerging literature including 15 studies carried out in countries most affected by the pandemic.20 Despite the absence of antimicrobial stewardship in urgent response, the hospital's initiation of drastic empirical administration was crucial for preventing or treating suspected infections. In addition, the hospital’s guideline adherence for empiric antimicrobial therapy and the other drugs was adequate.\n\nCOVID-19 patients are at risk of fungal infections during the latter stages of the disease, due to seriously damaged alveoli and the decline in leukocyte counts.21 Based on the knowledge of SARS in 2003 and the invasive Aspergillosis, it is vital to consider the possibility of a life-threatening fungal infection accompanying COVID-19. At the beginning of blood/sputum culturing, the number of cases infected by A. fumigatus was 157. Initially, those patients were given antibacterial regimens before and during their ICU stay; because fluconazole was costly to obtain. By January, confirmed fungal infections were treated with fluconazole. This had reduced the average ICU stay from six days to less than two days, and the mortality rate from A. fumigatus decreased from 4.5% to 0%. Throughout the pandemic, specialists realized the risks of fungal co-infection. Therefore, the French High Council for Public Health recommended that clinicians should concentrate on fungal infections in COVID patients, particularly in severe cases of the disease.21\n\nBacterial co-infection was recorded in 51.1% of cases, with higher mortality rates among Enterobacter infected patients; this may be due to its known drug resistance. It should be noted that normal oral flora colonization or contamination may occur, particularly in the sputum specimens. In general, the empirical treatment with ceftriaxone or ampicillin/sulbactam showed minimal benefits to the clinical status. However, we observed a better prognosis with ceftriaxone than ampicillin/sulbactam, with mortality rates at 4% and 17.3% respectively; this association needs more investigation.\n\nThe wide-spectrum antimicrobial regimens are administered once the bacterial co-infection is confirmed and the patient is admitted into the ICU. Unfortunately, there is no available data to compare COVID-19 patients who received antibacterial agents with those who did not, which could help to determine the therapeutic efficacy. However, a regimen of piperacillin with tazobactam and levofloxacin resembles meropenem and vancomycin in terms of clinical outcomes and management rate. This counters a previous study that revealed a higher rate of mortality and organ failure in patients administered meropenem.17 Furthermore, after the recovery and discharge from the hospital, all outpatients were prescribed azithromycin, which also has antiviral activity and may decrease the incidence of acute organ failure.17\n\nEarlier examinations illustrated that multiple antibiotic administrations did not alter the disease results or had joined with higher mortality rates.22 In our study, it appeared to induce a good prognosis. Ceftriaxone, meropenem, and vancomycin regimens have been linked with more favorable outcomes and lower mortality rates. Until solid evidence is available, antimicrobials should be maintained for critical cases and constantly re-evaluated based on the patient's progress. Most importantly, the therapy must only cover the suspected or confirmed bacterial infection.\n\nAntibiotic resistance and allergic reactions are multifactorial issues, and the pandemic has impacted the health system and provided a good environment for bacteria to become resistant to antimicrobials. In our study, all COVID-19 patients were admitted to the ICU and received at least four diverse types of broad-spectrum antibacterial agents; in addition, the accessibility of over-the-counter antimicrobials had undeniably grown through the pandemic.19 This inappropriate behavior will lead to the evolution of high levels of antibiotic-resistant bacteria.\n\nThe unusual incidence of bacterial or fungal infections in our study differs from other published studies.11,23 This significant finding is due to the participant characteristics of critically ill patients receiving therapy via invasive catheters and being at risk of infection by nosocomial pathogens. Moreover, the unusual rate of infection has been credited to the exhaustion in the clinical care system creating a prolonged hospital exposure, principally in the major waves of the virus.\n\nIn our study, 100% of the patients were severe-critical ill. Therefore, it is necessary to differentiate between them and mild-moderate patients and prioritize the ICU admittance. Fever was the notable symptom in SARS-CoV-2 infection identified at the early stages of the disease. Regarding laboratory findings, leukocytosis occurred in critically ill patients with distinct grades, and it was observed in 11.4% severe COVID-19 cases.24 Leukocytosis aids in the disease progress evaluation, and its intensity reflects the severity of COVID-19 infection; it is exacerbated by the cytokine storm and inflammatory mediators that drive apoptosis and pulmonary microvascular destruction, creating alveolar oedema. The increased level of CRP is a diagnostic biomarker for coronavirus in distinguishing moderate and critical patients. The pathogenesis of COVID-19 involves a vigorous inflammatory response that manages a dysregulated flood of immune cells and signaling molecules.25 In general, viral respiratory infections have been linked to hypoxia. COVID-19 patients are considered hypoxic if their oxygen saturation level is <90%, while the normal SpO2 is ≥95% at rest in healthy people. Hypoxia is a fearful condition that is monitored and adjusted by mechanical ventilation.26 Although several studies27,28 reported links between laboratory findings and clinical outcomes, our cases did not show a significant link.\n\nThroughout the coronavirus pandemic, the issues of tobacco smoking and the risk of infection were constantly reviewed. Published research29 indicated that smokers are twice as likely to develop severe COVID-19 as nonsmokers, as smoking tobacco induces alterations in the respiratory tract and cell-mediated immune response.29 Furthermore, current smokers have higher ACE-2 gene expression than non-smokers; this gene is responsible for ACE-2 receptors production, which COVID-19 attaches to and penetrates the cells, thus raising the chance of infection.30 Our study did not find an association between smoking habits and the duration of ICU stay or clinical prognosis.\n\nNumerous investigations31,32 found that older COVID-19 patients aged ≥50 years were correlated with a higher risk for severe signs, atypical presentation, the opportunity for co-infections, and higher fatality rates than patients <50 years of age. The rate usually increases rapidly with age, which is not surprising due to the drop in natural immunity with aging and associated comorbidities. In addition, it is believed that older people are prone to adverse drug reactions.32 In general, people of older ages are more prone to becoming infected with the COVID virus than younger people.32 A review reported that the fatality rate is doubled in males compared to females; it stated that male patients may have higher ACE-2 enzyme activity, directed by male sex hormones, contributing to more risk factors for SARS-CoV-2 infection and worsening clinical outcomes.33 Additionally, the smoking rate is higher in males.33\n\nEffects of comorbidities such as hypertension, diabetes mellitus, coronary heart disease, and cancer were compared between survivors and non-survivors of COVID-19. Participants with comorbid conditions have a significantly greater fatality rate compared to participants without comorbid conditions, because they have decreased natural immunity and are poly-pharmacy patients.34,35 There was no association between age, gender, or comorbidities with the clinical outcomes and ICU stay duration in our study.\n\nPrevious reports had described mild anemia in COVID-19 patients at the ICU; due to severe inflammation which consumes iron,36 the innate immune system limits the bioavailability of iron in order to diminish viral replication and infection. Accordingly, iron absorption from the diet is reduced, and the liver generates hepcidin which blocks the carrying of iron out of the cell. Accordingly, iron supplementation may exacerbate the disease and increase the inflammatory process.37 However, no solid investigations were performed on the relation between iron and clinical results in COVID-19 patients. In our study, 62.6% of the patients had received IV iron supplement for three days, based on a randomized clinical trial, and 99% of them had improved and stayed for a shorter time (1-6 days) in the ICU than those who did not receive IV iron; thus it can be suggested that the iron provided an enhancement to immunity. Therefore, there is a strong association between low serum levels of iron and an increased infection rate and morbidity.\n\nCOVID-19 produces oxidative stress irregularity, and this process has been enhanced by glutathione reduction. Thiones are synthesized in a multi-step process involving N-acetyl-cysteine (NAC). Thiones are also ACE-2 blockers, thereby diminishing SARS-CoV-2 penetration into the cell. In a placebo-controlled study, NAC administration had reduced plasma inflammatory biomarker levels via several mechanisms. Besides antioxidant activity, NAC has vasodilator activity, especially in the intravenous route. In addition, it has mucolytic properties, inhibits RNA virus replication, and has confirmed protective effects against comorbid conditions, including cardiovascular diseases.38 In our study, patients received NAC 1200 mg/day during the hospital stay, and even after discharge they showed a good prognosis and improvement in their health status.\n\nThis is the first research addressing co-infection among COVID-19 patients in Palestine and offering clinical base recommendations for patient management. Our study shows a high prevalence of fungus and bacterial co-infection among COVID-19 patients admitted to the ICU, which requires appropriate management and attention. The study findings support the importance of assessing fungus co-infection in COVID-19 patients, and the early initiation of an antifungal agent will decrease morbidity and mortality. Our examination regarding the impacts of employing antifungals to manage COVID-19 patients can work as a successful reference for future COVID-19 therapy.\n\nThis research has some limitations: first, it is a retrospective cross-sectional study holding obstacles restricting the potential bias and difficulty proofing the relation between the exposure and the outcome. Additionally, it is a single-center study, and its results could vary in another setting. These conclusions present data supporting a conservative antibiotic administration for severely unwell COVID-19 infected patients.\n\n\nConclusion\n\nThe COVID-19 pandemic exerts pressure on healthcare professionals, including a high probability of infection. It is eminent to save lives during this pressure, even if it means multi-drug antimicrobial regimens for prevention or treatment. However, the insufficiency of data about antibiotic types, dosage, and duration of treatment through the pandemic continues to be challenging to health care providers. Bacterial and fungal co-infection is common among COVID-19 patients at the ICU in Palestine; it is not evident if these cases are attributed to SARS-CoV-2 or coincidental as there is little available data. Finally, antimicrobial stewardship, appropriate patient assessment, and selecting the appropriate antimicrobial agents for the right patient at the right time will decrease hospital stay, mortality, and health care costs.\n\n\nData availability\n\nDRYAD: Raw data and SPSS analysis for the article Bacterial and fungal co-infections among ICU COVID-19 hospitalized patients in a Palestinian hospital: Incidence and antimicrobial stewardship. https://doi.org/10.5061/dryad.08kprr53r.\n\nThis project contains the following underlying data:\n\n- raw_data.xlsx (raw underlying data)\n\n- Readme.docx (data key)\n\n- variabels_and_Output_final.pdf (SPSS output file)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAuthor contributions\n\nHN Project Administration, Supervision, Writing – Review & Editing, UM and YS Data Curation, Writing – Original Draft Preparation, Formal Analysis, NA Formal Analysis, Writing – Original Draft Preparation, AA Methodology, Writing – Review & Editing, MD Methodology, Writing – Review & Editing, IA Data Curation, MF Writing – Review & Editing. All authors read and approved the final manuscript.",
"appendix": "Acknowledgments\n\nWe would like to express our appreciation to the health workers at Beit-Jala Governmental Hospital, Palestine, for their support and cooperation. A previous version of this manuscript appeared on medRxiv.\n\n\nReference\n\nSinghal T: A Review of Coronavirus Disease-2019 (COVID-19). Indian J. Pediatr. 2020; 87: 281–286. PubMed Abstract | Publisher Full Text\n\nMiranda C, Silva V, Capita R, et al.: Implications of antibiotics use during the COVID-19 pandemic: Present and future. J. Antimicrob. Chemother. 2020; 75: 3413–3416. Publisher Full Text\n\nHendaus MA, Jomha FA: Covid-19 induced superimposed bacterial infection. J. Biomol. Struct. Dyn. 2020; 39: 4185–4191. Publisher Full Text\n\nChaplin S: COVID -19: a brief history and treatments in development. Prescriber. 2020; 31: 23–28. Publisher Full Text\n\nMorris DE, Cleary DW, Clarke SC: Secondary bacterial infections associated with influenza pandemics. Front. Microbiol. 2017; 8. PubMed Abstract | Publisher Full Text\n\nHuttner BD, Catho G, Pano-Pardo JR, et al.: COVID-19: don’t neglect antimicrobial stewardship principles!. Clin. Microbiol. Infect. 2020; 26(7): 808–810. Elsevier B.V. 2020 Jul\n\nKaraba SM, Jones G, Helsel T, et al.: Prevalence of co-infection at the time of hospital admission in COVID-19 patients, a multicenter study. InOpen forum infectious diseases. US: Oxford University Press; 2021 Jan; (Vol. 8, No. 1, p. ofaa578).\n\nElabbadi A, Turpin M, Gerotziafas GT, et al.: Bacterial coinfection in critically ill COVID-19 patients with severe pneumonia. Infection. 2021 Jun; 49(3): 559–562. PubMed Abstract | Publisher Full Text\n\nKarami Z, Knoop BT, Dofferhoff ASM, et al.: Few bacterial co-infections but frequent empiric antibiotic use in the early phase of hospitalized patients with COVID-19: results from a multicentre retrospective cohort study in The Netherlands. Infect. Dis. (Auckl). 2021; 53: 102–110. Publisher Full Text\n\nPrasetyoputri A: Detection of Bacterial Coinfection in COVID-19 Patients Is a Missing Piece of the Puzzle in the COVID-19 Management in Indonesia. ACS Infect. Dis. 2021; 7: 203–205. PubMed Abstract | Publisher Full Text\n\nPeng J, Wang Q, Mei H, et al.: Fungal co-infection in COVID-19 patients: evidence from a systematic review and meta-analysis.2021; 13: 7745–7757.\n\nPrasso JE, Deng JC: Postviral Complications: Bacterial Pneumonia. Clin. Chest. Med. 2017; 38: 127–138. PubMed Abstract | Publisher Full Text\n\nAvadhanula V, Rodriguez CA, DeVincenzo JP, et al.: Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species-and cell type-dependent manner. J. Virol. 2006 Feb 15; 80(4): 1629–1636. PubMed Abstract | Publisher Full Text\n\nLangford BJ, So M, Raybardhan S, et al.: Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clin. Microbiol. Infect. 2020 Jul 22; 26: 1622–1629. PubMed Abstract | Publisher Full Text\n\nLucien MAB, Canarie MF, Kilgore PE, et al.: Antibiotics and antimicrobial resistance in the COVID-19 era: Perspective from resource-limited settings. Int. J. Infect. Dis. 2021. Elsevier B.V.\n\nSieswerda E, de Boer MGJ , Bonten MMJ, et al.: Recommendations for antibacterial therapy in adults with COVID-19 – an evidence based guideline. Clin. Microbiol. Infect. 2021; 27: 61–66. PubMed Abstract | Publisher Full Text\n\nLiu C, Wen Y, Wan W, et al.: Clinical characteristics and antibiotics treatment in suspected bacterial infection patients with COVID-19. Int. Immunopharmacol. 2021; 90: 107157. Publisher Full Text\n\nPulia MS, Wolf I, Schulz LT, et al.: COVID-19: An emerging threat to antibiotic stewardship in the emergency department. West J. Emerg. Med. 2020; 21: 1283–1286. PubMed Abstract | Publisher Full Text\n\nAbelenda-Alonso G, Padullés A, Rombauts A, et al.: Antibiotic prescription during the COVID-19 pandemic: A biphasic pattern. Infect. Control Hosp. Epidemiol. 2020; 41: 1371–1372. PubMed Abstract | Publisher Full Text\n\nQuah P, Li A, Phua J, Phua J: Mortality rates of patients with COVID-19 in the intensive care unit: A systematic review of the emerging literature. Crit. Care. 2020; 24: 285. BioMed Central Ltd. PubMed Abstract | Publisher Full Text\n\nSong G, Liang G, Liu W: Fungal Co-infections Associated with Global COVID-19 Pandemic: A Clinical and Diagnostic Perspective from China. Mycopathologia. 2020; 185: 599–606. PubMed Abstract | Publisher Full Text\n\nDu Y, Tu L, Zhu P, et al.: Clinical features of 85 fatal cases of COVID-19 from Wuhan: A retrospective observational study. Am. J. Respir. Crit. Care Med. 2020; 201: 1372–1379. PubMed Abstract | Publisher Full Text\n\nYang X, Yu Y, Xu J, et al.: Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med. 2020; 8: 475–481. PubMed Abstract | Publisher Full Text\n\nFrater JL, Zini G, d’Onofrio G, et al.: COVID-19 and the clinical hematology laboratory. Int. J. Lab. Hematol. 2020; 42: 11–18. PubMed Abstract | Publisher Full Text\n\nYamada T, Wakabayashi M, Yamaji T, et al.: Value of leukocytosis and elevated C-reactive protein in predicting severe coronavirus 2019 (COVID-19): A systematic review and meta-analysis. Clin. Chim. Acta. 2020; 509: 235–243. PubMed Abstract | Publisher Full Text\n\nGreenhalgh T, Knight M, Inda-Kim M, et al.: Remote management of covid-19 using home pulse oximetry and virtual ward support. BMJ. 2021; 372. Publisher Full Text\n\nPourbagheri-Sigaroodi A, Bashash D, Fateh F, et al.: Laboratory findings in COVID-19 diagnosis and prognosis. Clinica Chimica Acta; International Journal of Clinical Chemistry. 2020 Nov; 510: 475–482. PubMed Abstract | Publisher Full Text\n\nYamada T, Wakabayashi M, Yamaji T, et al.: Value of leukocytosis and elevated C-reactive protein in predicting severe coronavirus 2019 (COVID-19): a systematic review and meta-analysis. Clin. Chim. Acta. 2020 Oct 1; 509: 235–243. PubMed Abstract | Publisher Full Text\n\nReddy RK, Charles WN, Sklavounos A, et al.: The effect of smoking on COVID-19 severity: A systematic review and meta-analysis. J. Med. Virol. 2021; 93: 1045–1056. PubMed Abstract | Publisher Full Text\n\nLeung JM, Leung JM, Yang CX, et al.: Current smoking is not associated with COVID-19. Eur. Respir. J. 2020; 55: 2001340–2001310. PubMed Abstract | Publisher Full Text\n\nZhang H, Wang X, Fu Z, et al.: Potential Factors for Prediction of Disease Severity of COVID-19 Patients.2020. Publisher Full Text\n\nGómez-Belda AB, Fernández-Garcés M, Mateo-Sanchis E, et al.: COVID-19 in older adults: What are the differences with younger patients?. Geriatr. Gerontol. Int. 2021; 21: 60–65. PubMed Abstract | Publisher Full Text\n\nAgrawal H, Das N, Nathani S, et al.: An Assessment on Impact of COVID-19 Infection in a Gender Specific Manner. Stem Cell Rev. Rep. 2021; 17: 94–112. PubMed Abstract | Publisher Full Text\n\nBiswas M, Rahaman S, Biswas TK, et al.: Association of Sex, Age, and Comorbidities with Mortality in COVID-19 Patients: A Systematic Review and Meta-Analysis. Intervirology. 2021; 64: 36–47. PubMed Abstract | Publisher Full Text\n\nQiu P, Zhou Y, Wang F, et al.: Clinical characteristics, laboratory outcome characteristics, comorbidities, and complications of related COVID-19 deceased: a systematic review and meta-analysis. Aging Clin. Exp. Res. 2020; 32: 1869–1878. PubMed Abstract | Publisher Full Text\n\nBaron DM, Franchini M, Goobie SM, et al.: Patient blood management during the COVID–19 pandemic: a narrative review. Anaesthesia. 2020; 75: 1105–1113. PubMed Abstract | Publisher Full Text\n\nTaneri PE, Gómez-Ochoa SA, Llanaj E, et al.: Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis. Eur. J. Epidemiol. 2020; 35: 763–773. PubMed Abstract | Publisher Full Text\n\nDe Flora S, Balansky R, La Maestra S: Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB J. 2020; 34: 13185–13193. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "119466",
"date": "01 Feb 2022",
"name": "Maher Khdour",
"expertise": [
"Reviewer Expertise clinical pharmacy",
"pharmacy practice",
"pharmaceutical care",
"medications",
"drug utilization",
"disease management."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nBacterial and fungal co-infections among ICU COVID-19 hospitalized patients in a Palestinian hospital: a retrospective cross-sectional study\nThe paper and subject are both valuable and are important to the scientific community, especially in this situation during the pandemic Covid-19. The paper is well-written, however some issues were raised during the review process and should be addressed:\nIn the abstract it is not clear whether the patients get infected at admission or during their stay in the ICU.\n\nAll results data e.g. \"The rate of bacterial co-infection was 51.1%...\" should include infected patients / total patients and for mortality rate please state the CI.\n\nAbstract conclusion (see if it fit the journal regulations as I see it long?).\n\nStudy design should be clearer to readers.\n\n458 records screened and 321 positive (this will result in 70% infected); if this is the case, please add the over all co-infection in the sample of 70% to your results.\n\nBetween 4.5-8.5 mg/dL was rated as moderate and ≥8.5 mg/dL was rated as severe. Leukocyte results in the 4.6-8 g/L range were considered mild, while >8 g/L indicated seriously ill patients: this is not mentioned in your results or in the abstract and you can find a good correlation between the severity and co-infection, I think this will make the abstract much better.\n\nHow did you calculate the mortality rate (should be stated in the method section, all causes)?\n\nSome significant data in tables 2 and 3 worth mentioning in the results of abstract with P values.\n\nUnder the tables, please state the test you used (Chi square) and be sure the abbreviations match too.\n\nIn the discussion (mortality rate 8.1 vs 25% in other developed countries) do you think there is under-reporting or documentation of co-infection in Palestinian hospitals, or is this due to the broad antibiotic used which is restricted in other countries due to resistance concerns?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7774",
"date": "03 Feb 2022",
"name": "Hani Naseef",
"role": "Author Response",
"response": "Dear Dr. Maher Thank you for your valuable comments, when the article has received a second peer review report I will submit a revised version 2 of the article incorporating the changes as you requested."
},
{
"c_id": "8279",
"date": "23 May 2022",
"name": "Hani Naseef",
"role": "Author Response",
"response": "Dear Dr. Maher Thank you for your valuable comments. Following are our responses point-by-point to your comments: 1- comment 1: Clarified \"with a confirmed diagnosis of COVID-19 via reverse transcriptase-polymerase chain reaction assay conducted on a nasopharyngeal swab and has a positive culture for bacteria or fungi as upon hospital admission\". 2- comment 2: Done in all the text. 3- comment 3: As per the Article Guidelines: the abstract should be up to 300 words long, The abstract of the manuscript fits the journal's instructions. 4- comment 4: Changed and clarified the text. 5- comment 5: Clarified \" A total of 458 records of moderate-severe COVID-19 ill patients were screened and evaluated. Of those, 321 patients with positive cultures for bacteria or fungi were included in the study, and patients with negative cultures were excluded\". 6- comment 6: This is already done and written in Table 2, but due to the absence of the association, as the chi-square result revealed, we did not mention it either in the text or in the abstract. 7- comment 7: Rewritten: \"The overall mortality rate for our sample in this study was (26/321*100%= 8.1%)\". 8- comment 8: Done \" A significant association was found between the residency duration and SpO 2 ( P=0.032). The results revealed a significant association between ICU residency duration and the empirical antibiotics ( P<0.001).\" 9- comment 9: Done for tables 2 and 3. 10- comment 10: Done \"The mortality rate of 8.1% (26) for patients admitted to the ICU due to Covid-19 coinfections found by this study is much lower than other reported rates of 25.7 % in a systematic review that included 15 studies in different countries. Despite the absence of antimicrobial stewardship in urgent response, the hospital's initiation of drastic empirical administration was crucial for preventing or treating suspected infections. In addition, the hospital’s guideline adherence to empiric antimicrobial therapy and the other drugs was adequate. Furthermore, many factors could affect this finding, including the age and living situations; in our sample, two-thirds of participants were less than 65 years old. In addition, all participants did not live in nursing homes or elderly homes where a higher rate of antimicrobial resistance is expected.\""
}
]
},
{
"id": "130200",
"date": "16 May 2022",
"name": "Hamza Maswade",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript entitled \"Bacterial and fungal co-infections among ICU COVID-19 hospitalized patients in a Palestinian hospital: a retrospective cross-sectional study\" is a study to investigate the burden of bacterial and fungal co-infections outcomes on COVID-19 patients. It is a single center cross-sectional study of hospitalized COVID-19 patients at Beit-Jala hospital in Palestine. The study is important and well written; however there are some comments, such as:\nPlease, add the duration of ICU stay (day) chronic cross tabulation.\n\nPlease, if it's possible, classify patients according to the number of chronic diseases for each patient.\n\nTable 1 the author(s) provide the percent for:\nDiabetes mellitus 250 (77.9%) Atrial hypertension 213 (66.4%) Obesity 118 (36.8%) Coronary heart disease 74 (23.1%) Cancer\nHowever; in table 2 \"Impact of different non-significant values on the duration in the ICU\", they did not mention the data for coronary heart disease and for cancer. Please add the data in table 2 and make a discussion for the results concerning patients with coronary heart disease and cancer.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8280",
"date": "23 May 2022",
"name": "Hani Naseef",
"role": "Author Response",
"response": "Dear Dr. Hamza, Thank you for your valuable comments. Following are our responses point-by-point to your comments: 1- Comment 1: Done. 2- Comment 2: Done, added to table 2. 3- Comment 3: Done \"A significant association was found between the residency duration and having a personal history with no chronic diseases (P= 0.035): (3; 23.1%) of patients with no chronic diseases have died after being admitted to ICU compared to (23; 7.5%) of patients diagnosed with at least one chronic disease.\""
}
]
}
] | 1
|
https://f1000research.com/articles/11-30
|
https://f1000research.com/articles/11-112/v1
|
28 Jan 22
|
{
"type": "Case Report",
"title": "Case Report: Godoy & Godoy method of cervical lymphatic therapy – indirect evaluation of the effect of the duration of stimulation on ocular edema",
"authors": [
"Jose Maria Pereira de Godoy",
"Henrique Jose Pereira de Godoy",
"Ana Carolina Pereira de Godoy",
"Maria de Fatima Guerreiro Godoy",
"Henrique Jose Pereira de Godoy",
"Ana Carolina Pereira de Godoy",
"Maria de Fatima Guerreiro Godoy"
],
"abstract": "The aim of the present study is to report the indirect evaluation of cervical stimulation considering the effect of the duration of the stimulus on the control of intraocular pressure in a patient with bilateral glaucoma with important ocular edema. A 47-year-old woman reported the onset of pain and bilateral tearing in the eyes at 35 years of age and was diagnosed with glaucoma. The patient began clinical treatment, but intraocular pressure remained 35 to 40 mmHg even with the use of four eye medications in the form of drops. The patient reported that her vision was always blurred despite the use of the eyedrops. The patient was submitted to the Godoy & Godoy method of cervical lymphatic therapy to reduce the edema. The ophthalmologist measured her intraocular pressure every two and three days. We found that the pressure was maintained below 20 mmHg when lymphatic therapy was performed every two days, but intraocular pressure increased and the vision became blurred when therapy was performed every three days. The Godoy & Godoy method of cervical lymphatic therapy constitutes a novel lymphatic system stimulation strategy that maintains its effect on intraocular pressure for approximately 48 hours, as demonstrated through an indirect evaluation.",
"keywords": [
"Ophthalmology",
"Godoy & Godoy method",
"lymphatic therapy",
"glaucoma"
],
"content": "Introduction\n\nThe Godoy & Godoy method of cervical lymphatic therapy is a novel lymphatic stimulation concept developed in recent years based on the adaptation of the manual lymphatic drainage technique using linear movements for the treatment of facial lymphedema.1–3 The method emerged from the development of a novel therapeutic option that did not involve manual drainage in the region of the carotid body to avoid the complications of its stimulation. The strategy was to drain only below the midline of the neck. However, during the treatment of a patient with cervical clearance and an ulcerated lesion below the midline with intense fibrosis, the option was to perform small sliding movements in this region. This was initially an attempt to perform linear drainage with short elongation of the skin. The following day, the patient reported improvements in both pain and neck mobility and had slept better. This information led to the decision to perform the technique 15 to 20 minutes per day. The improvement was continuous over the subsequent days, with the clinical reversal of the fibrosis, which led to an improvement in the quality of life of this patient.2\n\nAnother patient with cervical clearance who was unable to close their mouth and required the use of a nasogastric tube was treated daily. After three months, the child began to eat and a dental prosthesis was adapted, leading to an improvement in quality of life. Another patient with facial edema who was unable to open the eyes and the tongue did not fit in the mouth was submitted to three days of treatment; the child was evaluated on the fifth day, at which time the patient was able to open and close the eyes and the tongue had reduced in size.3\n\nBased on these observations, the results of this method as monotherapy for lower limb lymphedema were evaluated. A two-year evaluation of this cervical method as monotherapy revealed improvement in all patients.4 The assessment of this method as monotherapy for upper limb lymphedema was then performed5 and a report of the results after ten years of follow-up was published.6 Several studies combining this method with other forms of treatment for lymphedema have been conducted over the years.7 The aim of the present study is to report the indirect evaluation of cervical stimulation considering the effect of the duration of the stimulus on the control of intraocular pressure in a patient with bilateral glaucoma with important ocular edema.\n\n\nCase report\n\nA 47-year-old woman (white, photographer) reported in January 2009, the onset of pain and bilateral tearing in the eyes at 35 years of age and was diagnosed with glaucoma. The patient began clinical treatment, but intraocular pressure remained 35 to 40 mmHg even with the use of four eye medications in the form of drops. She sought 13 ophthalmologists to undergo surgery for glaucoma, but none was willing to perform surgery due to the excessive edema. At 36 years of age, the patient sought a clinic for the treatment of lower limb varicose veins. CEAP C2 and hyperemia with periorbital edema were findings that drew the attention of the health team. The patient reported that her vision was always blurred despite the use of the eye drops (Figure 1). The patient was submitted to the Godoy & Godoy method of cervical lymphatic therapy to reduce the edema (Figure 2), which resulted in an improvement in the first session. This therapy consists of gentle elongating movements of approximately 0.5 cm on the skin surface, supraclavicular neck, at a rate of 30 movements per minute, for 20 minutes per day (Figure 3).\n\nThe patient began to see better and no longer had blurred vision beginning with the first session. In an initial phase, cervical lymphatic therapy was performed daily and subsequently every other day. The patient’s vision was no longer blurred. Intraocular pressure was reduced to less than 20 mmHg and the ophthalmologist reduced the prescription to two medications. Periorbital edema and hyperemia were normalized. During one weekend, the patient’s vision became blurred again. The patient had spent three days without undergoing therapy. We asked the ophthalmologist to measure her intraocular pressure every two and three days. We found that the pressure was maintained below 20 mmHg when lymphatic therapy was performed every two days, but intraocular pressure increased and the vision became blurred when therapy was performed every three days.\n\nThe patient was followed up at the clinic for two years, when she was able to find an ophthalmologist to perform glaucoma surgery. Ocular pressure reduced to 7 to 8 mmHg in both eyes and remains at this level. However, even after surgery, the vision became blurred again, which was improved with cervical lymphatic therapy.\n\nIt has been nine years since the patient was submitted to surgery. She initially needed to perform cervical lymphatic therapy more often, but currently undergoes this therapy sporadically. Cervical lymphatic therapy maintained intraocular pressure controlled for 48 hours, but surgery brought a more lasting benefit.\n\nThis study received approval from the institutional review board of the São Jose do Rio Preto School of Medicine (reference number 4.962.509), and the patient signed a consent form.\n\n\nDiscussion\n\nThe present study is an indirect way of evaluating the Godoy & Godoy method of cervical stimulation, which is currently denominated the Godoy & Godoy method of cervical lymphatic therapy. The improvement in vision with the first session drew the attention of the researchers, who then performed therapy on the patient 15 to 20 minutes per day, leading to the disappearance of the blurred vision. The initial question was how to quantify these results. However, the ophthalmologist noted an improvement in intraocular pressure from approximately 40 mmHg to less than 20 mmHg, with the reduction from four eye medications to two.\n\nDaily therapy led to the maintenance of non-blurred vision, but the vision blurred when the patient performed physical effort, which led to an increase in intraocular pressure. Another important observation was the fact that the patient’s vision became blurred when she spent three days without cervical lymphatic therapy and improved again when returning to therapy. Thus, the decision was made to standardize the ocular evaluation every two and three days, which revealed that normal vision was maintained for two days and became blurred on the third day due to the increase in intraocular pressure, suggesting that cervical lymphatic therapy maintains the results for approximately 48 hours. Therefore, this is a novel form of stimulating the lymphatic system that maintains its effects for 48 hours. One of the hypotheses is neurological stimulus, which remains activated for various hours.\n\nThis experiment was conducted several times over a two-year period until the patient was able to undergo glaucoma surgery. However, her vision frequently becomes blurred and improves with cervical lymphatic therapy, which was initially required more often and is currently only needed sporadically. The Godoy & Godoy method of cervical lymphatic therapy constitutes a novel lymphatic system stimulation strategy that maintains its effect on intraocular pressure for approximately 48 hours, as demonstrated through an indirect evaluation, but further studies are needed to confirm more lasting benefit and for similar cases.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.",
"appendix": "References\n\nPereira de Godoy HJ, Troitino RO, Pereira de Godoy LM, et al.: Cervical stimulation therapy after treatment laryngeal cancer reduces lymphedema. J. Phlebol. Lymphol. 2017; 2017(1): 1–4. Publisher Full Text\n\nGodoy JMP, Godoy MFG, Braile DM: Lymphatic drainage and quality of life in a patient with laryngectomy. Rev. Port. ORL. 2000; 38: 47–49.\n\nGodoy JM, Godoy MF, Meza MC: Godoy & Godoy technique of cervical stimulation in the reduction of edema of the face after cancer treatment. QJM. 2008Apr; 101(4): 325–326. Publisher Full Text\n\nde Godoy JMP , de Godoy ACP , Guimarães TD, et al.: The Godoy & Godoy cervical stimulation technique in treatment of primary congenital lymphedema. Pediatr. Rep. 2012; 4: 1108–1111. PubMed Abstract | Publisher Full Text\n\nPereira de Godoy LM, de Godoy P , Capeletto P, et al.: Cervical Stimulation in the Treatment of Children with Lymphedema of All Four Extremities: A Case Report and Literature Review. Case Rep. Pediatr. 2017; 2017: 9724524–9724524. PubMed Abstract | Publisher Full Text\n\nPereira de Godoy AC, Pereira de Godoy JM, Guerreiro Godoy MF: Primary Congenital Lymphedema with More Than 10 Years of Treatment Using the Godoy Method Through to Adolescence. Pediatr. Rep. 2021; 13: 91–94. PubMed Abstract | Publisher Full Text\n\nde Godoy ACP , de Godoy JMP : Lymphedema in children. Turk. Arch. Pediatr. 2021. Publisher Full Text"
}
|
[
{
"id": "121447",
"date": "08 Feb 2022",
"name": "Evangelos Dimakakos",
"expertise": [
"Reviewer Expertise Lymphedema VTE AND cancer"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper entitled Case Report: Godoy & Godoy method of cervical lymphatic therapy – indirect evaluation of the effect of the duration of stimulation on ocular edema, is a case report paper very well written and explains a novel therapeutic option on ocular edema. The background of the case’s history is described in sufficient detail, the method and the explanation of the treatment and its results are very clearly described. In the discussion, the authors analyzes with a clear way the importance of the treatment and the results of this new therapeutic method in a way that is very useful for other practitioners.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
},
{
"id": "127076",
"date": "29 Mar 2022",
"name": "Attilio Cavezzi",
"expertise": [
"Reviewer Expertise Vascualr Surgery",
"vascular medicine",
"longevity medicine",
"psychoneuroendocrineimmunology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors report their experience with an original manual method to improve lymphatic drainage in a selective indication. This case-report correctly indicates the possibilities and limitations of manual lymphatic drainage in these specific cases and the authors have presented their own method, with interesting outcomes. In order to facilitate the review of the text, a detailed proposal of text revision is provided below Lastly, some more references regarding head and neck manual lymphatic therapy could be added in the introduction and/on discussion section. For this purpose, a link with a few references is provided here: https://pubmed.ncbi.nlm.nih.gov/?term=manual+lymph+drainage+neck+face&sort=date\nHere is my proposed revision: Godoy Review\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "8035",
"date": "28 Apr 2022",
"name": "Jose Maria Pereira de Godoy",
"role": "Author Response",
"response": "The authors report their experience with an original manual method to improve lymphatic drainage in a selective indication. This case-report correctly indicates the possibilities and limitations of manual lymphatic drainage in these specific cases and the authors have presented their own method, with interesting outcomes. In order to facilitate the review of the text, a detailed proposal of text revision is provided below Lastly, some more references regarding head and neck manual lymphatic therapy could be added in the introduction and/on discussion section. For this purpose, a link with a few references is provided here: https://pubmed.ncbi.nlm.nih.gov/?term=manual+lymph+drainage+neck+face&sort=date Reply: The authors added references in the introduction. Here is my proposed revision: Godoy Review Is the background of the case’s history and progression described in sufficient detail? Partly Reply: The authors added. Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Reply: thanks. Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes Is the case presented with sufficient detail to be useful for other practitioners? Yes Reply: thanks."
}
]
}
] | 1
|
https://f1000research.com/articles/11-112
|
https://f1000research.com/articles/11-591/v1
|
30 May 22
|
{
"type": "Research Article",
"title": "Evaluation of selected semen parameters and biomarkers of male infertility – preliminary study",
"authors": [
"Michal Kups",
"Kamil Gill",
"Aleksandra Rosiak-Gill",
"Patryk Harasny",
"Tomasz Machalowski",
"Marta Grabowska",
"Rafal Kurzawa",
"Olimpia Sipak",
"Malgorzata Piasecka",
"Michal Kups",
"Kamil Gill",
"Aleksandra Rosiak-Gill",
"Patryk Harasny",
"Tomasz Machalowski",
"Marta Grabowska",
"Rafal Kurzawa",
"Olimpia Sipak"
],
"abstract": "Background: Because the etiopathogenesis of male infertility is multifactorial our study was designed to clarify the relationship between standard semen parameters, testicular volume, levels of reproductive hormones and the fragmentation of sperm nuclear DNA (SDF). Methods: Patients (n = 130) were clustered as subjects: 1) with an abnormal volume (utrasonography) of at least one testis (<12 mL) or with a normal volume of testes and 2) with abnormal levels of at least one of the reproductive hormones (FSH, LH, PRL, TSH, total T – electrochemiluminescence method) or with normal hormonal profiles and 3) with high level of SDF (>30%), moderate (>15–30%) or low (≤15%) (sperm chromatin dispersion test).\nResults: In subjects with a decreased testicular volume and in subjects with abnormal levels of reproductive hormones, decreased basic semen parameters were found. Participants with abnormal testicular volume had a higher percentage of SDF and a higher level of FSH (Mann–Whitney U test). In turn, men with a high level of SDF had lower testicular volume and conventional sperm parameters than men with a low level of SDF (Kruskal–Wallis test). Conclusions: We showed that spermatogenesis disorders coexisted with decreased testicular volume and increased FSH levels. The disorders of spermatogenesis were manifested by reduced basic sperm characteristics and a high level of sperm nuclear DNA damage.",
"keywords": [
"male infertility",
"semen characteristics",
"testicular volume",
"reproductive hormones",
"sperm nuclear DNA integrity"
],
"content": "Introduction\n\nThe etiopathogenesis of male infertility is a multifactorial medical problem and is correlated with many congenital and acquired defects of the urogenital tract, cancers, urogenital infections, heat stress in the scrotum, hormonal disorders, genetic abnormalities and immunological factors. It is estimated that approximately 30–50% of male infertility cases are recognized as idiopathic, very often associated with low-quality of spermatozoa.1–4 On the other hand, unexplained infertility (couples where male patients have normal basic semen parameters and female patients have normal ovulation and fallopian tube potency) is diagnosed in 15–30% of cases.1–4 Therefore, the comprehensive evaluation of male fertility status should be developed using scrotal ultrasonography (USG) and assessment of the key reproductive hormone as well as advanced seminological tests.3,5–12\n\nAvailable data has suggested that it is possible that infertile men could have normal standard semen characteristics.1,13,14 Therefore, it is important to look beyond conventional semen analysis. Many authors report that among the advanced sperm tests, the assays that verify sperm nuclear DNA fragmentation (SDF) are the most clinically useful. Furthermore, evaluation of the percentage of SDF could significantly help in determining the most beneficial treatment algorithm for couples trying to have offspring.4,5,7,15–20 An SDF ≤15% is considered a normal value (low level of nuclear DNA damage) and correlates with high male fertility potential. In these cases, the chance of becoming pregnant naturally or by intrauterine insemination (IUI) is high. In turn, SDF >15–30% (moderate level of DNA damage) can be associated with a reduced chance of becoming pregnant through natural conception and IUI or even in vitro fertilization (IVF) treatment. This range of SDF values and history of previous unsuccessful attempts to achieve pregnancy might indicate the need to introduce intracytoplasmic sperm injection (ICSI). Finally, a high level of SDF (>30%) is strongly associated with a significantly increased risk of reproductive failure, including ICSI treatment. It should be highlighted that even if pregnancy due to assisted reproductive technology (ART) is achievable, the percentage of sperm cells with a fragmented genome >30%, especially >40%, may significantly increase the risk of pregnancy loss.4,16,19,21–30 These three ranges of sperm DNA damage (≤15%, >15–30% and >30) were primarily recommended for interpretation of the SCSA test results,16,22,25,26,29 however similar ranges also have been successfully adapted to sperm chromatin dispersion test (SCD).19,23,31 Hence, an in-depth assessment of male fertility status, including testicular ultrasound, the levels of reproductive hormones and basic and advanced semen analysis, is clinically justified. Therefore, our study was designed to 1) determine the relationship between testicular volume, levels of reproductive hormones (follicle-stimulating hormone – FSH, luteinizing hormone – LH, prolactin – PRL, total testosterone – total T, thyroid-stimulating hormone – TSH), standard semen analysis and sperm genomic integrity and 2) compare standard semen parameters and investigated biomarkers of male infertility between groups of participants with low, moderate and high levels of nuclear DNA fragmentation.\n\n\nMethods\n\nIn accordance with the Declaration of Helsinki, all participants in the study indicated their written conscious and voluntary consent to participate in the scientific project. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Pomeranian Medical University, Szczecin, Poland (KB-0012/21/18, date of approval: 5 February 2018).\n\nThe study population consisted of 130 male infertile participants (median age: 33.00 years; range: 23–51 years) who were treated in 2018-2021 in the Individual Specialist Medical Practice (Szczecin, Poland) and The Fertility Partnership Vitrolive in Szczecin (Poland) – Gynaecology and Fertility Clinic and who gave their consent to participate in the study. All patients were partners of women (n = 130; median age: 30.00 years; range: 22–46 years) who did not become pregnant during one year (median: 2 years; range: 1.00–14.00 years) of regular intercourse without contraception (Figure 1). All initially qualified participants during a medical interview reported to the Laboratory of Andrology in the Department of Histology and Developmental Biology (Pomeranian Medical University, Szczecin, Poland) for seminological analysis. Based on the performed basic semen analysis, men with azoospermia and cryptozoospermia were excluded from the study group.\n\nFSH – follicle-stimulating hormone, LH – luteinizing hormone, SDF – sperm DNA fragmentation, PRL – prolactin, TSH – thyroid-stimulating hormone, total T – total testosterone.\n\nThe infertile status of subjects was verified based on an in-depth medical interview conducted by a specialist in urology (M. K.). The interview included information about factors that may affect fertility potential (genital injuries, cryptorchidism, varicocele, urogenital infections, chronic diseases, pharmacotherapy, use of anabolic steroids, operations and treatments, exposure to harmful factors, lifestyle, stimulants and others) (the interview form can be found as Extended data.111 Moreover, the physical medical examination included body assessment (body and hair proportions), and palpation (penis, gonads, epididymides, seminal cords, inguinal canal, prostate and mammary glands) was carried out.\n\nStandard semen analysis was carried out according to World Health Organization (WHO) recommendations.32 Semen samples were collected in a sterile urine container by masturbation after a two- to seven-day sexual abstinence. After complete liquefaction of semen (at 37 °C), standard semen analysis was carried out at room temperature – 22°C. The macroscopic evaluation of the semen included color, viscosity, volume and pH. In turn, the microscopic assessment (light/phase-contrast microscope DM500, Lecia, Heerbrugg, Switzerland) included the initial verification of the samples (presence of mucus bands, erythrocytes, epithelial cells, spermine crystals, residual bodies, aggregation and agglutination of sperm) as well as the assessment of the sperm concentration and the total sperm count, motility (progressive and nonprogressive motility), morphology, vitality and the concentration of inflammatory cells. Sperm concentration (analyzed in an improved Neubauer hemocytometer – Heinz Hernez Medizinalbedarf GmbH, Hamburg, Germany, ref no 1080339), sperm motility and vitality (eosin-positive cells and hypoosmotic-reactive cells: HOS test-positive cells) were assessed under a light/phase-contrast microscope using a 40× objective. To evaluate sperm cell morphology (including the teratozoospermia index reflecting multiple morphological defects per spermatozoon – TZI), native sperm smears were fixed and stained according to the Papanicolaou method (Aqua-Med, Lodz, Poland) and were analyzed under a bright light microscope using a 100× objective oil immersion lens. The concentration of leukocytes (peroxidase-positive cells) was calculated using the Endtz test (LeucoScreen kit, FertiPro N.V., Beernem, Belgium) and assessed in an improved Neubauer hemocytometer.\n\nTo verify sperm nuclear DNA fragmentation, a commercial chromatin dispersion test – a Halosperm G2® kit (Halotech DNA, Madrid, Spain) – was applied. The procedure was performed strictly according to the manufacturer’s guidelines and was described in detail in our previous publications.33–36\n\nTo calculate the percentage of sperm cells with fragmented DNA, a minimum of 300 sperm cells per sample was counted under the 100x objective of a bright light microscope. According to the manufacturer’s guidelines, the following evaluation criteria were used: (1) sperm cells without nuclear DNA fragmentation (spermatozoa with a large halo – equal to or higher than the diameter of the core of spermatozoa and spermatozoa with a medium-sized halo – >1/3 of the diameter of the core of spermatozoa) and (2) sperm cells with nuclear DNA fragmentation (spermatozoa with a small halo – ≤1/3 of the diameter of the core of spermatozoa and spermatozoa without a halo but with a strongly stained core or without a halo and degraded chromatin – sperm cells showing no halo and simultaneously presenting an irregularly or weakly stained core) (Figure 2). The results of the SCD test (SDF) are presented as the sum of spermatozoa with nuclear DNA fragmentation divided by the total number of assessed sperm cells and multiplied by 100%.\n\nMicrographs obtained by light microscopy, 100×. Scale bar = 5 μm. Raw micrographs were edited in Corel Photo-Paint 2019 (Corel Corporation, Ottawa, Canada, RRID:SCR_014235). Editing included only: cropping (to center the presented sperm cells), rotation, brightening, contrast enhancing and enlargement.\n\nTo assess the panel of basic hormones influencing male fertility, potential vein blood was collected from participants in the morning (7.30–09.00), and the following hormones presented in Table 1 were measured. The hormone levels were determined by the electrochemiluminescence method (ECLIA) using the Cobas e801 analytical unit (Roche Diagnostics GmbH, Mannheim, Germany). The ECLIA method is based on the binding of biotinylated monoclonal-specific antibodies directed against the measured hormones and specific monoclonal antibodies labeled with a complex containing ruthenium metal (sandwich complex). In the next step, streptavidin-bound microparticles were used to bind to biotinylated antibodies directed against the measured hormones. Unbound substances were removed. The bound microparticles were magnetically trapped on the electrode surface. The electrode voltage induced chemiluminescence emission, which was measured by a photomultiplier. The result was determined based on a two-step calibration. All hormonal analyses were assessed strictly in accordance with the manufacturer's instructions.\n\nTo verify testicular volume, USG of the scrotum (ultrasound system Z-5 with a 75L38EA linear head; frequency range of 5–10 MHz, Mindray, Shenzhen, China) was performed by a senior urologist. The measurements were calculated using the following formula: length × width × height × 0.71. Furthermore, they were expressed in mL. According to the most commonly accepted criterion in clinical practice, the hypotrophic gonad was considered when the volume of the testis was less than 12 mL.37 Additionally, the homogeneity and echogenicity of the gonadal parenchyma as well as the presence of possible focal lesions and microcalcifications were assessed.\n\nBecause the Shapiro–Wilk test showed that the data were not normally distributed, a nonparametric Mann–Whitney U test and Kruskal–Wallis test were applied to compare quantitative variables between two or more studied groups, respectively. Quantitative variables are expressed as the median with the range and mean ± standard deviation (SD). Additionally, to verify the relationships between study parameters, the Spearman’s rank (rs) correlation coefficient was calculated (Figure 1). To interpret the strength of dependence between parameters, the following levels of correlation were presumed: <0.2 – lack of linear dependence (regardless of the p value), 0.2–0.4 – weak dependence, >0.4–0.7 – moderate dependence, >0.7–0.9 – strong dependence and >0.9 very strong dependence. For all statistical analyses, a p value < 0.05 was considered significant. Data analysis was performed using Statistica version 13.3 (StatSoft, Krakow, Poland, RRID:SCR_014213) and MedCalc version 18.2.1 (MedCalc Software, Ostend, Belgium, RRID:SCR_015044). Open source statistical software which can be used in the study – GNU PSPP.\n\n\nResults\n\nOf 130 obtained semen samples, 26 were classified as normozoospermia (total sperm count ≥39 × 106 cells, sperm progressive motility ≥32%, normal sperm morphology ≥4%), 36 as teratozoospermia (abnormal sperm morphology), 36 as oligoasthenoteratozoospermia (simultaneously abnormal total sperm count, progressive motility and morphology), 19 as oligoteratozoospermia (simultaneously abnormal total sperm count and morphology), nine as asthenoteratozoospermia (simultaneously abnormal progressive sperm motility and morphology), three as oligozoospermia (abnormal sperm total count) and one as asthenozoospermia (abnormal sperm progressive motility). Moreover, 51 men had abnormal levels of at least one of the assessed reproductive hormones (FSH, LH, PRL, total T, TSH), and 37 men had an abnormal volume of at least one testis (<12 mL). The descriptive statistics of the investigated parameters are provided in Table 2.\n\nCompared groups did not differ in age. The subjects from the group with abnormal testicular volume (n = 37) had significantly higher levels of FSH than the reference group (n = 91) (median: 8.05 mIU/mL vs. 5.29 mIU/mL), whereas the levels of other study hormones (LH, PRL, total T, TSH) did not differ significantly (Table 3). On the other hand, in case of seminological parameters, patients with decreased testicular volume had a significantly reduced sperm concentration (medians: 6.25 × 106 cells/mL vs. 19.00 ×106 cells/mL), total sperm count (medians: 15.35 × 106 cells vs. 60.12 × 106 cells), sperm morphology (medians: 0.00% vs. 1.00%), progressive motility (medians: 37.00% vs. 51.00%), total motility (medians: 43.50% vs. 57.00%) and vitality – eosin-negative sperm cells (medians: 73.00% vs. 79.00%) and hypoosmotic (HOS) test-positive sperm cells (medians: 73.50% vs. 78.00%). It should be highlighted that in the group of men with abnormal testicular volume, a significantly higher percentage of SDF was found (medians: 27.00% vs. 17.00%) (Table 4).\n\nThere were no significant differences in age between the compared groups, whereas higher levels of FSH, LH, PRL and TSH were noted in infertile men with abnormal hormonal profiles (n = 51) than in infertile men with normal hormonal profiles (n = 79). Unexpectedly, the study groups did not differ in the level of total T (Table 5). Regarding the semen parameters, infertile men with hormonal disorders had significantly lower total sperm count (medians: 30.25 × 106 cells vs. 54.00 × 106 cells), sperm morphology (medians: 0.00% vs. 1.00%), progressive motility (medians: 35.00% vs. 50.00%) and total motility (medians: 41.00% vs. 57.00%). Furthermore, the percentage of SDF was increased in the group with hormonal abnormalities, but the difference was not statistically significant (medians: 22.00% vs. 18.00%). Additionally, the compared groups did not differ in testicular volume (Table 6).\n\nBased on the publications of other authors,16,19,22,23,25,26,29,31 the study group was divided into three subgroups: 1) with a high level of sperm nuclear DNA damage (SDF >30%, low fertility potential), 2) with a moderate level of sperm nuclear DNA damage (SDF >15–30%, moderate fertility potential) and 3) with a low level of sperm nuclear DNA damage (SDF ≤15%, high fertility potential) (Tables 7, 8).\n\nStatistical analysis revealed some significant differences between men with SDF >30% (n = 28) and men with SDF ≤15% (n = 43). The first group had significantly lower left testis volume (medians: 13.00 mL vs. 16.00 mL) and right testis volume (medians: 12.00 mL vs. 16.00 mL), sperm concentration (medians: 5.65 ×106 cells/mL vs. 21.75 ×106 cells/mL), total sperm count (medians: 20.02 ×106 cells vs. 70.76 ×106 cells), sperm morphology (medians: 0.00% vs. 3.00%), progressive motility (medians: 26.00% vs. 63.00%), total motility (medians: 33.00% vs. 68.00%) and vitality – eosin-negative sperm cells (medians: 67.00% vs. 86.00%) and HOS test-positive sperm cells (medians: 67.00% vs. 83.00%) (Tables 7, 8).\n\nIn addition, in contrast to men with SDF ≤15%, infertile men with SDF >15–30% (n = 59) had a significantly lower total sperm count (medians: 41.25 × 106 cells vs. 70.76 × 106 cells), sperm morphology (medians: 0.00% vs. 3.00%), progressive motility (medians: 40.00% vs. 63.00%), total motility (medians: 48.00% vs. 68.00%) and sperm vitality – eosin-negative sperm cells (medians: 74.00% vs. 86.00%) and HOS test-positive sperm cells (medians: 72.00% vs. 83.00%) (Table 7).\n\nOn the other hand, we did not observe any significant differences between men with SDF >30% and men with SDF >15–30% in any study parameters. Additionally, in the case of age, hormone levels (FSH, LH, PRL, total T, TSH), TZI index, sperm nonprogressive motility and concentration of peroxidase-positive cells in semen, no significant differences between the compared three groups were recorded (Tables 7, 8).\n\nCorrelations between SDF, male age, basic semen parameters, testicular volume and hormone levels\n\nAnalysis of the Spearman’s rank correlation coefficient showed a linear relationship between SDF and selected parameters. SDF was negatively correlated with sperm concentration (rs = –0.3461; weak dependence), total sperm count (rs = –0.3343; weak dependence), sperm morphology (rs = –0.4482; moderate dependence), progressive motility (rs = –0.5476; moderate dependence), total motility (rs = –0.5374; moderate dependence) and vitality – eosin-negative sperm cells (rs = –0.6389; moderate dependence) and HOS test-positive sperm cells (rs = –0.5811; moderate dependence). In turn, there were no significant correlations between SDF and age, ejaculate volume, nonprogressive sperm motility or peroxidase-positive cell concentration. Moreover, a negative correlation between SDF and the volume of the left testis was found (rs = –0.2055; weak dependence), whereas there were no significant correlations between SDF and the volume of the right testis or study hormone levels (Tables 9, 10).\n\nCorrelations between testicular volume, hormone levels and basic semen parameters\n\nIn the examined group, the left and right testis volumes were negatively correlated with the level of FSH (rs = –0.2491 and rs = –0.2402, respectively; weak dependences) but was not correlated with other hormones (LH, PRL, total T, TSH). Moreover, the volumes of the left and right testes were positively correlated with sperm concentration (rs = 0.4345 and rs = 0.4019, respectively; moderate dependences) and total sperm number (rs = 0.4191 and rs = 0.3452, respectively; moderate and weak dependences). Additionally, positive correlations between left testis volume and sperm progressive motility (rs = 0.2048) as well as total motility (rs = 0.2115; weak dependence) were found. Furthermore, the LH level was negatively correlated with sperm concentration (rs = –0.2205; weak dependence) and total sperm count (rs = –0.2350; weak dependence), but there were no other significant correlations between the levels of assessed hormones and conventional semen parameters (Tables 9, 10).\n\nThe raw data can be found as Underlying data.109,110\n\n\nDiscussion\n\nBased on the obtained data, it can be suggested that the failure to become a biological father could be due to disorders of spermatogenesis manifested by reduced standard seminological parameters. It is worth noting that in our study, the median morphologically normal sperm was only 1%, and as many as 100 out of 130 infertile men had teratozoospermia (isolated or coexisting with other semen disorders). Additionally, studies conducted by other authors confirm the relationship between standard sperm parameters and male fertility.38–40 Slama et al.40 proved a significantly shorter time to pregnancy (TTP) in women whose partners had a higher percentage of sperm with normal morphology. Moreover, it was found that the percentage of morphologically normal sperm was decreased in men from couples with a history of recurrent miscarriage.41–44 Additionally, morphologically normal sperm cells play an important role not only in the case of natural conception but also in medically assisted conception (IUI, fertilization in vitro),45 and it has been shown that sperm morphology may also influence embryo development.43 On the other hand, reproductive success might be achieved even when morphologically normal sperm cells are not observed in the semen. Shabtaie et al.46 emphasize that in the case of only abnormal sperm morphology (assuming no female infertility factor), first-line therapy should not assist ART without undertaking a sufficiently long attempt at natural conception. Therefore, opinions about the predictive value of sperm morphological assessment for both natural conception and medically assisted conception are controversial.46–49\n\nAdditionally, in our study, 46 cases of asthenozoospermia (isolated or coexisting) and 58 cases of oligozoospermia (isolated or coexisting) were observed. Many authors confirm that progressive motility is one of the most important parameters influencing reproductive success both in terms of natural conception and medically assisted conception.38,50,51 Furthermore, Lotti et al.39 revealed a negative correlation between sperm vitality and TTP. Also, analyzing a large group of infertile men and men from the control group (candidates to be sperm donors), Li et al.43 showed that in the first group, there were significantly more men with azoospermia, asthenozoospermia and oligoasthenozoospermia, whereas surprisingly isolated oligoozospermia were detected more often in men from the control group. Some authors52 even suggest greater clinical implications of the total sperm count in relation to the sperm concentration.\n\nHowever, it should be emphasized that low standard seminological parameters are not always synonymous with infertility status. Not all authors53 recognize the arbitrary division of men into fertile and infertile groups based only on the basic semen characteristics according to the WHO.32 Therefore, except for azoospermia, necrozoospermia, and globo- and macrozoospermia, it is difficult to determine male fertility potential considering only standard seminological parameters. This thesis is also confirmed by our previous studies, in which 19 cases of reduced basic semen parameters were found in a group of men with proven fertility (n = 64).33 Therefore, in this research, the standard seminological assessment was not only one criterion for qualifying a man as infertile. The patient's infertility was established by an interview indicating unsuccessful attempts for offspring during one year of regular intercourse without the use of contraception.\n\nThe results of our research suggest the coexistence of spermatogenesis disorders with a reduced testicle volume and a higher FSH level. It is known that the process of spermatogenesis, reflecting testicular function, depends on a hypothalamic–pituitary–gonadal axis function, in which gonadotropins LH and FSH play a key role in maintaining testosterone biosynthesis and the function of the seminiferous epithelium, respectively. In addition, it has been proven that the function of the male gonad is influenced by thyroid hormones and prolactin.10,54–57 Importantly, a significant decrease in testicular volume can be associated with both reduced hormonal activity (lower levels of androgens) and reproductive activity manifested by seminiferous tubule atrophy.58–60 Therefore, our study included an evaluation of not only standard seminological parameters but also testicular volume and reproductive hormone levels (FSH, LH, PRL, total T, TSH). It should be noted that the selection of the assessed hormones was based on data from the literature.11,61 Unfortunately, to date, there have been no strict guidelines regarding the hormonal test profile that should be determined in the routine diagnosis of male infertility. On the other hand, the European Academy of Andrology (EAA) in guidelines from 2018 postulates evaluation of total T, FSH and LH in every case of an infertile man with oligoasthenoteratozoospermia (OAT).61 These recommendations are in line with the guidelines of the European Society Urology (EAU) from 2021.11 However, it is believed that the remaining hormonal tests should be performed based on an individual assessment of the patient. The levels of commonly recognized markers of spermatogenesis and Sertoli cell function (FSH, inhibin B) have been most frequently studied in the available literature.62–65 In addition, the authors of the study also paid attention to the analysis of the levels of SHBG,66 prolactin,67 estradiol,66 TSH,68–70 cortisol,71,72 growth hormone (GH) and insulin-like growth factor 1 (IGF-1).73\n\nBased on testicular volume measurement in our study, two groups of infertile participants were distinguished: men with a volume of at least one testis below the norm (<12 mL) and men with a normal volume of both testes.74 Our results showed that infertile men with a reduced volume of at least one testis had a significantly higher FSH level and a lower sperm count, sperm morphology, motility and vitality. Moreover, it should be especially highlighted that we found a significantly increased fragmentation of sperm nuclear DNA in the first group. These results were confirmed by correlation analysis. The testicular volume was negatively correlated with the level of FSH and the SDF value and positively correlated with the number and motility of sperm. Surprisingly, we did not find an association between testicular volume and total T level.\n\nThe obtained findings were partially consistent with the data published by other authors. Numerous researchers have reported relationships between testicular volume, conventional semen parameters, gonadotropin and testosterone levels as well as the results of advanced sperm tests (chromatin status, mitochondrial potential, apoptosis).57,60,75–78 The coexistence of reduced standard semen parameters, decreased testosterone levels and testicular volume presented by Bahk et al.75 and Condorelli et al.57 suggest that the reduction of testicular volume may be associated not only with impaired spermatogenesis but also with decreased hormonal function of male gonads. Condorelli et al.57 recommend periodic assessment of testosterone levels for patients with hypotrophic gonads. On the other hand, the obtained results presented by other authors are not always unambiguous. For example, in contrast to our results, Condorelli et al.57 revealed a relationship between testicular volume and testosterone levels, but they did not find a correlation between testicular volume and gonadotropin levels.\n\nAs mentioned above, we discovered that a group of men with at least one testis volume <12 mL had significantly reduced integrity of the sperm genome. The data could suggest that spermatogenesis disorders coexist with decreased testicular volume and are manifested not only by reduced conventional sperm parameters but also by molecular disorders of sperm chromatin. The relationship between testicular volume and sperm DNA strand brakes was also confirmed by our other findings. The participants with a high level of SDF (>30%) had significantly smaller testes than men with a low level of SDF (≤15%). Moreover, we noted a negative correlation between testicular volume and sperm chromatin fragmentation. Similar results were obtained by other authors who observed a negative correlation between the fragmentation of nuclear sperm DNA (verification using the TUNEL method), its denaturation (verification using acridine orange), sperm chromatin density (verified using propidium iodide) and the volume of testes.57,76,78\n\nIn the next step of our research, we compared two groups of subjects: men with abnormal levels of at least one of the assessed hormones and men with normal hormonal profiles. The obtained findings provided nonobvious data. We noted that in the first group, sperm count, morphology and motility were reduced, but testicular volume did not differ significantly between the two groups. Moreover, the LH level was negatively correlated with the total sperm count. Additionally, other authors have confirmed the statistical relationship between the level of selected hormones and standard seminological parameters.63,79,80 Wei et al.80 showed that in patients with OAT, total T was positively correlated with sperm morphology, whereas PRL was correlated with sperm concentration and motility. Moreover, Lu et al.79 and Uhler et al.63 revealed a negative correlation between FSH level and semen volume, sperm concentration, morphology and motility as well as between LH level and sperm concentration in infertile men or healthy volunteers.\n\nIt should be pointed out that we did not find significant differences in the percentage of sperm cells with fragmented DNA between participants with abnormal levels of at least evaluated hormones and those with normal hormonal profiles. This comparative analysis was consistent with Spearman's rank correlation test, which did not show a significant correlation between the SDF value and the level of the assessed hormones. However, other authors’ data indicated statistical relationships between sperm chromatin quality and the hormonal profile79,81,82 The coexistence of sperm DNA fragmentation with abnormally high or low levels of gonadotropins was shown in research published by Wdowiak et al.82 These results were partially consistent with the studies of Lu et al.83 and Smit et al.,81 who showed a negative correlation between sperm DNA fragmentation and elevated levels of FSH and LH. In turn, the association between sperm nuclear DNA damage and testosterone level is not always unequivocal. Some researchers Wdowiak et al.82 have found a negative correlation between these parameters, whereas others did not confirm these findings.81,83\n\nThe open question is why there was no statistically significant difference in our research in the percentage of SDF between the groups of men differing in the level of at least one of the assessed hormones. There is no doubt that the obtained results could have been influenced by the limited number of infertile men (n = 130) enrolled in our study and the hormonal heterogeneity of the group of men with abnormal levels of at least one of the verified hormones. Disturbances in the level of hormones can be both a factor influencing infertility and a consequence of such a state. In other words, an abnormal hormonal profile can be responsible for reduced semen quality or may be only a secondary effect of pathological processes in testes. In addition, it should be emphasized that there are many potential factors (e.g., obesity, occupational exposure, comorbidities, age, pharmacotherapy, stress) that may affect the interrelationship between spermatogenesis and hormone levels.84–90\n\nIt can be assumed that in our investigated group of infertile patients, one of the major factors that limited the ability of male gametes to fertilize was probably an increased level of sperm nuclear DNA fragmentation. It was found that the group of men with SDF >30% had a significantly reduced sperm count, morphology, motility and vitality in comparison to infertile men with a normal SDF rate of ≤15%. Similarly, Erenpreiss et al.91 showed that if males had diagnosed astheno- and teratozoospermia, the odds ratio (OR) for >20% DFI or for >30% DFI was 1.9–4.0-fold higher or 2.8–6.2-fold higher, respectively, than in subjects with normal sperm motility and morphology. Additionally, Vinnakota et al.29 observed a decrease in sperm motility in participants with SDF >30%. Moreover, we showed that the level of SDF was negatively correlated (Spearman’s rank correlation test) with sperm count, morphology, motility and vitality, and our findings have been confirmed by the research of other authors.30,83,92,93 However, some researchers have not always found a correlation between SDF and basic sperm parameters.94–96\n\nImportantly, it should be highlighted that in our study, the median SDF was 20%. In fact, according to the manufacturer of the Halosperm G2® kit, these results are in the normal range (SDF below 30%). It seems that the threshold of 30% SDF is too high (risk of a false-negative result). In our previous publications, we demonstrated that the median SDF in the group of men with confirmed fertility and/or with high reproductive potential (healthy volunteers with normozoospermia) ranged from 12% to 14%.33–36 In addition, these studies also showed a significantly satisfactory predictive value of the sperm chromatin dispersion (SCD) test to discriminate males with normal reproductive potential from those with reduced reproductive potential (based on receiver operating characteristic [ROC] analysis). The cut-off value was 18% and 20% SDF.34–36 Moreover, we obtained a threshold of 18% SDF to distinguish infertile men from fertile men (unpublished data).\n\nThese observations were in agreement with other authors who also clearly showed that the level of sperm nuclear DNA fragmentation was correlated with male infertility and that the acceptable threshold for sperm genome fragmentation was not below 30% but rather below 20%.4,16,21,27–29,91,97–102 For example, Bungum et al.97 showed that in the case of subjects with sperm nuclear DNA fragmentation in the range of 0–20%, the chance of spontaneous pregnancy is constant, but an increase in sperm DNA fragmentation >20% is associated with a reduced ability to achieve pregnancy. Moreover, Majzoub et al.101 estimated that the mean value of SDF for fertile subjects was 15.68%, whereas in the infertile group, it was 27.60%. In turn, comparing the groups of fertile and infertile men, Wiweko and Utami102 found not only significant differences in the SDF value between the study groups (medians: 19.90% vs. 29.95%, respectively) but also reported that SDF at the cutoff point of 26.1% had a higher diagnostic value. Similar results were presented by Javed et al.100 (the SDF at the cutoff point was 24.47%). Moreover, Evenson16 emphasized that the percentage of sperm with damaged chromatin >15–25 could increase the risk of male infertility and that >20–35% spermatozoa with damaged DNA could significantly reduce the chances of becoming pregnant using in vitro fertilization. Therefore, based on own research and analysis of the results of other researchers, Evenson16 concluded that when the percentage of sperm with abnormal chromatin status was >20, male fertility was decreased, and in vitro fertilization as first-line therapy should be considered. These conclusions were also confirmed by Giwercman et al.,103 who performed a comparison of ORs for the occurrence of infertility depending on the percentage of DFI. The authors showed that in the group of men with DFI 10–20%, the risk of reproductive failure was higher (OR = 2.5) than that in men with DFI <10%. In addition, Giwercman et al.103 observed a significant increase in the risk of infertility (OR = 8.4) in men with DFI> 20% compared to men with DFI <10%. Finally, in two most recent publications both Esteves et al.4 and Agarwal et al.21 reported that cut-off point of 20% sperm cells with fragmented DNA (verified both by SCSA, TUNEL and SCD assay) is the best criterion to discriminate fertile men from infertile.\n\nAdditionally, the influence of DFI on the fertilization process has been confirmed. Simon et al.51 revealed a higher risk (OR = 9.5) of a low percentage of fertilized oocytes (<40% fertilized oocytes) when men had DFI >40% compared to men with DFI ≤40%. Therefore, we can assume that sperm chromatin abnormalities may be accompanied by lowered standard sperm parameters synergistically affecting male fertility.\n\n\nConclusions\n\nOur comprehensive assessment of male infertility factors allowed us to conclude that in the study clinical cases, spermatogenesis disorders coexisted with decreased testicular volume and increased FSH levels. Moreover, they were manifested not only by reduced basic sperm characteristics but also, very importantly, by a high level of sperm nuclear DNA damage, which has great clinical utility both in terms of natural conception and in terms of ART (Figure 1). Furthermore, our current and previous findings suggest that the cut-off value of 30% SDF given by manufacturer of the Halosperm G2® kit seems too high and should be revised/downgraded to 20%, for better prognosis of male fertility. What’s more, clarification of the relationship between standard semen parameters, testicular volume, levels of reproductive hormones, SDF and clinical features might help to develop new personalized strategies for therapeutic interventions. In the case of infertile men, a complete andrological examination including in-depth medical interview, physical examination, standard semen analysis, scrotal ultrasound, assessment of reproductive hormones and integrity of sperm genome is justified. This medical approach is necessary not only due for verification of the causes of infertility but also due to the need to detect serious health disorders that may be life-threatening. For example, it has been proven that infertile men have an increased risk of testicular cancer, which determines the recommendation of periodic ultrasound examinations of the scrotum and gonadal self-examination.11,104 Therefore, the introduction of a complex diagnosis of male infertility factors is justified and needed.\n\nSome limitations of our study should be addressed. One of the most important factors influencing our results is the limited number of participants. In total, 130 men from couples with confirmed infertility were included to this project. It is known that the most reliable data are obtained from well-designed studies on large cohorts of patients. Due to the limited number of participants in our research, the presented results should be approached critically, and it should be borne in mind that studies conducted on a larger group could provide different results and conclusions. Moreover, the number of compared men in particular groups was not equal, which may affect the obtained statistical differences between groups. In the assessed hormonal profile, we did not include the determinations of some markers which could also be important for assessing the status of male fertility (i.a. inhibin B, SHBG, GH, estradiol, cortisol). Finally, sperm chromatin dispersion (SCD) test was performed to assess SDF. This test is a standardized diagnostic method but often not considered the gold standard for sperm DNA assessment because it does not directly evaluate breaks of DNA.\n\n\nData availability\n\nZenodo: Evaluation of selected semen parameters and biomarkers of male infertility – preliminary study. https://doi.org/10.5281/zenodo.6536196.109\n\nThis project contains the following underlying data:\n\n- Kups et al. for database.xlsx (raw data)\n\nZenodo: Evaluation of selected semen parameters and biomarkers of male infertility – preliminary study. https://doi.org/10.5281/zenodo.6538474.110\n\nThis project contains the following underlying data:\n\n- Raw microphotographs\n\nZenodo: Evaluation of selected semen parameters and biomarkers of male infertility – preliminary study. https://doi.org/10.5281/zenodo.6542238.111\n\nThis project contains the following extended data:\n\n- Urological and andrological medical interview Michal Kups.pdf (Patient card used during the medical interview)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nMinhas S, Bettocchi C, Boeri L, et al.: European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 Update on Male Infertility. Eur. Urol. 2021; 80: 603–620. PubMed Abstract | Publisher Full Text\n\nQuaas A, Dokras A: Diagnosis and Treatment of Unexplained Infertility. Rev. Obstet. Gynecol. 2008; 1: 69–76. PubMed Abstract\n\nAgarwal A, Parekh N, Panner Selvam MK, et al.: Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility. World J. Mens Health. 2019; 37: 296–312. PubMed Abstract | Publisher Full Text\n\nEsteves SC, Zini A, Coward RM, et al.: Sperm DNA Fragmentation Testing: Summary Evidence and Clinical Practice Recommendations. Andrologia. 2021; 53: e13874. PubMed Abstract | Publisher Full Text\n\nAgarwal A, Baskaran S, Parekh N, et al.: Male Infertility. Lancet. 2021; 397: 319–333. Publisher Full Text\n\nArafa M, Henkel R, Agarwal A, et al.: Correlation of Oxidation-Reduction Potential with Hormones, Semen Parameters and Testicular Volume. Andrologia. 2019; 51: e13258. PubMed Abstract | Publisher Full Text\n\nBarbăroșie C, Agarwal A, Henkel R: Diagnostic Value of Advanced Semen Analysis in Evaluation of Male Infertility. Andrologia. 2021; 53: e13625. PubMed Abstract | Publisher Full Text\n\nCasarini L, Crépieux P, Reiter E, et al.: FSH for the Treatment of Male Infertility. Int. J. Mol. Sci. 2020; 21: E2270. PubMed Abstract | Publisher Full Text\n\nKrausz C, Riera-Escamilla A: Genetics of Male Infertility. Nat. Rev. Urol. 2018; 15: 369–384. Publisher Full Text\n\nLateef OM, Akintubosun MO: Sleep and Reproductive Health. J. Circadian Rhythms. 2020; 18: 1. Publisher Full Text\n\nSalonia A, Bettocchi C, Carvalho J, et al.: Sexual and Reproductive Health. Uroweb. 2021.\n\nThurston L, Abbara A, Dhillo WS: Investigation and Management of Subfertility. J. Clin. Pathol. 2019; 72: 579–587. Publisher Full Text\n\nFaduola P, Kolade CO: Sperm Chromatin Structure Assay Results in Nigerian Men with Unexplained Infertility. Clin. Exp. Reprod. Med. 2015; 42: 101–105. PubMed Abstract | Publisher Full Text\n\nMayorga-Torres BJM, Camargo M, Cadavid ÁP, et al.: Are Oxidative Stress Markers Associated with Unexplained Male Infertility?. Andrologia. 2017; 49: e12659. PubMed Abstract | Publisher Full Text\n\nDutta S, Henkel R, Agarwal A: Comparative Analysis of Tests Used to Assess Sperm Chromatin Integrity and DNA Fragmentation. Andrologia. 2021; 53: e13718. PubMed Abstract | Publisher Full Text\n\nEvenson DP: Evaluation of Sperm Chromatin Structure and DNA Strand Breaks Is an Important Part of Clinical Male Fertility Assessment. Transl. Androl. Urol. 2017; 6: S495–S500. PubMed Abstract | Publisher Full Text\n\nRashki Ghaleno L, Alizadeh A, Drevet JR, et al.: Oxidation of Sperm DNA and Male Infertility. Antioxidants (Basel). 2021; 10: 97. Publisher Full Text\n\nMartinez M, Majzoub A: Best Laboratory Practices and Therapeutic Interventions to Reduce Sperm DNA Damage. Andrologia. 2021; 53: e13736. PubMed Abstract | Publisher Full Text\n\nNguyen TT, Trieu TS, Tran TO, et al.: Evaluation of Sperm DNA Fragmentation Index, Zinc Concentration and Seminal Parameters from Infertile Men with Varicocele. Andrologia. 2019; 51: e13184. Publisher Full Text\n\nRibas-Maynou J, Yeste M, Becerra-Tomás N, et al.: Clinical Implications of Sperm DNA Damage in IVF and ICSI: Updated Systematic Review and Meta-Analysis. Biol. Rev. Camb. Philos. Soc. 2021; 96: 1284–1300. PubMed Abstract | Publisher Full Text\n\nAgarwal A, Farkouh A, Parekh N, et al.: Sperm DNA Fragmentation: A Critical Assessment of Clinical Practice Guidelines. World J. Mens Health. 2022; 40: 30–37. PubMed Abstract | Publisher Full Text\n\nAbdelbaki SA, Sabry JH, Al-Adl AM, et al.: The Impact of Coexisting Sperm DNA Fragmentation and Seminal Oxidative Stress on the Outcome of Varicocelectomy in Infertile Patients: A Prospective Controlled Study. Arab. J. Urol. 2017; 15: 131–139. PubMed Abstract | Publisher Full Text\n\nAl Omrani B, Al Eisa N, Javed M, et al.: Associations of Sperm DNA Fragmentation with Lifestyle Factors and Semen Parameters of Saudi Men and Its Impact on ICSI Outcome. Reprod. Biol. Endocrinol. 2018; 16: 49. PubMed Abstract | Publisher Full Text\n\nCissen M, van Wely M , Scholten I, et al.: Measuring Sperm DNA Fragmentation and Clinical Outcomes of Medically Assisted Reproduction: A Systematic Review and Meta-Analysis. PLoS One. 2016; 11: e0165125. PubMed Abstract | Publisher Full Text\n\nCheng H, Han M, Ding J, et al.: Importance of a Semen Analysis Report for Determining the Relationship between SCSA Sperm DNA Fragmentation Index and Assisted Reproductive Technology Pregnancy Rate. Reprod. Biol. 2020; 20: 460–464. Publisher Full Text\n\nLeach M, Aitken RJ, Sacks G: Sperm DNA Fragmentation Abnormalities in Men from Couples with a History of Recurrent Miscarriage. Aust. N. Z. J. Obstet. Gynaecol. 2015; 55: 379–383. Publisher Full Text\n\nOleszczuk K, Giwercman A, Bungum M: Sperm Chromatin Structure Assay in Prediction of in vitro Fertilization Outcome. Andrology. 2016; 4: 290–296. Publisher Full Text\n\nSimon L, Emery BR, Carrell DT: Review: Diagnosis and Impact of Sperm DNA Alterations in Assisted Reproduction. Best Pract. Res. Clin. Obstet. Gynaecol. 2017; 44: 38–56. PubMed Abstract | Publisher Full Text\n\nVinnakota C, Cree L, Peek J, et al.: Incidence of High Sperm DNA Fragmentation in a Targeted Population of Subfertile Men. Syst. Biol. Reprod. Med. 2019; 65: 451–457. PubMed Abstract | Publisher Full Text\n\nYang H, Li G, Jin H, et al.: The Effect of Sperm DNA Fragmentation Index on Assisted Reproductive Technology Outcomes and Its Relationship with Semen Parameters and Lifestyle. Transl. Androl. Urol. 2019; 8: 356–365. PubMed Abstract | Publisher Full Text\n\nKhalafalla K, Majzoub A, Elbardisi H, et al.: The Effect of Sperm DNA Fragmentation on Intracytoplasmic Sperm Injection Outcome. Andrologia. 2021; 53: e14180. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: WHO Laboratory Manual for the Examination and Processing of Human Semen. 5th ed.Geneva, Switzerland:World Health Organization Press;2010.\n\nGill K, Kups M, Harasny P, et al.: The Negative Impact of Varicocele on Basic Semen Parameters, Sperm Nuclear DNA Dispersion and Oxidation-Reduction Potential in Semen. Int. J. Environ. Res. Public Health. 2021; 18: 5977. PubMed Abstract | Publisher Full Text\n\nGill K, Rosiak-Gill A, Jakubik J, et al.: The Higher Risk for Sperm DNA Damage in Infertile Men. Ginekol. Pol. 2019; 90: 684–691. PubMed Abstract | Publisher Full Text\n\nGill K, Jakubik J, Rosiak-Gill A, et al.: Utility and Predictive Value of Human Standard Semen Parameters and Sperm DNA Dispersion for Fertility Potential. Int. J. Environ. Res. Public Health. 2019; 16: E2004. PubMed Abstract | Publisher Full Text\n\nJakubik-Uljasz J, Gill K, Rosiak-Gill A, et al.: Relationship between Sperm Morphology and Sperm DNA Dispersion. Transl. Androl. Urol. 2020; 9: 405–415. PubMed Abstract | Publisher Full Text\n\nPedersen MR, Rafaelsen SR, Møller H, et al.: Testicular Microlithiasis and Testicular Cancer: Review of the Literature. Int. Urol. Nephrol. 2016; 48: 1079–1086. PubMed Abstract | Publisher Full Text\n\nElbashir S, Magdi Y, Rashed A, et al.: Relationship between Sperm Progressive Motility and DNA Integrity in Fertile and Infertile Men.2018. Publisher Full Text\n\nLotti F, Frizza F, Balercia G, et al.: The European Academy of Andrology (EAA) Ultrasound Study on Healthy, Fertile Men: Clinical, Seminal and Biochemical Characteristics. Andrology. 2020; 8: 1005–1020. PubMed Abstract | Publisher Full Text\n\nSlama R, Eustache F, Ducot B, et al.: Time to Pregnancy and Semen Parameters: A Cross-Sectional Study among Fertile Couples from Four European Cities. Hum. Reprod. 2002; 17: 503–515. PubMed Abstract | Publisher Full Text\n\nCao X, Cui Y, Zhang X, et al.: The Correlation of Sperm Morphology with Unexplained Recurrent Spontaneous Abortion: A Systematic Review and Meta-Analysis. Oncotarget. 2017; 8: 55646–55656. PubMed Abstract | Publisher Full Text\n\nJayasena CN, Radia UK, Figueiredo M, et al.: Reduced Testicular Steroidogenesis and Increased Semen Oxidative Stress in Male Partners as Novel Markers of Recurrent Miscarriage. Clin. Chem. 2019; 65: 161–169. PubMed Abstract | Publisher Full Text\n\nLi B, Ma Y, Huang J, et al.: Probing the Effect of Human Normal Sperm Morphology Rate on Cycle Outcomes and Assisted Reproductive Methods Selection. PLoS One. 2014; 9: e113392. PubMed Abstract | Publisher Full Text\n\nMcQueen DB, Zhang J, Robins JC: Sperm DNA Fragmentation and Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis. Fertil. Steril. 2019; 112: 54–60.e3. Publisher Full Text\n\nGatimel N, Moreau J, Parinaud J, et al.: Sperm Morphology: Assessment, Pathophysiology, Clinical Relevance, and State of the Art in 2017. Andrology. 2017; 5: 845–862. PubMed Abstract | Publisher Full Text\n\nShabtaie SA, Gerkowicz SA, Kohn TP, et al.: Role of Abnormal Sperm Morphology in Predicting Pregnancy Outcomes. Curr. Urol. Rep. 2016; 17: 67. PubMed Abstract | Publisher Full Text\n\nDanis RB, Samplaski MK: Sperm Morphology: History, Challenges, and Impact on Natural and Assisted Fertility. Curr. Urol. Rep. 2019; 20: 43. Publisher Full Text\n\nKohn TP, Kohn JR, Lamb DJ: Role of Sperm Morphology in Deciding Between Various Assisted Reproduction Technologies. Eur. Urol. Focus. 2018; 4: 311–313. PubMed Abstract | Publisher Full Text\n\nKovac JR, Smith RP, Cajipe M, et al.: Men with a Complete Absence of Normal Sperm Morphology Exhibit High Rates of Success without Assisted Reproduction. Asian J. Androl. 2017; 19: 39–42. PubMed Abstract | Publisher Full Text\n\nBjörndahl L: The Usefulness and Significance of Assessing Rapidly Progressive Spermatozoa. Asian J. Androl. 2010; 12: 33–35. Publisher Full Text\n\nSimon L, Lewis SEM: Sperm DNA Damage or Progressive Motility: Which One Is the Better Predictor of Fertilization in Vitro?. Syst. Biol. Reprod. Med. 2011; 57: 133–138. Publisher Full Text\n\nKuriya A, Agbo C, Dahan MH: Do Pregnancy Rates Differ with Intra-Uterine Insemination When Different Combinations of Semen Analysis Parameters Are Abnormal?. J. Turk. Ger. Gynecol. Assoc. 2018; 19: 57–64. PubMed Abstract | Publisher Full Text\n\nPatel AS, Leong JY, Ramasamy R: Prediction of Male Infertility by the World Health Organization Laboratory Manual for Assessment of Semen Analysis: A Systematic Review. Arab. J. Urol. 2018; 16: 96–102. PubMed Abstract | Publisher Full Text\n\nZivlak-Radulovic N, Banjac V, Miskovic M: Hyperprolactinemia as a Side Effect of Long-Acting Injectable Risperidone Therapy or a Symptom of Klinefelter Syndrome - a Diagnostic and Therapeutic Dilemma. Psychiatr. Danub. 2018; 30: 99–103. PubMed Abstract | Publisher Full Text\n\nDabbous Z, Atkin SL: Hyperprolactinaemia in Male Infertility: Clinical Case Scenarios. Arab. J. Urol. 2018; 16: 44–52. PubMed Abstract | Publisher Full Text\n\nLa Vignera S, Vita R: Thyroid Dysfunction and Semen Quality. Int. J. Immunopathol. Pharmacol. 2018; 32: 2058738418775241. PubMed Abstract | Publisher Full Text\n\nCondorelli R, Calogero AE, La Vignera S: Relationship between Testicular Volume and Conventional or Nonconventional Sperm Parameters. Int. J. Endocrinol. 2013; 2013: 145792–145796. PubMed Abstract | Publisher Full Text\n\nHuang I-S, Huang WJ, Lin AT: Distinguishing Non-Obstructive Azoospermia from Obstructive Azoospermia in Taiwanese Patients by Hormone Profile and Testis Size. J. Chin. Med. Assoc. 2018; 81: 531–535. PubMed Abstract | Publisher Full Text\n\nNieschlag E, Vorona E: MECHANISMS IN ENDOCRINOLOGY: Medical Consequences of Doping with Anabolic Androgenic Steroids: Effects on Reproductive Functions. Eur. J. Endocrinol. 2015; 173: R47–R58. PubMed Abstract | Publisher Full Text\n\nSakamoto H, Yajima T, Nagata M, et al.: Relationship between Testicular Size by Ultrasonography and Testicular Function: Measurement of Testicular Length, Width, and Depth in Patients with Infertility. Int. J. Urol. 2008; 15: 529–533. PubMed Abstract | Publisher Full Text\n\nColpi GM, Francavilla S, Haidl G, et al.: European Academy of Andrology Guideline Management of Oligo-Astheno-Teratozoospermia. Andrology. 2018; 6: 513–524. PubMed Abstract | Publisher Full Text\n\nCorinne TM, Anatole PC, Jeanne NY: Comparison of Serum Inhibin B and Follicle-Stimulating Hormone (FSH) Level between Normal and Infertile Men in Yaoundé. Int. J. Reprod. Med. 2020; 2020: 4765809–4765809. PubMed Abstract | Publisher Full Text\n\nUhler ML, Zinaman MJ, Brown CC, et al.: Relationship between Sperm Characteristics and Hormonal Parameters in Normal Couples. Fertil. Steril. 2003; 79 Suppl 3: 1535–1542. PubMed Abstract | Publisher Full Text\n\nMabeck LM, Jensen MS, Toft G, et al.: Fecundability According to Male Serum Inhibin B--a Prospective Study among First Pregnancy Planners. Hum. Reprod. 2005; 20: 2909–2915. PubMed Abstract | Publisher Full Text\n\nMeeker JD, Godfrey-Bailey L, Hauser R: Relationships between Serum Hormone Levels and Semen Quality among Men from an Infertility Clinic. J. Androl. 2007; 28: 397–406. Publisher Full Text\n\nRing JD, Lwin AA, Köhler TS: Current Medical Management of Endocrine-Related Male Infertility. Asian J. Androl. 2016; 18: 357–363. PubMed Abstract | Publisher Full Text\n\nVilar L, Abucham J, Albuquerque JL, et al.: Controversial Issues in the Management of Hyperprolactinemia and Prolactinomas - An Overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism. Arch. Endocrinol. Metab. 2018; 62: 236–263. Publisher Full Text\n\nKrajewska-Kulak E, Sengupta P: Thyroid Function in Male Infertility. Front. Endocrinol. 2013; 4. PubMed Abstract | Publisher Full Text\n\nKrassas GE, Papadopoulou F, Tziomalos K, et al.: Hypothyroidism Has an Adverse Effect on Human Spermatogenesis: A Prospective, Controlled Study. Thyroid. 2008; 18: 1255–1259. PubMed Abstract | Publisher Full Text\n\nSingh R, Hamada J, Agarwal A: Thyroid Hormones in Male Reproduction and Fertility. Open Reprod. Sci. J. 2011; 3: 98–104. Publisher Full Text\n\nFozooni R, Jafarzadeh Shirazi MR, Saedi S, et al.: Male Subfertility Effects of Sub-Chronic Ethanol Exposure during Stress in a Rat Model. Alcohol. 2021; 96: 63–71. PubMed Abstract | Publisher Full Text\n\nPerumal P, Chang S, De AK, et al.: Slow Release Exogenous Melatonin Modulates Scrotal Circumference and Testicular Parameters, Libido, Endocrinological Profiles and Antioxidant and Oxidative Stress Profiles in Mithun. Theriogenology. 2020; 154: 1–10. Publisher Full Text\n\nSimopoulou M, Philippou A, Maziotis E, et al.: Association between Male Infertility and Seminal Plasma Levels of Growth Hormone and Insulin-like Growth Factor-1. Andrologia. 2018; 50: e13048. PubMed Abstract | Publisher Full Text\n\nPedersen MR, Osther PJS, Rafaelsen SR: Ultrasound Evaluation of Testicular Volume in Patients with Testicular Microlithiasis. Ultrasound Int. Open. 2018; 04: E99–E103. Publisher Full Text\n\nBahk JY, Jung JH, Jin LM, et al.: Cut-off Value of Testes Volume in Young Adults and Correlation among Testes Volume, Body Mass Index, Hormonal Level, and Seminal Profiles. Urology. 2010; 75: 1318–1323. PubMed Abstract | Publisher Full Text\n\nLotti F, Tamburrino L, Marchiani S, et al.: DNA Fragmentation in Two Cytometric Sperm Populations: Relationship with Clinical and Ultrasound Characteristics of the Male Genital Tract. Asian J. Androl. 2017; 19: 272–279. PubMed Abstract | Publisher Full Text\n\nSchurich M, Aigner F, Frauscher F, et al.: The Role of Ultrasound in Assessment of Male Fertility. Eur. J. Obstet. Gynecol. Reprod. Biol. 2009; 144(Suppl 1): S192–S198. Publisher Full Text\n\nZorn B, Golob B, Ihan A, et al.: Apoptotic Sperm Biomarkers and Their Correlation with Conventional Sperm Parameters and Male Fertility Potential. J. Assist. Reprod. Genet. 2012; 29: 357–364. PubMed Abstract | Publisher Full Text\n\nLu J-C, Jing J, Dai J-Y, et al.: Body Mass Index, Waist-to-Hip Ratio, Waist Circumference and Waist-to-Height Ratio Cannot Predict Male Semen Quality: A Report of 1231 Subfertile Chinese Men. Andrologia. 2015; 47: 1047–1054. Publisher Full Text\n\nWei T-C, Huang WJ, Lin ATL, et al.: The Role of Hormones on Semen Parameters in Patients with Idiopathic or Varicocele-Related Oligoasthenoteratozoospermia (OAT) Syndrome. J. Chin. Med. Assoc. 2013; 76: 624–628. PubMed Abstract | Publisher Full Text\n\nSmit M, Romijn JC, Wildhagen MF, et al.: Sperm Chromatin Structure Is Associated with the Quality of Spermatogenesis in Infertile Patients. Fertil. Steril. 2010; 94: 1748–1752. PubMed Abstract | Publisher Full Text\n\nWdowiak A, Raczkiewicz D, Stasiak M, et al.: Levels of FSH, LH and Testosterone, and Sperm DNA Fragmentation. Neuro Endocrinol. Lett. 2014; 35: 73–79. PubMed Abstract\n\nLu J-C, Jing J, Chen L, et al.: Analysis of Human Sperm DNA Fragmentation Index (DFI) Related Factors: A Report of 1010 Subfertile Men in China. Reprod. Biol. Endocrinol. 2018; 16: 23. PubMed Abstract | Publisher Full Text\n\nAmjad S, Baig M, Zahid N, et al.: Association between Leptin, Obesity, Hormonal Interplay and Male Infertility. Andrologia. 2019; 51: e13147. Publisher Full Text\n\nBundhun PK, Janoo G, Bhurtu A, et al.: Tobacco Smoking and Semen Quality in Infertile Males: A Systematic Review and Meta-Analysis. BMC Public Health. 2019; 19: 36. PubMed Abstract | Publisher Full Text\n\nIlacqua A, Izzo G, Emerenziani GP, et al.: Lifestyle and Fertility: The Influence of Stress and Quality of Life on Male Fertility. Reprod. Biol. Endocrinol. 2018; 16: 115. PubMed Abstract | Publisher Full Text\n\nKesari KK, Agarwal A, Henkel R: Radiations and Male Fertility. Reprod. Biol. Endocrinol. 2018; 16: 118. PubMed Abstract | Publisher Full Text\n\nMiranda-Contreras L, Gómez-Pérez R, Rojas G, et al.: Occupational Exposure to Organophosphate and Carbamate Pesticides Affects Sperm Chromatin Integrity and Reproductive Hormone Levels among Venezuelan Farm Workers. J. Occup. Health. 2013; 55: 195–203. PubMed Abstract | Publisher Full Text\n\nPalmer NO, Bakos HW, Fullston T, et al.: Impact of Obesity on Male Fertility, Sperm Function and Molecular Composition. Spermatogenesis. 2012; 2: 253–263. PubMed Abstract | Publisher Full Text\n\nSemet M, Paci M, Saïas-Magnan J, et al.: The Impact of Drugs on Male Fertility: A Review. Andrology. 2017; 5: 640–663. Publisher Full Text\n\nErenpreiss J, Elzanaty S, Giwercman A: Sperm DNA Damage in Men from Infertile Couples. Asian J. Androl. 2008; 10: 786–790. Publisher Full Text\n\nBelloc S, Benkhalifa M, Cohen-Bacrie M, et al.: Sperm Deoxyribonucleic Acid Damage in Normozoospermic Men Is Related to Age and Sperm Progressive Motility. Fertil. Steril. 2014; 101: 1588–1593. PubMed Abstract | Publisher Full Text\n\nGiwercman A, Richthoff J, Hjøllund H, et al.: Correlation between Sperm Motility and Sperm Chromatin Structure Assay Parameters. Fertil. Steril. 2003; 80: 1404–1412. Publisher Full Text\n\nBoushaba S, Belaaloui G: Sperm DNA Fragmentation and Standard Semen Parameters in Algerian Infertile Male Partners. World J. Mens Health. 2015; 33: 1–7. PubMed Abstract | Publisher Full Text\n\nBounartzi T, Dafopoulos K, Anifandis G, et al.: Pregnancy Prediction by Free Sperm DNA and Sperm DNA Fragmentation in Semen Specimens of IVF/ICSI-ET Patients. Hum. Fertil. (Camb.). 2016; 19: 56–62. PubMed Abstract | Publisher Full Text\n\nCohen-Bacrie P, Belloc S, Ménézo YJR, et al.: Correlation between DNA Damage and Sperm Parameters: A Prospective Study of 1,633 Patients. Fertil. Steril. 2009; 91: 1801–1805. PubMed Abstract | Publisher Full Text\n\nBungum M, Bungum L, Giwercman A: Sperm Chromatin Structure Assay (SCSA): A Tool in Diagnosis and Treatment of Infertility. Asian J. Androl. 2011; 13: 69–75. PubMed Abstract | Publisher Full Text\n\nBungum M: Sperm DNA Integrity Assessment: A New Tool in Diagnosis and Treatment of Fertility. Obstet. Gynecol. Int. 2012; 2012: 531042. Publisher Full Text\n\nEvenson DP: The Sperm Chromatin Structure Assay (SCSA(®)) and Other Sperm DNA Fragmentation Tests for Evaluation of Sperm Nuclear DNA Integrity as Related to Fertility. Anim. Reprod. Sci. 2016; 169: 56–75. PubMed Abstract | Publisher Full Text\n\nJaved A, Talkad MS, Ramaiah MK: Evaluation of Sperm DNA Fragmentation Using Multiple Methods: A Comparison of Their Predictive Power for Male Infertility. Clin. Exp. Reprod. Med. 2019; 46: 14–21. PubMed Abstract | Publisher Full Text\n\nMajzoub A, Arafa M, Mahdi M, et al.: Oxidation-Reduction Potential and Sperm DNA Fragmentation, and Their Associations with Sperm Morphological Anomalies amongst Fertile and Infertile Men. Arab. J. Urol. 2018; 16: 87–95. PubMed Abstract | Publisher Full Text\n\nWiweko B, Utami P: Predictive Value of Sperm Deoxyribonucleic Acid (DNA) Fragmentation Index in Male Infertility. Basic Clin. Androl. 2017; 27: 1. PubMed Abstract | Publisher Full Text\n\nGiwercman A, Lindstedt L, Larsson M, et al.: Sperm Chromatin Structure Assay as an Independent Predictor of Fertility in Vivo: A Case-Control Study. Int. J. Androl. 2010; 33: e221–e227. PubMed Abstract | Publisher Full Text\n\nBaird DC, Meyers GJ, Hu JS: Testicular Cancer: Diagnosis and Treatment. Am. Fam. Physician. 2018; 97: 261–268. PubMed Abstract\n\nWang F, Zhao S, Xie Y, et al.: Novo SOX10 Nonsense Mutation in a Patient with Kallmann Syndrome, Deafness, Iris Hypopigmentation, and Hyperthyroidism. Ann. Clin. Lab. Sci. 2018; 48: 248–252. PubMed Abstract\n\nSanti D, Crépieux P, Reiter E, et al.: Follicle-Stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles. J. Clin. Med. 2020; 9: E1014. PubMed Abstract | Publisher Full Text\n\nHolota H, Thirouard L, Monrose M, et al.: FXRα Modulates Leydig Cell Endocrine Function in Mouse. Mol. Cell. Endocrinol. 2020; 518: 110995. PubMed Abstract | Publisher Full Text\n\nSertkaya Z, Tokuç E, Özkaya F, et al.: Acute Effect of Microdissection Testicular Sperm Extraction on Blood Total Testosterone and Luteinising Hormone Levels. Andrologia. 2020; 52: e13655. PubMed Abstract | Publisher Full Text\n\nKups M, Gill K, Rosiak-Gill A, et al.: Evaluation of selected semen parameters and biomarkers of male infertility – preliminary study (Final) [Data set]. Zenodo. 2022; Publisher Full Text\n\nKups M, Gill K, Rosiak-Gill A, et al.: Evaluation of selected semen parameters and biomarkers of male infertility – preliminary study. [Data set]. Zenodo. 2022. Publisher Full Text\n\nKups M, Gill K, Rosiak-Gill A, et al.: Evaluation of selected semen parameters and biomarkers of male infertility – preliminary study. [Data set]. Zenodo. 2022. Publisher Full Text"
}
|
[
{
"id": "228728",
"date": "01 Feb 2024",
"name": "Abdul S Ansari",
"expertise": [
"Reviewer Expertise Reproductive physiology",
"Male contraception",
"infertility diagnosis",
"cancer diagnosis",
"endocrinology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the present manuscript the author(s) evaluated etiopathogenesis of male infertility by investigation of the relationship between standard semen parameters, testicular volume, levels of reproductive hormones and the fragmentation of sperm nuclear DNA (SDF). A total of 130 subjects, divided into three groups, with at least one abnormal testis volume, minimum low level among any reproductive hormones and with SDF. Results obtained from the study revealed that the subjects with decreased testicular volume and abnormal levels of hormones were observed with decreased basic semen parameters. Abnormal testicular volume also had, respectively, higher percentage of SDF and enhanced levels of FSH. Subjects with high SDF level had low testicular volume and seminal parameters. Authors concluded that spermatogenesis disorders coexisted with decreased testicular volume and increased FSH levels which manifested by reduced seminal characteristics and high sperm nuclear damage. However, the research article contains several lacunae in terms of writing the manuscript, language, presentation of data, etc. Moreover, the title of the article does not match the contents of the article. It correlated several parameters.\nSpecific comments: Abstract:\n\nPage 1: Methods: The participants of the study were not patients, instead they are subjects. Modify the sentence as “Participant subjects (n=130) were divided into”.\nIntroduction:\nPage 3, Introduction: Write full form of SCSA test followed by its abbreviation SCSA in parentheses. Page 3, Methods (Study population): The study population , i.e., 130 male infertile subjects is very small. If the number would have been more, it is easy to draw a conclusion. Page 3, Methods (Study population): Replace “All patients …” with All subjects …”. Page 3, Methods (Study population): How many subjects with azoospermia and cryptozoospermia were excluded? Mention their number. Page 3, Methods (Study population): Replace the phrase “seminal cords” with “spermatic cords”. Page 4, Methods (Conventional semen analysis): Room temperature is not -20 °C. Correct the sentence. Page 4, Methods (Conventional semen analysis): Add “liquefaction time” of semen as a macroscopic semen analysis parameter. Page 4, Methods (Conventional semen analysis): The terminology total sperm count has changed by WHO as “sperm density” (million/ejaculate). Replace the same with new terminology. Page 4, Methods (Conventional semen analysis): The sperm vitality or viability is carried out the mixing of a well mixed semen sample with eosin-nigrosin stain and and spreaded on a slide and dried. The unstained spermatozoa are regarded as alive/vital, while pink coloured sperms are considered dead. The HOS test is done with the mixing of a semen sample with a hypoosmotic solution and incubated. After incubation spermatozoa with coiled tails are counted, and calculated in percent (%), termed as HOS positive sperms. How vitality indicating both eosin-positive cells and hypoosmotic-reactive cells (HOS test-positive cells can be assessed? Page 4, Methods (Sperm Chromatin Dispersion (SCD) test): The chromatin dispersion test carried out in the study with Halosperm G2 kit is sort of In vitro Nuclear Chromatin Decondensation (NCD) Test of WHO routinely carried out for infertility diagnosis for fertilizing ability. In the test Sperm heads decondensed which results into swelling of heads, appears as, halos. Whereas, Non-fertilizable sperm heads remain condensed due to defective nuclear chromatin. Decondensed sperms heads are counted versus condensed sperm heads and represented as percent. I am surprised that why so expensive SCD test was carried out when other several simple tests are available. A detailed comment is required from author(s) on this point. Page 4, Methods (Hormone profile of infertile subjects): Add Inter-assay and Intra-asssay coefficient of variation of each hone assayed.\nResults:\nPage 6, Seminological Characteristics of study population: Replace the word “Seminological” with “Seminal”. Page 6, Comparison … (each ≥ 12 mL): Write P (significant) value of FSH.\nDiscussion:\nPage 14, Para 1, Line 5: This is not a thesis, instead a study or investigation. Change the phrase “This thesis” with an appropriate phrase. Page 14, Para 3, Line 2: Complete the word “norm” as “normal”. The write-up of discussion is too lengthy, reduced the same to half length. Conclusions: A brief conclusion of the study carried out similar with Abstract is required. Data availability: Replace the word “project” with “research article”. References: Reference Nos. 27, 51: Italicize the words “in Vitro”. Reference 59: The title of the reference in upper (capital) case. Change the same as per Instruction to Authors. References 109 to 111 are related to the present research article, thus should be delated from the list of References. Tables: Table 1: This table contains all assayed hormones in the study and well described in the text, therefore, should be deleted. Tables 2, 4, 6, 8, 10: In all these tables data on Sperm nonprogressive motility (%) have been depicted. When data on Sperm progressive motility (%) are presented, there is no use of depicting this. The rest of Sperm progressive motility (%) will obviously related to the Sperm nonprogressive motility (%). The present study contains a total 10 tables. Presentation of data in the present research article merely only in tables is not so impressive and very hard to understand by readers. Prepare histograms or bar diagrams for depiction of data. Table 10: The data of this table should be depicted with Scatter diagrams.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "238141",
"date": "20 Feb 2024",
"name": "Nafisa Balasinor",
"expertise": [
"Reviewer Expertise Reproductive endocrinology",
"male fertility and epigenetics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the present manuscript the authors have studied the association between standard semen parameters, testicular volume, reproductive hormones profile and the sperm nuclear DNA fragmentation. Overall the study is well done and has clinical utility. However, there are few points which needs to be addressed: 1. How was the sample size of 130 calculated? 2. Was infertility due to known female factor ruled out? 3. The authors should mention how they categorized abnormal hormonal levels. 4. Table 3: volume in the right testis of normal volume group ranged between 9 to 25ml. However, testicular volume of > or equal to12 was taken as normal testicular volume. Please check the data. 5. Table 5: Men with abnormal hormonal profile group had increase in all hormones except Testosterone. However, the values do not indicate so. Hence need to check if correct statistical tool was used. 6. The authors need to check testosterone levels in this infertile group as compared to fertile group or normal range. 7. SDF in men with normal semen and sperm parameters should be analyzed. If SDF is found in this group too than the importance to including SDF in male infertility work out will be evident. 8. It would be interesting to see the sperm parameters in individuals in which all 3 parameters, namely, Volume, hormone profile and SDF.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "238146",
"date": "20 Feb 2024",
"name": "Eva Tvrdá",
"expertise": [
"Reviewer Expertise Sperm quality",
"oxidative stress",
"antioxidants",
"molecular andrology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a nicely written and appropriately designed study evaluating and interconnecting standard semen parameters in infertile men. While I appreciate papers that turn \"back to the basics\" and re-evaluate/re-verify the importance of traditional parameters of sperm quality, I am missing the originality of the study. The authors should place more emphasis on the originality and scientific rigour of their experiments as well as provide a solid justification as to why such types of papers on generally well-accepted knowledge are necessary. Finally, the title of the article hints evaluation of biomarkers of male infertility. if so, what are the biomarkers and why should these be more of a center focus for the andrologists?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-591
|
https://f1000research.com/articles/11-590/v1
|
30 May 22
|
{
"type": "Study Protocol",
"title": "Meditation and yoga impact on dysmenorrhea (MY-ID): a study protocol",
"authors": [
"Shalini G. Nayak",
"Dr Linu Sara George",
"Anil Raj Assariparambil",
"Anice George",
"Dr Kiranmai S Rao",
"Dr Annapoorna K",
"Dr. Vinutha R Bhat",
"Dr Ravishankar N",
"Shalini G. Nayak",
"Dr Linu Sara George",
"Anil Raj Assariparambil",
"Dr Kiranmai S Rao",
"Dr Annapoorna K",
"Dr. Vinutha R Bhat",
"Dr Ravishankar N"
],
"abstract": "Primary dysmenorrhea is one of the most prevalent gynecologic condition affecting women, especially adolescent girls. Among adolescents, associated symptoms of dysmenorrhea impact the general health status, negatively influence the quality of life, resulting in school absenteeism and decreased academic performance. This study protocol was developed to estimate the prevalence of dysmenorrhea and evaluate the effectiveness of Meditation and Yoga intervention on dysmenorrhea among adolescent girls. In phase I, data will be collected from adolescent girls (N» 5000) aged between 13 and 18 years to estimate the prevalence of dysmenorrhea and in the second phase, Cluster-Randomized Controlled Trial will be conducted to evaluate the impact of Meditation and Yoga on dysmenorrhea. From the first phase, those adolescent girls (N=400) with high pain intensity (numerical pain rating scale ≥ 4) from each school, with schools as clusters, will be assigned to the interventional and control arm. The interventional arm will receive the proposed Meditation and Yoga intervention for 12 weeks under supervision and the control arm will continue with standard routine care. The outcomes such as pain intensity, stress, academic performance, self-efficacy and biomarker levels (Hb, Progesterone, Estrogen, Prostaglandins F2α and E2) will be assessed at baseline and 12 weeks after the intervention. Yoga's popularity and medical benefits have grown with the growing interest in alternative and complementary medicine. There is insufficient evidence to support yoga as a treatment for dysmenorrhea symptoms. This research contributes to the evidence on the impact of meditation and yoga on primary dysmenorrhea among adolescent girls.",
"keywords": [
"Primary dysmenorrhea",
"yoga",
"meditation",
"pain",
"adolescent"
],
"content": "1. Introduction\n\nDysmenorrhea, characterized by painful menstruation, is the most prevalent gynecologic condition affecting women, especially adolescent girls. Primary dysmenorrhea is associated with a normal ovulatory cycle during menstruation without an identifiable cause (Ferries-rowe, Corey, & Archer, 2020) and occurs in the absence of pelvic pathology. Increased prostaglandins and leukotriene levels mediate the inflammation, causing uterine contractility, cramping pain and discomfort (Mckenna, Fogleman, & Lancaster, 2021). The prevalence of dysmenorrhea ranges from 16% to 90% (Acheampong et al., 2019; Mckenna et al., 2021), with higher rates reported among adolescent girls. Furthermore, the estimated prevalence rate of dysmenorrhea is 85% in the United States of America (Acheampong et al., 2019), 84.2% in India (Kural, Noor, Pandit, Joshi, & Patil, 2015) and 83.6% in Ghana (Paul, Ameade, Amalba, & Mohammed, 2018).\n\nDysmenorrhea causes varying intensities of discomfort and pain ranging from minor discomfort to severe restriction in the ability to perform daily activities (Ferries-rowe et al., 2020). It is also associated with a decreased quality of life (Mckenna et al., 2021). An estimated 15% of adolescent females report significant pain, negatively influencing their quality of life (Dharmapuri, 2019). In menstrual-related symptoms, lower abdominal and back pain were more strongly associated with absenteeism from school and decreased efficacy among adolescent girls (Ferries-rowe et al., 2020). Greater school absenteeism is yet another concern and one-half of female students miss school at least once due to dysmenorrhea (Mckenna et al., 2021), missing school for 1 to 3 days per menstrual cycle (Dharmapuri, 2019) and 10% to 15% of them with frequent absence (Mckenna et al., 2021). According to studies, dysmenorrhea is also related to decreased academic performance, poor sleep quality, mood changes (Dharmapuri, 2019) and a higher risk of depression and anxiety (Dharmapuri, 2019; Mckenna et al., 2021). Dysmenorrhea is the most prevalent menstrual disorder and probably the most common gynecological disorder; however, the true burden is not very well known (Chhabra S, 2018). A study among Japanese women aimed to estimate the health care resource utilization describing treatment patterns and associated costs showed approximately 2–3-times higher annual healthcare costs in patients with dysmenorrhea than women without the condition (Akiyama, Tanaka, Cristeau, Onishi, & Osuga, 2017). Evidence supports that dysmenorrhea has been linked to an increased incidence of chronic pelvic pain syndrome (Tu & Hellman, 2021).\n\nMany adolescent girls experience dysmenorrhea as a common problem. Suffering from severe spasmodic dysmenorrhea interrupts their academic and social life (Agarwal & Agarwal, 2010). Myometrial contractions, hypersensitization of pain nerve fibers, vasoconstriction, and ultimately the pain is mediated by prostaglandins F2α (PGF2α) and E2 (PGE2). Higher circulating levels of PGF2α and PGE2 are reported in women with dysmenorrhea compared with asymptomatic women during menstruation. These prostaglandin levels peak during the first 48 hours of menstruation when symptoms zenith (Iacovides, Avidon, & Baker, 2015). The severity of menstrual pain is also directly proportional to the release of prostaglandins (Dawood, 2006; Iacovides et al., 2015).\n\nFindings from various studies reveal that primary dysmenorrhea is the leading cause of school absenteeism (Karanth & Liya, 2018; Omidvar, Bakouei, Amiri, & Begum, 2016), and has a negative impact on academic and daily activities (Yesuf, Eshete, & Sisay, 2018). Several other symptoms, such as sleep disturbances (Agarwal & Agarwal, 2010; Karanth & Liya, 2018), low quality of life (Karanth & Liya, 2018), nervousness, depression, loss of appetite, headache and impact on general health status (Agarwal & Agarwal, 2010) were also reported by the adolescent girls along with painful menstruation. Dysmenorrhea significantly influences women’s lives, indicating a substantial public health burden (Zhu et al., 2021). Thus, the evidence from existing literature supports the considerable burden of this issue on public health.\n\nThe management approaches for primary dysmenorrhea can be pharmacological, non-pharmacological, or surgical. Pharmacological management by non-steroidal anti-inflammatory drugs is the most common treatment for menstrual pain; however, the research continues in alternative medicine to alleviate this excruciating pain (Dawood, 2006). In a study conducted to assess the management of primary dysmenorrhea, a small proportion of girls reported having sought medical advice. The majority of them were using self-selected medicine without a doctor’s consultation. The practice of staying in bed, having a hot water bath, use of special food or drink to reduce pain and distraction by watching TV, reading etc., are the measures to relieve pain (Omidvar et al., 2016). Findings of a study conducted by Karanth et al. showed that taking medications, heat application, and lying down were the strategies adopted by a group of adolescent nursing students to overcome the dysmenorrhea symptoms (Karanth & Liya, 2018). Adolescent girls relied more on readily available over-the-counter medications to alleviate the symptoms reported in many research studies. The pharmacological measures may give only temporary relief from pain and certainly will have ill effects on the human body.\n\nYoga is one of the promising fields in alternative systems of medicine. Yoga typically combines physical poses, breathing techniques and meditation or relaxation to improve physical fitness and relieve stress (Yang & Kim, 2016). A growing body of evidence to supports that yoga and meditation could improve physical and mental health via down-regulation of the hypothalamo-pituitary-adrenal axis and the sympathetic nervous system. Yoga also plays a vital role in reducing stress, reducing sympathetic activity, increasing parasympathetic activity and improving quality of life (Nag & Kodali, 2013; Yang & Kim, 2016).\n\nWorldwide, during the 21st century, yoga serves as one of the interventions to improve general health, stress, flexibility, muscle strength and alleviate specific physical symptoms such as chronic pain. Yoga can reduce the severity of menstrual pain and improve physical fitness and quality of life, thus suggesting yoga as a possible complementary treatment for primary dysmenorrhea (Yonglitthipagon et al., 2017). The effects of three yoga poses in women with primary dysmenorrhea showed a significant reduction in the pain intensity and duration. The findings suggest that yoga poses are a safe and simple treatment for primary dysmenorrhea (Rakhshaee, 2011). Some special breathing and meditation techniques also positively influence the central nervous system to control pain and pain tolerance, thereby reducing school absenteeism (Nag & Kodali, 2013). However, only a few studies were conducted to assess the effectiveness of yoga on primary dysmenorrhea (Nag & Kodali, 2013). A systematic review of randomized controlled trials (RCTs) on effects of yoga on dysmenorrhea identified only two potential trials for review from CINAHL, the Cochrane Library, Embase, PsycINFO, PubMed, and KoreaMed electronic databases. The evidence from these two RCTs showed good effectiveness of yoga for dysmenorrhea. However, the review also concluded that further high-quality RCTs were needed to investigate the hypothesis that yoga alleviates menstrual pain since the number of RCTs was small and with quality limitations (Ko, Le, & Kim, 2016).\n\nAcross the globe, the burden of dysmenorrhea is well studied. However, there is a dearth of evidence on the impact of dysmenorrhea among adolescent girls’ academic concentration and self-efficacy. Self-efficacy is an essential element that enhances adolescents’ general health and wellbeing, a psychological mediator for health and academic accomplishment and academic success. A high levels of self-efficacy is also necessary for motivation in educational activities (Armum & Chellappan, 2016). Thus, there is a need to explore the impact of these variables in the context of dysmenorrhea. Prostaglandins play a significant role in the pathomechanism of dysmenorrhea (Grzybowska & Barcikowska, 2020) and performing aerobic exercises can improve dysmenorrhea (Dehnavi, Jafarnejad, & Kamali, 2018). However, there is not ample evidence from published literature on the effect of yoga and pelvic stretching exercises in prostaglandin synthesis among adolescent girls with primary dysmenorrhea. There is also a need for educating adolescent girls on effective and appropriate management of dysmenorrhea to cope with menstrual pain, as it is associated with many other symptoms. Interventions such as mediation can mediate happiness, the experience of reward and develop positive motivation (Babu et al., 2020). Hence, a paradigm shift is essential for practicing the potentially non-harmful and generally effective method. Thus, practicing comprehensive interventions such as yoga and meditation may change the lifestyle to improve wellbeing during painful menstruation and the adolescents’ health.\n\nThe conceptual framework for the proposed project is developed based on Betty Neuman’s system’s model (Chandran & Kumar, 2017), which indicates that the stressors from various sources cause a reaction within the system. Stressors are classified as intra-, inter- and extra-personal by Betty Neuman. Intrapersonal stressors are the ones that originate within the system and the intrapersonal stressors identified in the study are age, prostaglandin, estrogen and progesterone levels, body mass index and other menstruation-related problems. Interpersonal stress occurs within one or more individual systems in the immediate environment. In this study, the interpersonal factors identified are economic status, birth order and level of study. Extra personal stress occurs to the forces outside that system’s control or influence. The extra personal stressors identified in the proposed research are stressful and unpleasant situations such as examinations and food items that influence dysmenorrhea.\n\nA “flexible line of defense” against stressors that reflect the current wellness status of the system and a “normal line of defense” which reflects a state of wellness that has developed over some time, will be reflected with an estimation of the prevalence of dysmenorrhea and associated symptoms. Neuman identifies three levels of prevention, i.e. primary, secondary, and tertiary prevention to strengthen the individual’s different systems. In this study, the purpose of meditation and yoga in primary prevention is to strengthen the healthy lifestyle, whereas its practice as secondary prevention aims at reducing the stressors causing dysmenorrhea.\n\n\n2. Methods\n\nThe overall aims of the study are to estimate the prevalence of dysmenorrhea and evaluate the effectiveness of Meditation and Yoga intervention on dysmenorrhea among adolescent girls.\n\nObjectives developed for achieving the aims are:\n\n1. Estimate prevalence of dysmenorrhea among adolescent girls of Udupi District using the Dysmenorrhea Questionnaire (DYSQ)\n\n2. Evaluate the effectiveness of meditation and yoga intervention on dysmenorrhea outcomes such as pain intensity, stress, academic performance, self-efficacy and biomarker level (Hb, Progesterone, Estrogen, Prostaglandins F2α and E2).\n\nThe trial is designed to test all the hypotheses at a 0.05 level of significance. The hypotheses formulated are as follows:\n\nThere will be a significant difference in the mean post-test scores on the outcomes such as pain intensity, stress, academic performance, self-efficacy and biomarker level between the intervention and control arms.\n\nThere will be a significant difference in the mean pre-test and post-test scores on the outcomes such as pain intensity, stress, academic performance, self-efficacy and biomarker level within the intervention arm.\n\nThis research proposes a prospective, school-based study and will be conducted in two phases to meet the objectives (Figure 1). The proposed trial will be conducted at high schools and pre-university colleges across Udupi district, Karnataka, Southern India, Asia. There are 108 Pre-university colleges and 304 high schools spread across six taluks in the Udupi district. The study’s target population consists of adolescent girls between the age group of 13 and 18 years. Adolescent girls who attained menarche willing to participate and can read/understand Kannada (the local language of the state where the study will be conducted) or the English language will be included.\n\nPhase I: An exploratory survey will be conducted to estimate the prevalence of dysmenorrhea among adolescent girls. Data will be collected from all high schools and pre-university colleges (both government & private) of two randomly selected taluks (district subdivisions) of the Udupi district in Karnataka (out of six taluks).\n\nPhase II: The proposed second phase of the trial will be a cluster randomized controlled trial to evaluate the impact of meditation and yoga on dysmenorrhea. From the first phase, those adolescent girls with high pain intensity (numerical pain rating scale ≥4) from each school will be selected for the second phase. Schools will be the clusters and the cluster size will be determined based on phase I findings. Clusters will be randomly allocated to either the intervention arm or control arm. The intervention arm will receive the proposed meditation and yoga intervention for 12 weeks and the control arm will continue with standard routine care. The outcomes will be re-assessed among study participants after 12 weeks of intervention.\n\nTwo taluks out of six will be randomly selected for the exploratory survey in phase I. High-schools and pre-university schools will be then chosen randomly to conduct the study.\n\nFor phase I, the sample size is calculated based on the estimation of proportion. With a 50% prevalence of dysmenorrhea, 2% absolute error, considering the design effect (Cluster effect, the calculated sample size is ≈5000.\n\nIn phase II, a comparison of two means formulae is used to calculate the sample size. At a 5% level of significance, with 80% power, 0.5 (moderate)Δ-effect size, the sample required in each arm is 63. The sample size has to be increased by 20% as the primary outcome, ‘pain’ is an ordinal outcome that must be analyzed by a non-parametric test. Accounting for an attrition rate of 20%, the calculated sample size is 200 in each group, and approximately 20 schools will be selected for phase II. However, the number of schools chosen will be finalized based on phase I findings.\n\nThe schools will be the unit of randomization and will be allocated to either an intervention or control arm through simple randomization. The random allocation sequence is generated from https://www.sealedenvelope.com. The sequence will be generated by preparing sequentially numbered, opaque sealed envelopes (SNOSE) by the person not part of the study for the allocation concealment. There is no blinding in this study.\n\nThe proposed study aims to estimate the prevalence of dysmenorrhea and evaluate the effectiveness of meditation and yoga intervention on dysmenorrhea among adolescent girls. In Phase 1, by estimating the prevalence of dysmenorrhea among adolescent girls, the research team will implement Meditation and Yoga intervention for adolescent girls with dysmenorrhea in Phase II. Pain intensity, stress, academic performance, self-efficacy and biomarker levels (Hb, progesterone, estrogen, prostaglandins F2α and E2) will be assessed at baseline and 12 weeks after the intervention.\n\n2.6.1 Socio-demographic proforma of adolescent girls\n\nSocio-demographic proforma consists of eight items to collect the socio-demographic details of the participants and this tool will be used in Phase I of the study.\n\n2.6.2 Dysmenorrhea questionnaire (DYSQ)\n\nThe dysmenorrhea questionnaire has 14 items to collect menstrual history and dysmenorrhea information. This tool consists of items related to age at menarche, details of family members having dysmenorrhea, regularity of menstruation, details of dysmenorrhea with associated symptoms, use of medications and other strategies, and effects of dysmenorrhea on other activities. The DYSQ will be used in phase I of the study.\n\n2.6.3 Numerical pain rating scale\n\nThis is a numerical rating scale to assess the pain experienced by participants during menstruation. The scale has a 0 to 10 rating and participants will indicate their pain by encircling one number on the scale. The scale will be used in phase I and Phase II of the study.\n\n2.6.4 Stress scale (SSc)\n\nThe tool is a Likert scale consisting of 55 items to assess stress among adolescent girls. The score ranges from 55 to 220. Participants scoring below 110 are considered to have mild stress, between 110 and 142 are considered to have moderate stress and score above 142 as having severe stress. The scale will be used in Phase II of the study.\n\n2.6.5 Academic performance (absenteeism and concentration)\n\nThis tool will have two sections. Researchers will use section A to assess the school absenteeism and the data will be collected from school attendance records with the reason for school absenteeism. Academic performance will be assessed through the scores obtained by the adolescent girls in the previous academic assessments. Section B consists of a Likert scale with six items to assess concentration in studies among adolescent girls during menstruation. The possible scores range from 0 to 18 and the higher the score, the concentration. The scale will be used in Phase II of the study.\n\n2.6.6 Generalized self-efficacy scale (GSE)\n\nIt is a 10-item standardized scale used to measure the participants’ self-efficacy. For the GSE, the total score ranges between 10 and 40, with a higher score indicating more self-efficacy (Schwarzer & Jerusalem 1995). The scale also will be used in Phase II of the study.\n\n2.6.7 Estimation of bio-markers (Hb, progesterone, estrogen, prostaglandins F2α and E2)\n\nEstimation of hemoglobin will be done by using a Sahlis Hemoglobinometer. Assessment of the levels of progesterone, estrogen, and prostaglandins in the blood will be done by a competitive ELISA kit. Biomarkers will be assessed in Phase II of the study.\n\nStudy status: Phase I data collection is ongoing, and completed nearly 2000 adolescent girls.\n\n2.7.1 Study protocol\n\nThe study protocol has been reviewed by the Institutional research committee of Manipal College of Nursing, Manipal and approved by the expert panel of the Institutional Ethics Committee of Kasturba Medical College & Kasturba Hospital Manipal (IEC: 414/2021). The protocol is presented in the scientist’s forum of the Department of Science and Technology of Yoga and Meditation (DST SATYAM) and approved. The protocol is registered prospectively in the Clinical Trials Registry of India with the ID number (CTRI/2021/11/037703).\n\n2.7.2 Study instruments\n\nThe numerical rating scale and the general self-efficacy scale are developed and validated internationally (Luszczynska, Scholz, & Schwarzer, 2005). This instrument has been translated and validated for the Indian population. Other tools used in the study were developed by researchers and reviewed five experts. The experts from nursing, mental health, pediatric, and education were included in the panel. The content validity of the instruments was established. The study instruments were then finalized after making necessary modifications as suggested by the panel. The questionnaires were translated to the local language and did the back translation to ensure the language validity of the instruments. The reliability of the study instruments will be calculated for internal consistency by administering it to 50 adolescent girls.\n\n2.7.3 Meditation and yoga program\n\nThe experts from the division of yoga prepared the meditation and yoga protocol. The protocol was refined, validated, and approved by Morarji Desai National Institute of Yoga (MDNIY), an autonomous organization under the Ministry of AYUSH, Government of India.\n\n2.8.1 Phase I: Exploratory survey\n\nAdministrative permission from the Deputy Director of Public Instruction (DDPI) of Udupi district has been obtained to conduct the research study. Permission from headteachers and principals of respective high schools and pre-university colleges will be obtained. Written informed consent forms will be sent to the parents along with the participant information sheet and written assent will be taken from adolescent girls. Upon approval, the data will be collected by distributing the socio-demographic proforma, DYSQ and numerical pain scale among the study participants by the researchers. Phase I data collection will take six months to reach the estimated sample size.\n\n2.8.2 Phase II: Cluster randomized controlled trial\n\nAdolescent girls with high pain intensity (numerical pain rating scale ≥4) in Phase I will be selected for Phase II. The school will be the clusters and the cluster size will be determined based on phase I findings. After obtaining the consent from parents and assent from adolescent girls, data on the numerical pain rating scale, stress, academic performance, perceived self-efficacy and bio-markers (Hb, prostaglandins, estrogen and progesterone) will be assessed on the first day of the menstrual cycle. A trained phlebotomist will collect the required amount of blood in the vacutainers. The session on meditation and yoga will be conducted for 12 weeks. It includes Aumkar meditation, relaxation, loosening exercises, yogasanas and pranayamas. These yoagasanas and meditation will be introduced gradually, and adolescent girls will be performing the intervention for 45 minutes under the supervision of the investigator every day, five days a week for 12 weeks, except the days of menstruation. After 12 weeks of intervention, the data will be collected using the same tools as the pretest. After the posttest assessment, the meditation and yoga intervention will be taught to the control group participants. The collected blood will be used only for the said analysis and the remaining blood won’t be stored for any purposes, and it will be discarded as per the institutional protocol.\n\nIn phase I, descriptive statistics such as frequency and percentage will describe socio-demographic characteristics, estimate of the prevalence of dysmenorrhea and related factors among adolescent girls. In Phase II, Chi-squared (χ2) and the independent sample t-test will be used to compare the baseline variables of the intervention and the control arms. An intention-to-treat analysis (ITT) will be adopted to manage the missing data. An independent group ‘t’ test will be used to analyze the outcome variables. Data will be analyzed using Statistical Package for Social Sciences (SPSS version 16) (RRID: SCR_002865).\n\nAdministrative permission from the Deputy Director for Public Instructions (DDPI) of the Udupi district is obtained. Administrative permission from headteachers and Principals will be obtained from all the high schools and pre-university colleges before the process of data collection. After obtaining administrative permissions, consent will be sent to the parents and a participant information sheet consisting of a complete explanation of the research project. They have the right to consent voluntarily or decline to participate and the right to withdraw their participation at any time in-between. Assent will be obtained from adolescent girls after obtaining consent from parents. Participants’ privacy, anonymity, and confidentiality will be secured and maintained throughout and after the conduct of the study.\n\nIn phase I of the proposed study, the prevalence of dysmenorrhea and related factors will be estimated from adolescent girls. Upon estimating the prevalence, in the second phase of the study the research team will focus on meditation and yoga intervention’s impact on adolescent girls with dysmenorrhea. The expected outcomes of meditation and yoga intervention in phase II of the trial are a reduction in dysmenorrhea and its associated symptoms. This would further help reduce stress, decrease school absenteeism, and improve concentration, self-efficacy and academic performance of adolescent girls. Thus, the simple, non-harmful and comprehensive intervention of meditation and yoga would change the lifestyle, improve the adolescents’ health and quality of life and reduce the public health burden. Yoga and meditation generally do not cause any adverse effects if performed as instructed. Appropriate referrals will be given if any adverse effects are identified.\n\n\n3. Discussion\n\nYoga could be an effective non-pharmacological option for adolescent girls with primary dysmenorrhea. Pain can be diagramed as a spiral in medical theory: pain/tension/fear/pain. Yoga is thought to aid the brain’s pain center regulation by the spinal cord’s gate controlling mechanism and the body’s natural painkiller release. Meditation and yoga also have much awareness and control of one’s breathing. Relaxation and stress reduction can be aided by exhaling. Breathing awareness allows for calmer, slower breathing, which aids in relaxation and pain control (Rakhshaee, 2011). Research conducted with yoga interventions showed significant improvement in trunk flexibility and leg muscle strength within the intervention group. Improvement in body movement and breathing is linked with activating ‘relaxation response’ in the neuroendocrine system improving holistic health (Yonglitthipagon et al., 2017). Yoga’s popularity and medical benefits have grown with the growing interest in alternative and complementary medicine (Rakhshaee, 2011). However, a study conducted by Yang et al. with yoga as an intervention for primary dysmenorrhea recommends conducting RCTs with larger sample size and assessing of objective outcomes such as prostaglandins (Yang & Kim, 2016; Yonglitthipagon et al., 2017). Though the current studies lay a strong foundation for future research and propose that yoga could be a safe and cost-effective treatment for dysmenorrhea’s growing public health issue, there is currently insufficient evidence to support the use of yoga to treat dysmenorrhea symptoms (Ko et al., 2016). Hence, this unique study attempts to establish the evidence on the effectiveness of meditation and yoga in primary dysmenorrhea symptoms among adolescent girls.\n\nThere was closure of the schools as the second wave of coronavirus disease 2019 (COVID-19) pandemic evolved around the proposed time of initial recruitment. Our team was challenged to recruit the participants due to the restrictions of ethical committee and school management. However, the recruitment for phase I has started on November 2021 with the school reopening. Schools approached for data collection to date are 25 and four have declined to participate. A total of 868 adolescents are screened and 335 (38.59%) are having numeric pain score (N>4). As the schools started functioning with offline classes and vaccinations and guidelines for the vaccinations for the age group has been implemented which would reduce COVID-19 related challenges.\n\n\n4. Limitation\n\nThe study will be conducted among adolescent girls between the ages of 13 and 18, and no blinding will limit the study’s generalization. The intervention will be performed for 12 weeks under direct supervision. As there is no further follow-up, the sustainability of the study findings purely relies on adolescent girls’ self-motivation.\n\n\n5. Conclusion\n\nA simple and comprehensive intervention like meditation and yoga among young adolescents would be beneficial for reducing dysmenorrhea-related symptoms from an early age and thereby improving the quality of life. The researchers recommend regular yoga training as a school program to improve adolescent health based on the expected outcome.\n\n\nData availability\n\nNo data are associated with this article.\n\nAssariparambil, Anil Raj; GEORGE, ANICE; Shalini, https://orcid.org/0000-0002-0798-7827 (2022): Participant Information Sheet & Informed Consent. figshare. Journal contribution. https://doi.org/10.6084/m9.figshare.19621110.v1.\n\n\nReporting guidelines\n\nAssariparambil, Anil Raj; GEORGE, ANICE (2022): SPIRIT Checklist_MYID Study. figshare. Journal contribution. https://doi.org/10.6084/m9.figshare.19620930.v1\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAcheampong K, Baffour-awuah D, Ganu D, et al.: Prevalence and Predictors of Dysmenorrhea, Its Effect, and Coping Mechanisms among Adolescents in Shai Osudoku District, Ghana. Obstet. Gynecol. Int. 2019; 2019: 1–7. PubMed Abstract | Publisher Full Text\n\nAgarwal AK, Agarwal A: Original Article A Study of Dysmenorrhea During Menstruation in Adolescent Girls. Indian J. Community Med. 2010; 35(1): 159–164. PubMed Abstract | Publisher Full Text\n\nAkiyama S, Tanaka E, Cristeau O, et al.: Evaluation of the treatment patterns and economic burden of dysmenorrhea in Japanese women, using a claims database. ClinicoEconomics Outcomes Res. 2017; 9: 295–306. PubMed Abstract | Publisher Full Text\n\nArmum P, Chellappan K: Social and emotional self-efficacy of adolescents: measured and analysed interdependencies within and across academic achievement level. Int. J. Adolesc. Youth 2016; 21: 279–288. Publisher Full Text\n\nBabu M, Kadavigere R, Koteshwara P, et al.: Rajyoga meditation induces grey matter volume changes in regions that process reward and happiness. Sci. Rep. 2020; 10(1): 16177. PubMed Abstract | Publisher Full Text\n\nChandran S, Kumar A: Application of Nursing Theories. Jaypee publishers; 2017; 87–94.\n\nChhabra S, Yadav S, Gokhale S: Burden of Primary Dysmenorrhea – Way Forward. J. Gynecol. Women’s Health. 2018; 9(1). Publisher Full Text\n\nDawood MY: Clinical Expert Series Primary Dysmenorrhea Advances in Pathogenesis and Management Primary Dysmenorrhea Advances in Pathogenesis and Management. Obstet. Gynecol. 2006; 108(2): 428–441. Publisher Full Text\n\nDehnavi ZM, Jafarnejad F, Kamali Z: The Effect of aerobic exercise on primary dysmenorrhea: A clinical trial study. J. Educ. Health Promot. 2018; 7: 3–5. Publisher Full Text\n\nDharmapuri S: Dysmenorrhea in adolescents. Pediatr. Med. 2019; 2(34): 1–9. Publisher Full Text\n\nFerries-rowe E, Corey E, Archer JS: Primary Dysmenorrhea Diagnosis and Therapy. Obstet. Gynecol. 2020; 136(5): 1047–1058. Publisher Full Text\n\nGrzybowska ME, Barcikowska Z: Inflammatory Markers in Dysmenorrhea and Therapeutic Options. Int. J. Environ. Res. Public Health 2020; 17: 1–14. PubMed Abstract | Publisher Full Text\n\nIacovides S, Avidon I, Baker FC: What we know about primary dysmenorrhea today: a critical review. Hum. Reprod. Update 2015; 21(6): 762–778. PubMed Abstract | Publisher Full Text\n\nKaranth S, Liya SR: Prevalence and risk factors for dysmenorrhoea among nursing student and its impact on their quality of life. Int. J. Reprod. Contracept. Obstet. Gynecol. 2018; 7(7): 2661–2667. Publisher Full Text\n\nKo H, Le S, Kim S: Alternative & Integrative Medicine Effects of Yoga on Dysmenorrhea: A Systematic Review of Randomized Controlled Trials. Altern. Integr. Med. 2016; 05(4): 1–5. Publisher Full Text\n\nKural M, Noor NN, Pandit D, et al.: Menstrual characteristics and prevalence of dysmenorrhea in college going girls. J. Family Med. Prim. Care. 2015; 4(3): 426–431. PubMed Abstract | Publisher Full Text\n\nLuszczynska A, Scholz U, Schwarzer R: The General Self-Efficacy Scale: Multicultural Validation Studies. J. Psychol. 2005; 139(5): 439–457. PubMed Abstract | Publisher Full Text\n\nMckenna KA, Fogleman CD, Lancaster PM: Dysmenorrhea. Am. Fam. Physician. 2021; 104(2): 164–170. PubMed Abstract\n\nNag U, Kodali M: Effect of Yoga on Primary Dysmenorrhea and Stress in Medical Students. IOSR Journal of Dental and Medical Sciences (IOSR-JDMS) 2013; 4(1): 69–73. Publisher Full Text\n\nOmidvar S, Bakouei F, Amiri FN, et al.: Primary Dysmenorrhea and Menstrual Symptoms in Indian Female Students: Prevalence, Impact and Management. Global J. Health Sci. 2016; 8(8): 135. PubMed Abstract | Publisher Full Text\n\nPaul E, Ameade K, Amalba A, et al.: Prevalence of dysmenorrhea among University students in Northern Ghana; its impact and management strategies. BMC Womens Health. 2018; 18(39): 39–39. PubMed Abstract | Publisher Full Text\n\nRakhshaee Z: Effect of three yoga poses (cobra, cat and fish poses) in women with primary dysmenorrhea: a randomized clinical trial. J. Pediatr. Adolesc. Gynecol. 2011; 24(4): 192–196. PubMed Abstract | Publisher Full Text\n\nSchwarzer R, Jerusalem M: Generalized Self-Efficacy scale. Weinman J, Wright S, Johnston M, editors. Measures in health psychology: A user’s portfolio. Causal and control beliefs Windsor, UK: NFER-NELSON; 1995; pp. 35–37.\n\nTu F, Hellman K: Primary Dysmenorrhea: Diagnosis and Therapy. Obstet. Gynecol. 2021; 137(4): 752. Publisher Full Text\n\nYang N-Y, Kim S-D: Effects of a Yoga Program on Menstrual Cramps and Menstrual Distress in Undergraduate Students with Primary Dysmenorrhea: A Single-Blind, Randomized Controlled Trial. J. Altern. Complement. Med. 2016; 22(9): 732–738. PubMed Abstract | Publisher Full Text\n\nYesuf TA, Eshete NA, Sisay EA: Dysmenorrhea among University Health Science Students, Northern Ethiopia: Impact and Associated Factors. Int. J. Reprod. Med. 2018; 2018: 1–5. PubMed Abstract | Publisher Full Text\n\nYonglitthipagon P, Muansiangsai S, Wongkhumngern W, et al.: Effect of yoga on the menstrual pain, physical fi tness, and quality of life of young women with primary dysmenorrhea. J. Bodyw. Mov. Ther. 2017; 21(4): 840–846. PubMed Abstract | Publisher Full Text\n\nZhu X, Bensoussan A, Zhu L, et al.: Primary dysmenorrhoea: A comparative study on Australian and Chinese women. Complement. Ther. Med. 2021; 17(2009): 155–160. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "160701",
"date": "09 Feb 2023",
"name": "Helen A Weiss",
"expertise": [
"Reviewer Expertise Epidemiology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPrimary dysmenorrhoea (menstrual pain) is highly prevalent but many girls do not how best to manage the pain. This protocol paper describes the design of a school-based cluster-randomised trial to evaluate the effectiveness of a 12 week meditation and yoga intervention on dysmenorrhoea among adolescent girls in India.\nIntroduction\nSome of the statements sound a little too definitive- e.g. there is little robust data on the amount of school absenteeism due to menstruation, so the authors should reflect this.\n\nSimilarly there is stronger evidence for an association between dysmenorrhea and sleep quality, mood changes and depression/anxiety than for academic performance, so this should also be reflected in the text\n\nThere is also quite a lot of repetition in the introduction (e.g. the association of dysmenorrhoea with school attendance is mentioned in the 2nd and 4th paragraphs, as are other associations). The flow of the introduction should be improved to reduce this.\n\nWhen you cite studies, please give the country/context in which it took place where relevant e.g. in terms of help-seeking behaviours for dysmenorrhea\n\nWhat is your evidence for the statement “The pharmacological measures may give only temporary relief from pain and certainly will have ill effects on the human body.”. Are you saying that a minimal dose of ibuprofen for dysmenorrhoea will have ill effects? Please remove this sentence unless you can provide specific evidence.\n\nWhen citing the literature, please indicate the setting, study design, strength of evidence provided (and/or the number of individuals in the study)\n\nPlease give references for the two RCTs that you mention on the effects of yoga on dysmenorrhea\n\nPlease show the conceptual framework as a Figure\nMethods\nPlease describe the setting, as these interventions may work differently in different contexts (you mention Udupi District in the first objective, but not the country or state)\n\nYou don’t need Hypothesis 2 if it is a randomised trial and you compare endline score (H1) because the randomisation means the baseline scores should be similar in both arms (and you can adjust for these if this is not the case)\n\nYou should do the pre-test scores prior to randomisation to minimise bias, and allow yourselves to ensure balance on this with the randomisation.\n\nPlease show Figure 1 as a CONSORT figure for cluster randomised trials. E.g. you should show the number of clusters (schools) per arm, as these are the unit of randomisation\n\nWhy don’t you have a longer-term follow up, rather than just 12 weeks, to see if the intervention is sustainable?\n\nThe sample size for the prevalence study seems too large. Why do you need 2% precision for the prevalence estimate? Why not e.g. 5% and reduce your sample size? What design effect are you assuming, and what is this based on?\n\nWhat is the proposed effect size for the CRT based on?\n\nWhy don’t you have pain as a binary outcome at the end, which would be easier to interpret and report?\n\nWhy don’t you hold a public randomisation ceremony to ensure buy-in from the schools? You don’t need sequential randomisation for a cluster-randomised trial – you can randomise all at once when you have identified the eligible schools.\n\nWhat are the eligibility criteria for the schools?\n\nPlease give references for all the scales used.\n\nHow accurate are the school attendance records? Have you piloted using these for outcomes and triangulated with other measures?\n\nWhich scale are you using for concentration?\n\nWhy don’t you also use the menstrual self-efficacy scale by Erin Hunter? Development and validation of the Self-Efficacy in Addressing Menstrual Needs Scale (SAMNS-26) in Bangladeshi schools: A measure of girls’ menstrual care confidence\n\nPlease give further details of data collection and ethics for collecting the biomarker information. Is this at both baseline and endline?\n\nAs you have already collected data from 2000 girls in Phase 1, please give the prevalence of dysmenorrhea and use this for your Phase 2 sample size calculations\n\nHow confident are you that schools are willing for selected students to be free for 45 minutes of yoga every day for 12 weeks. How will they do this without missing class? How will you mitigate against stigmatising them?\n\nThe statistical analyses need to adjust for clustering, and need considerably more detail especially for Phase 2.\nDiscussion\nHere you say that 868 adolescents have been screened, but in section 2 you say that nearly 2000 girls have been screened. Please clarify, and use the prevalence found (38.6%) in your sample size calculation for the CRT. Also please give the design effect found, and use this also in your sample size calculation for the CRT.\nOther\nPlease say who is funding the study.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "198632",
"date": "30 Aug 2023",
"name": "Omero Benedicto Poli-Neto",
"expertise": [
"Reviewer Expertise Gynecology",
"pelvic pain",
"dysmenorrhea",
"endometriosis",
"adenomyosis"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear authors,\nFirst I would like to congratulate you for the initiative. However, I have a few comments about the proposal. I hope that my suggestions and recommendations will be interpreted in a constructive way.\nThe topic chosen is relevant. Dysmenorrhea is a common condition with the potential to negatively affect women's lives. I found the literature review presented in the introduction to be good and up to date. However, I think the text is a little wordy. Various information is presented in a repetitive manner. I suggest reviewing and organizing into subsections.\nThe section “Gaps in the existing literature” superficially addresses the gap presented in the paragraph that precedes it. There are some clinical trials, but the authors report that there are qualitative limitations, but they are not pointed out. I recommend that these points be explored in depth. Perhaps these explanations are more convincing to explain the gaps.\nFurthermore, I recommend that the physiological effects of meditation and yoga be discussed in their own detailed section. Despite the growing evidence in favor of these modalities, they are still surrounded by a certain mysticism, especially among Western countries. I believe this can make the article appealing to an even wider range of readers. This also applies to the “Conceptual framework” section. I recommend presenting in detail the pathophysiological bases for the proposed model.\nThe effectiveness of existing therapeutic approaches, with emphasis on non-steroidal anti-inflammatory drugs and hormonal contraceptives, is not adequately presented. These measures are suitable for most women and are sufficient to ensure a similar quality of life to the healthy population without the condition. Only a fraction of women have severe dysmenorrhea refractory to existing pharmacological treatment. The statement “…pharmacological measures… certainly will have ill effects on the human body” needs to be revised. If the authors really agree with this, a long argumentative explanation is necessary. In my opinion, this type of information can be harmful to the population, depriving them of known effective and safe measures.\nHypothesis 2 is not necessary.\nSome methodological points need to be reviewed and clarified. Dysmenorrhea is a condition that tends to occur monthly, but not necessarily in every consecutive menstrual cycle. Will the authors do just one interview with the young women? If yes, this single assessment may represent a bias. I recommend doing a serial assessment for at least 3-4 consecutive months. I recommend that randomization be done at the end of the first assessment, and that the professional responsible for it is not responsible for the randomization process.\nI strongly recommend that authors review the CONSORT (Consolidated Standards of Reporting Trials) guidelines (https://doi.org/10.1186/1745-6215-11-32.), and the special supplement for reporting clinical trials for treatment of pain (https://doi.org/10.1097/PR9.0000000000000621) and make the necessary changes to the text. Please advise where the clinical trial will be registered before it starts.\nWhich information collection instrument will be used? I recommend providing access or publishing the instrument. I also recommend specifying the scales that will be used and stating whether they have been validated in the target population. Please, provide validity references for each of them. I recommend describing the Lickert scale and perhaps using 7 items instead of 6.\nFor me there is a discrepancy in the sample size calculation. I recommend making it clear which outcome will be used and the expected effect size. For me, the use of prevalence alone is not adequate. I recommend using pain scores as suggested by the aforementioned guidelines.\nI think there are still some items missing: 1) how will the menstrual phase be diagnosed?; 2) how and which variables will be used for the adjustment? 3) how will the evaluation be carried out to exclude coexisting diseases?; 4) will psychological symptoms be evaluated?; 5) quality of life?; 6) catastrophism?; 7) how will the use of pain killers be controlled?; 8) how will the use of contraceptives be controlled?; Will the participants be guided to use these drugs or will they have free choice or will they still be guided not to use them?; 9) how do the authors ensure that all participants will have free time?; 10) will this not induce a selection bias?\nThe characteristic of the intervention hinders, but does not prevent, a simulated action that can function as a placebo. Considering the human characteristic of responding to placebo and nocebo, it is plausible to hypothesize that offering the intervention to one group may induce a placebo effect, while, on the other hand, depriving another group of the intervention may induce a nocebo effect. This can artificially magnify the difference in the measure of outcomes between groups. This would lead to potentially wrong conclusions and possibly harmful to the population. I strongly recommend including a control intervention. I also recommend that participants are not deprived of guidance regarding the existence of effective pharmacological measures, and that this is explicit in the free and informed consent form. Twelve weeks (or three months) is too short a period of time to evaluate the effectiveness of the method. I recommend a long follow-up of at least 6 months.\nThe predicted statistical analysis is not enough. As there are numerous potentially confounding variables, multiple analysis methods that allow adjustment for covariates must be provided.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-590
|
https://f1000research.com/articles/11-242/v1
|
28 Feb 22
|
{
"type": "Research Article",
"title": "Duration of dry and humidified incubation of single-step embryo culture medium and oxygen tension during sham culture do not alter metabolomics signature",
"authors": [
"Aswathi Cheredath",
"Shubhashree Uppangala",
"Gitanjali Asampille",
"Vani Lakshmi R.",
"David Joseph",
"Keyur Raval",
"Nagana Gowda G. A.",
"Guruprasad Kalthur",
"Satish Kumar Adiga",
"Aswathi Cheredath",
"Shubhashree Uppangala",
"Gitanjali Asampille",
"Vani Lakshmi R.",
"David Joseph",
"Keyur Raval",
"Nagana Gowda G. A.",
"Guruprasad Kalthur"
],
"abstract": "Background: The extended embryo culture using single-step medium gained popularity in clinical in vitro fertilisation (IVF). However, there are concerns about the degradation of unstable medium components and their negative effects on the developing embryos. Further, dry-incubation can increase osmolality, which can in-turn enhance the concentration of constituents of the media and their stability. Hence, this study was conducted to understand the immediate changes in the culture media metabolites in relation to clinically comparable situations such as single-step extended embryo culture and use of dry and humidified-incubation in two-different gaseous conditions. Methods: Commercially available single-step medium was sham-cultured in droplets under oil in two different conditions viz. dry (37°C; 6%CO2; 5%O2) and humidified (37°C; 6% CO2; atmospheric O2) for 0h, 72h, and 120h intervals. Droplets were subjected to the sensitivity-enhanced nuclear magnetic resonance (NMR)-based profiling using 800 MHz NMR equipped with a cryogenically cooled micro-coil (1.7mm) probe. Metabolomic signatures between the two groups were comprehensively assessed. Results: A total of ten amino acids and four energy substrates were identified from the culture medium. Metabolite levels showed a non-significant increase in the dry-incubation group at 72h and then declined at 120h. Humidified incubation had no effects on the level of the metabolite until 120h. No significant differences in the levels of metabolites were observed between the dry and humidified-groups at various time-points tested. Conclusions: A non-significant variation in the levels of metabolites observed in the dry-incubation of single-step medium most unlikely to influence a clinical outcome. However, the impact of these subtle changes on the (epi)genetic integrity of the embryos in a clinical set-up to be addressed.",
"keywords": [
"Embryo metabolomics",
"Medium stability",
"Single step embryo culture",
"Sensitivity enhanced nuclear magnetic resonance spectroscopy"
],
"content": "Introduction\n\nThe embryo culture medium is expected to mimic an in vivo environment for the growth and health of the human preimplantation embryo in vitro. It has been shown that culture medium is one of the many crucial factors influencing the key process of fertilization and early embryogenesis (Sunde et al., 2016; Dumoulin et al., 2010). On the other hand, culture medium can also affect the foetal growth and birthweight of the babies born through assisted reproductive technology (ART) (Kleijkers et al., 2016a; Nelissen et al., 2012; Dumoulin et al., 2010).\n\nSeveral factors can impact the efficacy and stability of embryo culture media. These include the composition of the medium, osmolality, and conditions within the incubator such as humidity, gaseous state, pH, and temperature (Mestres et al., 2021; Tarahomi et al., 2018, 2019; Swain et al., 2016). Despite its importance, the exact formulation of commercially available embryo culture media is still unknown due to a lack of transparency in revealing the ingredients. However, choice of incubator and maintaining stable incubator conditions are laboratory-controlled factors that can strongly influence the medium’s stability.\n\nExtended embryo culture in single step medium is gaining popularity due to its undisturbed culture, ability to monitor through time-lapse imaging, and importantly, the availability of single-step medium that supports embryonic development from one-cell to the blastocyst stage. However, one of the concerns with undisturbed extended embryo culture is the degradation of unstable components in the culture medium and their potential negative effects on the developing embryos. It has also been shown that uninterrupted embryo culture using single-step media in a dry atmosphere can increase osmolality, which can in turn enhance the concentration of constituents of the media and thereby alter the media’s stability (Mestres et al., 2021; Yumoto et al. 2019; Fawzy et al., 2017).\n\nRecently, a few studies tried to address the impact of factors influencing the stability of the embryo culture medium using various approaches (Mestres et al., 2021; Tarahomi et al., 2018, 2019; Swain et al., 2016). However, the availability of a large number of culture media and lack of uniformity in the culture methods employed by the embryologists, calls for extensive research on the individual products and methods used. In this study, experiments were specifically designed and executed to understand the immediate changes in the culture media metabolites in relation to clinically comparable situations such as single-step extended embryo culture and use of dry and humidified incubation in two different gaseous conditions (dry incubation, 6% CO2, 5% O2; humidified incubation, 6% CO2; atmospheric O2). In order to understand the direct effects of these variables on the chemical composition of the medium, high-resolution 800 MHz nuclear magnetic resonance (NMR) spectroscopy with the help of 1.7 mm TX1 cryo-probe was used as the analytical tool to understand the metabolomic signature of the culture medium.\n\n\nMethods\n\nThis prospective study was conducted at the Department of Clinical Embryology, Kasturba Medical College, Manipal and NMR Research Centre, Indian Institute of Science, Bangalore, India between September 2019-April 2021.\n\nThis study used a ready-to-use, protein supplemented V-ONESTEP medium (Cat No. V-OSM-20, Vitromed GmbH, Germany). Immediately upon arrival from the local distributor, ordered culture media were stored in a temperature monitored refrigerator (2–8°C). In total, three different batches were used in the study to investigate the metabolomic changes. The measurements were taken before the expiry dates.\n\nIn order to mimic the conditions followed in the ART laboratory, the medium and dish preparation were handled in the same biosafety cabinet with the heat stage turned off. The medium in the bottle was taken out of the refrigerator, transferred to 14 mL Nunc tubes, and equilibrated in the humidified incubator (HeraCell 150i, Germany) at 37°C and 6% CO2 for 4 h.\n\nAs depicted in Figure 1, droplet culture on a petri dish was used in the study. Nine droplets of 30 μL equilibrated medium were placed on each petri dish (Falcon®, USA; Cat No. 353001), overlaid with 3 mL pre-incubated oil (Vitromed GmbH, Germany; Cat No V-OIL-P100). The dishes were placed inside the incubator immediately after the preparation and the time was noted (0 h). Two sham culture systems were used; i) dry incubation, 6% CO2, 5% O2 (MIRI® Multiroom incubator, ESCO Medical, Singapore); ii) humidified incubation, 6% CO2; atmospheric O2 (HeraCell 150i, Germany). The sham culture was performed in a stable condition for a period of 5 days. The media samples were collected in triplicates for analysis at three-time points from both groups, i.e. immediately after the preparation of the dish (0 h), on day 3 (72 h), and on day 5 (120 h).\n\nNMR=nuclear magnetic resonance.\n\nFrom each droplet, 25 μL culture medium was carefully collected from randomly selected droplets without oil contamination and placed individually into labelled sterile cryovials, snap-frozen in liquid nitrogen, and then stored at -80°C until used for NMR analysis. A total of ten trials (N=10) were performed to confirm the reproducibility of the results.\n\nThe culture media samples were thawed for 10 minutes at room temperature. In total, 25 μL of each sample was diluted to 35 μL using deuterium oxide (D2O) solution containing a pre-calculated amount of TSP (Sodium salt of 2,2,3,3 tetradeutero 3-(trimethyl silyl) propionate) as a standard reference compound and transferred to 1.7 mm NMR tubes. Thus, all the metabolites present in the culture media were diluted by a factor of 1.4. The dilution solvent was prepared by adding 0.05 g of TSP/mL D2O and diluting by a factor of 10 using D2O solvent. This solution (10 μL) was added to 25 μL culture medium sample to get a working solution containing 8.29 mM of TSP.\n\nNMR experiments were performed on an 800 MHz Bruker AVANCE III NMR spectrometer equipped with a 1.7mm cryo-probe at 298 K. One dimensional (1D) 1H NMR spectra were obtained using the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence. CPMG 180-degree pulse train duration of 12 ms was used to suppress protein signals from the media. Each spectrum was obtained using 9615 Hz spectral width, 5 s relaxation delay, 16 k time-domain points, 4 dummy scans, and 256 transients. The time-domain data (FID's) were multiplied by a sine bell window function shifted by 90o and zero-filled to 65536 points prior to Fourier transformation. Bruker Topspin version 3.6.2 software (RRID:SCR_014227) was used for NMR data acquisition and processing.\n\nA total of 60 1D 1H spectra were acquired from ten trials. All data were analyzed using the Bruker TOPSPIN 3.6.2 software. Metabolites were identified based on the literature and the characteristic metabolite peak integrals were measured with respect to the TSP peak (which was normalized to 1.0). Subsequently, region wise (0.2 ppm) integration was performed using “intser” option. A total of 27 regions with metabolite peaks were considered for the analysis.\n\nAll the quantitative variables were represented as mean ± standard error of mean (SEM). Subsequently, a descriptive comparison of metabolites across various gaseous and culture conditions were performed. Principal component (PC) analysis was carried out to explore metabolic differences across two culture conditions (dry and humidified) in two different gaseous conditions. A two-dimensional bi-plot (Wickham, 2016) visualized the first two Principal Components (PCs; PC1 and PC2) that accounted for 99.41% of the variability in the data consisting of 27 integral regions captured across 60 samples from ten trials. The analysis was implemented in CRAN R 4.0 (RRID:SCR_003005).\n\nFurthermore, the statistical significance for the sham culture across different time points and gaseous conditions was assessed using repeated-measures analysis of variance (ANOVA) in Jamovi 1.8.1 (RRID:SCR_016142). The level of significance was set at 5% throughout the study.\n\n\nResults\n\nOverall, 14 metabolites were considered for the analysis as peaks that appeared were clear and distinct in all the spectra (Cheredath et al., 2022). This included the amino acid metabolites such as Leucine (Leu), Isoleucine (Ile), Valine (Val), Methionine (Met), Glycine (Gly), Lysine (Lys), Threonine (Thr), Tyrosine (Tyr), Histidine (His), and Phenylalanine (Phe). Carbohydrate and metabolic intermediates identified were Pyruvate (Pyr), Glucose (Glc), Lactate (Lac), and Citrate (Cit). Figure 2 shows a representative 1D proton NMR spectrum of V-ONESTEP medium with the assignments of peak.\n\nThe figure represents the assignment of peaks for different metabolites. X-axis represents the chemical shift in parts per million (ppm). NMR=nuclear magnetic resonance.\n\nTime dependent changes in the level of metabolites\n\nDry incubation of V-ONESTEP medium at 5% O2 subjected to NMR analysis revealed no significant changes in the level of metabolites at various time points tested. Interestingly, the level of all the identified metabolites found to be increasing on day 3 (72 h) started declining thereafter. However, differences were not statistically significant for the trend observed (Table 1). On the other hand, in the humidified incubation group, except pyruvate, the levels of all other metabolites minimally altered on day 3 (72 h) and thereafter remained unchanged until day 5 (120 h). However, citrate and glycine showed a moderate non-significant variation on day 5 (120 h) (Table 2).\n\nSEM=standard error of mean, TSP = Sodium salt of 2,2,3,3 tetradeutero 3-(trimethyl silyl) propionate.\n\nImpact of dry/5% O2 incubation vs humidified/atmospheric O2 incubation on the level of metabolites\n\nComparison of metabolites between dry/5% O2 incubation and humidified/atmospheric O2 incubation at different time points is presented in Table 3. Though the level of all the metabolites in dry/5% O2 incubation on day 3 and day 5 was higher than humidified/atmospheric O2 incubation group, the differences were not statistically significant. A multivariate exploration of the 27 integral regions captured from 60 samples from ten trials was performed using two-dimensional PC bi-plots (PC1 and PC2). The results of repeated measures ANOVA (Wilk's Lambda Method) reveal that there is no significant difference in the mean values of the relative concentration of metabolites across the three time points (p=0.96) and two gaseous conditions (p=0.65). Also, there is no statistically significant interaction effect (p=0.69). These observations demonstrate no identifiable differentiation between the metabolomic regions of sham culture performed at different incubator conditions at different time points (Figure 3). Overall, the effects of different incubator conditions and oxygen levels on sham culture of the ONESTEP media were not significant.\n\nSEM=standard error of mean, TSP = Sodium salt of 2,2,3,3 tetradeutero 3-(trimethyl silyl) propionate.\n\nBlue color () represents sample collected at 0h (baseline control) and light ash color () represents the sham culture performed at humidified/atmospheric O2 level and collected at 72 h, whereas orange color () represents the sham culture performed at dry/physiological O2 level and collected at 72 h. Dark grey color () represents the sham culture performed at humidified/atmospheric O2 level and collected at 120 h and dark chocolate color () represents the sham culture performed at 5 dry/physiological O2 level and collected at 120 h.\n\n\nDiscussion\n\nThe primary objective of this study was to test the stability of the single step culture medium and its interaction with the oxygen level (physiologic and atmospheric) within the dry and humidified incubation conditions. The end point assessment by analyzing the metabolomic signature at different time points revealed no significant extended culture impact using dry or humidified incubation at varying oxygen levels.\n\nSeveral culture media are available commercially for human preimplantation embryo culture. Due to popularity, most of the available media are now designed to support uninterrupted extended culture until day 5 of development. However, one of the concerns with undisturbed extended embryo culture is the degradation of unstable components in the culture medium and their potential adverse effects on the developing embryos. It was found that ammonium is accumulated in the ready-to-use IVF culture media during incubation at 37°C (Kleijkers et al., 2016b), which may have a significant adverse effect on developing embryos. Despite its importance, manufacturers often do not disclose media composition and there is no clear evidence for the ideal formulation of the media used in ART (Tarahomi et al., 2019; Morbeck et al., 2014a,b). Furthermore, there is no conclusive data comparing the stability of media when used in conjunction with non-humidified incubators and low oxygen culture system with humidified incubation at physiological oxygen level.\n\nEarlier, Tarahomi et al., (2019) analyzed the effects of storage and sham culture on 15 ready-to-use culture media and found that sham culture of the analysed media had a significant effect on the concentrations of 13 of the 37 analyzed components (Calcium, Phosphate, Albumin, total amount of Proteins, Tyrosine, Alanine, Methionine, Glycine, Leucine, Asparagine, Arginine, Proline, and Histidine). Though our study also had a similar objective, the use of a sensitivity-enhanced experiments using high frequency (800 MHz) NMR spectrometer facilitated the analysis of spent culture medium metabolites with improved resolution and sensitivity. Further, the cryogenically cooled micro-coil probe (1.7 mm) provided an extreme boost (>10 fold) to sensitivity. The use of this CryoMicroProbeTM enabled fast NMR data acquisition with a more than 200-fold reduction in experiment time. Hence, we believe that this tool is extremely useful for investigating even subtle changes in the levels of metabolites between the experimental groups tested in this study.\n\nThe effect on the culturing pre-implantation human embryos at physiological oxygen level was considered beneficial as it mimics in vivo situation (van Montfoot et al., 2020; Kasterskin et al., 2013; Meintjes et al., 2009; Fischer and Bavister, 1993). However, a recent retrospective study conducted between 2011 and 2013 found that oxygen level during embryo culture does not affect the live birth rate, birth weight, and gestational age (Castillo et al., 2020). This study was limited by its retrospective nature and results were primarily based on sequential media. We believe that our experiments helped compare two commonly employed incubator conditions precisely by keeping other variables comparable. A multivariate exploration of the corresponding metabolites’ integral regions captured across the samples using principal component analysis for the sham cultures across different oxygen levels and incubator types. This approach addressed the association between the metabolites present in the medium and not restricted to the fourteen metabolites identified in this study.\n\nEmbryo culture incubator is one of the critical factors that determine the stability of the culture media a (Simopoulou et al., 2018). Conventional/standard incubator is humidified and provides approximately 20% oxygen level (Castillo et al., 2020). On the other hand, a dry incubator with a controlled oxygen level can change the osmolality of the culture medium possibly through evaporation (Mestres et al., 2021 Mullen, 2021). Though the oil overlay is expected to prevent medium evaporation, osmolality of the oil-overlaid culture medium continued to increase until day 14 during dry incubation. Notably, the embryo quality and pregnancy rate were significantly lower in dry incubators (Fawzy et al., 2017). We have noticed an increase in the level of all the metabolites during 72h dry incubation. However, the differences were not statistically significant. Interestingly no further increase in metabolites was evident on day 5 (120h). Instead, there was a downward trend, which was again not statistically significant. At the moment, it is not possible to explain the reason behind this observation. In contrast, metabolite levels did not change either on day 3 or day 5 in the humidified incubator.\n\nThe limitations of our study are i) use of only one commercially available singe step medium ii) not testing the osmolality of the medium, iii) excluding embryos in the culture and iv) not having humidified incubation group for low oxygen group as an incubator with this specification was not available in the present set up. Hence, it is not possible to confirm the exclusive impact of oxygen tension on the metabolites.\n\n\nConclusion\n\nThis study demonstrated only a non-significant variation in the metabolites across the dry and humidified incubation systems using the NMR approach. Hence, the slight changes are unlikely to have any negative influence on embryological and clinical outcomes. Extensive studies are required to understand the impact of these subtle changes on the genetic and epigenetic integrity of the embryos in the clinical setup.\n\n\nData availability\n\nOpen Science Framework: Duration of dry and humidified incubation of single-step embryo culture medium and oxygen tension during sham culture do not alter metabolomics signature. https://doi.org/10.17605/OSF.IO/RCNZD (Cheredath et al., 2022).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgements\n\nThis study is dedicated to the memory of our late colleague, NMR scientist Prof. Hanudatta S. Atreya. The NMR facilities provided by Indian Institute of Science is gratefully acknowledged.\n\n\nReferences\n\nCastillo CM, Harper J, Roberts SA, et al.: The impact of selected embryo culture conditions on ART treatment cycle outcomes: a UK national study. Hum. Reprod. Open. 2020; 2020(1): hoz031. PubMed Abstract | Publisher Full Text\n\nCheredath A, Uppangala S, Asampille G, et al.: Duration of dry and humidified incubation of single-step embryo culture medium and oxygen tension during sham culture do not alter metabolomics signature.2022, February 16. Publisher Full Text\n\nDumoulin JC, Land JA, Van Montfoort A, et al.: Effect of in vitro culture of human embryos on birthweight of newborns. Hum. Reprod. 2010; 25(3): 605–612. Publisher Full Text\n\nFawzy M, AbdelRahman MY, Zidan MH, et al.: Humid versus dry incubator: a prospective, randomized, controlled trial. Fertil. Steril. 2017; 108(2): 277–283. PubMed Abstract | Publisher Full Text\n\nFischer B, Bavister BD: Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits. J. Reprod. Fertil. 1993; 99(2): 673–679. PubMed Abstract | Publisher Full Text\n\nKasterstein E, Strassburger D, Komarovsky D, et al.: The effect of two distinct levels of oxygen concentration on embryo development in a sibling oocyte study. J. Assist. Reprod. Genet. 2013; 30(8): 1073–1079. PubMed Abstract | Publisher Full Text\n\nKleijkers SH, Mantikou E, Slappendel E, et al.: Influence of embryo culture medium (G5 and HTF) on pregnancy and perinatal outcome after IVF: a multicenter RCT. Hum. Reprod. 2016a; 31(10): 2219–2230. PubMed Abstract | Publisher Full Text\n\nKleijkers SH, van Montfoort AP , Bekers O, et al.: Ammonium accumulation in commercially available embryo culture media and protein supplements during storage at 2-8°C and during incubation at 37°C. Hum. Reprod. 2016b; 31(10): 1192–1199. Publisher Full Text\n\nMeintjes M, Chantilis SJ, Douglas JD, et al.: A controlled randomized trial evaluating the effect of lowered incubator oxygen tension on live births in a predominantly blastocyst transfer program. Hum. Reprod. 2009; 24(2): 300–307. Publisher Full Text\n\nMestres E, García-Jiménez M, Casals A, et al.: Factors of the human embryo culture system that may affect media evaporation and osmolality. Hum. Reprod. 2021; 36(3): 605–613. PubMed Abstract | Publisher Full Text\n\nMorbeck DE, Krisher RL, Herrick JR, et al.: Composition of commercial media used for human embryo culture. Fertil. Steril. 2014a; 102(3): 759–766.e9. PubMed Abstract | Publisher Full Text\n\nMorbeck DE, Paczkowski M, Fredrickson JR, et al.: Composition of protein supplements used for human embryo culture. J. Assist. Reprod. Genet. 2014b; 31(12): 1703–1711. PubMed Abstract | Publisher Full Text\n\nMullen SF: Toward a predictive theoretical model for osmolality rise with non-humidified incubation: a randomized, multivariate response-surface study. Hum. Reprod. 2021; 36(5): 1230–1241. PubMed Abstract | Publisher Full Text\n\nNelissen EC, Van Montfoort AP, Coonen E, et al.: Further evidence that culture media affect perinatal outcome: findings after transfer of fresh and cryopreserved embryos. Hum. Reprod. 2012; 27(7): 1966–1976. PubMed Abstract | Publisher Full Text\n\nSimopoulou M, Sfakianoudis K, Rapani A, et al.: Considerations Regarding Embryo Culture Conditions: From Media to Epigenetics. In Vivo. 2018; 32(3): 451–460. PubMed Abstract | Publisher Full Text\n\nSunde A, Brison D, Dumoulin J, et al.: Time to take human embryo culture seriously. Hum. Reprod. 2016; 31(10): 2174–2182. PubMed Abstract | Publisher Full Text\n\nSwain JE, Carrell D, Cobo A, et al.: Optimizing the culture environment and embryo manipulation to help maintain embryo developmental potential. Fertil. Steril. 2016; 105(3): 571–587. PubMed Abstract | Publisher Full Text\n\nTarahomi M, de Melker AA , van Wely M , et al.: pH stability of human preimplantation embryo culture media: effects of culture and batches. Reprod. Biomed. Online. 2018; 37(4): 409–414. PubMed Abstract | Publisher Full Text\n\nTarahomi M, Vaz FM, van Straalen JP , et al.: The composition of human preimplantation embryo culture media and their stability during storage and culture. Hum. Reprod. 2019; 34(8): 1450–1461. PubMed Abstract | Publisher Full Text\n\nVan Montfoort APA, Arts EGJM, Wijnandts L, et al.: Reduced oxygen concentration during human IVF culture improves embryo utilization and cumulative pregnancy rates per cycle. Hum. Reprod. Open. 2020; 2020(1): hoz036. PubMed Abstract | Publisher Full Text\n\nWickham H: ggplot2. Elegant Graphics for Data Analysis. 2nd ed.New York; 2016.\n\nYumoto K, Iwata K, Sugishima M, et al.: Unstable osmolality of microdrops cultured in non-humidified incubators. J. Assist. Reprod. Genet. 2019; 36(8): 1571–1577. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "126045",
"date": "18 Mar 2022",
"name": "Erode N. Prabhakaran",
"expertise": [
"Reviewer Expertise Chemical Biology",
"Transcription engineering",
"Weak interactions in Proteins",
"Protein egineering."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSince extended embryo culture using single-step medium is now quite popularly applied in clinical in-vitro fertilization, it is important to test this commercially available single-step media for stability and for changes in metabolite profiles with variations in conditions. The authors have used dry and humidified-incubation in two different gaseous conditions to test the time-dependent variations in 10 amino acids and four energy substrate metabolite signals. They have chosen to analyze this variation through high-sensitive 1.7 mm cryoprobe in 800 MHz NMR spectral analyses.\nThe experiments are well-designed with a single medium – the single-step embryo culture – which is commercially available but is extensively in use. Appropriate sham-cultures were used along with the sample cultures, a sufficient number of times, to validate the data for reliability and reproducibility. In general, they observe no significant differences in metabolite levels upon change of conditions from dry to humidified incubation over 72 h. Interestingly, they notice a decline of the metabolite levels at 120 h – although the extent of variations are non-significant. These results have prompted them to infer that both of these two conditions should be similar in influencing the clinical outcome. This and such studies are important and essential, since embryo cultures need to accurately mimic in vivo environments of preimplantation embryo, and since they strongly influence subsequent fetal health and growth. I commend this work and suggest that further studies in similar lines be done to explore the influence of other conditions on the efficiencies of these crucial culture media.\nAs an advancement to such studies, the results may be compared between sets of media that have clinical records in influencing the growth of both healthy embryos and embryos with unhealthy aberrations.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "129570",
"date": "22 Apr 2022",
"name": "Borut Kovačič",
"expertise": [
"Reviewer Expertise Reproductive medicine",
"assisted reproductive techniques",
"biology of reproductive cells and embryos",
"embryo culture conditions"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIs the work clearly and accurately presented and does it cite the current literature?\nThe authors investigated the effect of dry and humid atmosphere and 5% and 20% oxygen concentrations in incubators on the changes of the composition of sham human embryo culture media. A high frequency (800 MHz) NMR spectrometer was used to analyse the changes in the concentrations of specific media components after 72 and 120 h incubation. The results did not show significant differences in the concentration of some media components after prolonged culturing at different incubation conditions. The work is well presented and relevant literature was cited.\n\nIs the study design appropriate and does the work have academic merit?\nThe study is original and interesting for reproductive biologists, but some potential factors of methodological origin that could have influenced the results should be commented on, particularly in the discussion.\n\nAre sufficient details of methods and analysis provided to allow replication by others?\nIt would be useful to explain what is meant by a dry and a humid atmosphere. Please describe how a humid atmosphere is achieved in the incubator.\nIt is important to mention the role of the oil used to prevent evaporation of the culture media. It should be mentioned in the Discussion that differences in the amount of overlayed oil can affect the results (osmolality of the medium and stability of the medium components). Was this taken into consideration during the study? Control measurements of the osmolality of the medium would be useful, and the authors mention this shortcoming in the limitations of the study.\nIn the literature it has also been shown that the components of a medium from the same batch can vary depending on the time from production to use. Have you taken this finding into account? If not, please mention the possibility of this effect in the discussion by using the relevant citation.\nWas triplicate sampling done from the same droplet or from different droplets / dishes?\nAs oil contamination is one of the main problems in the analysis of culture media components, the sampling method must be described in detail and it must be explained how oil contamination has been prevented.\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nThe main finding of this research was described as: »The level of all the identified metabolites found to be increasing on day 3 (72 h) started declining thereafter in a dry atmospere group«. Such a result is unexpected and the authors must try to find possible explanations. If they cannot confirm them with the results of other published studies, they should be self-critical enough to try to find possible reasons arising from possible methodological variations. Some suggestions have been given above.\nBy averaging the concentrations of the individual components of the medium, it was possible to mask the possible influence of unknown factors arising from technical details or from differently aged culture media of the same batch. Wouldn't it make sense to do a matched pairs sampling and relevant statistical analysis in such studies? It would be useful to present this option in the discussion and to provide a warning to the authors of future similar studies.\n\nAre all the source data underlying the results available to ensure full reproducibility?\nThe tables shown contain all the relevant numerical data.\n\nAre the conclusions drawn adequately supported by the results?\nThe conclusion should focus on the results obtained from the analysis rather than on possible clinical outcomes that were not the subject of the study. I suggest the following correction to the conclusion:\nNo significant differences in the concentrations of the selected culture media components after 120 hours of incubation were observed between dry and humidified atmosphere, nor between 5% and 20% oxygen concentration in the incubators. Only a very mild trend of increasing concentrations after 72 hours and then decreasing after 120 hours in dry incubators was observed, which could also be attributed to certain methodological reasons described in the discussion.\nMinor point\nMetabolites are the products of metabolism. It would be better to use the term 'medium constituents or components' instead of 'medium metabolites'. Please correct this throughout the text. The term 'metabolomic signature' should also be replaced by a more appropriate term.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8202",
"date": "13 May 2022",
"name": "Satish Adiga",
"role": "Author Response",
"response": "We thank reviewer for his constructive comments. What is meant by a dry and a humid atmosphere? Please describe how a humid atmosphere is achieved in the incubator. Dry incubation contained moisture free environment whereas the humid atmosphere was attained by supplying the water (~2.5 litres) at the bottom of the incubator. This information has been added in the methodology section of the revised manuscript. It is important to mention the role of the oil used to prevent evaporation of the culture media. It should be mentioned in the Discussion that differences in the amount of overlayed oil can affect the results (osmolality of the medium and stability of the medium components). Was this taken into consideration during the study? Control measurements of the osmolality of the medium would be useful, and the authors mention this shortcoming in the limitations of the study. We do agree with the reviewer’s point of view. Oil overlay plays an important role in preventing the medium evaporation and maintaining the osmolality of the medium. In addition, a recent theoretical model has predicted that oil density and oil thickness above the embryo culture medium along with surface area to volume ratio can significantly contribute towards rise in osmolality of the medium during dry incubation conditions (Mullen et al., 2021). We have taken precaution to maintain a constant volume of oil (3mL) throughout the study to overlay the medium. In addition, oil from the same batch was used for both the sets of experiments. We have now discussed these issues in the revised manuscript. However, the osmolality of the medium was not measured which is now stated as a limitation. In the literature it has also been shown that the components of a medium from the same batch can vary depending on the time from production to use. Have you taken this finding into account? If not, please mention the possibility of this effect in the discussion by using the relevant citation Yes. We do agree that storage can have significant effect on the medium components as discussed in the manuscript (Tarahomi et al., 2019). However, study could not maintain the uniform time gap between the date of manufacture and usage as the manufacture date was not available. As per the manufacturer’s specifications, medium should be used within 7 days after opening the bottle which was strictly followed in our experiments. Since we did not find differences in the metabolites tested, this aspect was not elaborated in the discussion. However, new version has these points. Was triplicate sampling was done from the same droplet or from different droplets / dishes? Triplicate sampling was done from the different droplets placed in a same dish during each trial. As oil contamination is one of the main problems in the analysis of culture media components, the sampling method must be described in detail and it must be explained how oil contamination has been prevented. We do agree that the oil contamination is one of the main concerns which can interfere in the NMR analysis of culture media. To minimise the oil contamination, we have collected only 25µL of medium from the 30µL culture medium droplet from the culture dish. Further, pipette was inserted to the base of the culture dish after pressing the pipette plunger and once 25 µL was aspirated, pipette was dislodged from the base of the dish. Any slight oil contamination can be seen as separate layer or droplet within the medium since they are immiscible. Such samples were not used in our study. Oil contamination can cause difficulty in shimming the sample while performing NMR profiling which was not experienced by us during NMR profiling. If applicable, is the statistical analysis and its interpretation appropriate? The main finding of this research was described as: »The level of all the identified metabolites found to be increasing on day 3 (72 h) started declining thereafter in a dry atmosphere group«. Such a result is unexpected and the authors must try to find possible explanations. If they cannot confirm them with the results of other published studies, they should be self-critical enough to try to find possible reasons arising from possible methodological variations. Some suggestions have been given above. By averaging the concentrations of the individual components of the medium, it was possible to mask the possible influence of unknown factors arising from technical details or from differently aged culture media of the same batch. Wouldn't it make sense to do a matched pairs sampling and relevant statistical analysis in such studies? It would be useful to present this option in the discussion and to provide a warning to the authors of future similar studies. The trend observed in our study is unique and unfortunately there is no evidence/published reports that can explain the possible reason for the trend. Although, we have taken the average of each metabolite, it was not possible to ignore the influence of external factors that affected our analysis as stated by the reviewer. The primary objective in this study was to test whether there are any statistically significant differences in the average values of the metabolite levels across three time points (0 hr, 72 hr and 120 hr) and two groups. Since the study included three time points, paired sample t-tests based approach is not appropriate. Whereas, the repeated-measures ANOVA approach used here is a natural extension to the paired samples approach to incorporate multiple time points across two or more groups."
}
]
}
] | 1
|
https://f1000research.com/articles/11-242
|
https://f1000research.com/articles/10-1114/v1
|
04 Nov 21
|
{
"type": "Research Article",
"title": "Evaluation of electrocardiogram: numerical vs. image data for emotion recognition system",
"authors": [
"Sharifah Noor Masidayu Sayed Ismail",
"Nor Azlina Ab. Aziz",
"Siti Zainab Ibrahim",
"Sophan Wahyudi Nawawi",
"Salem Alelyani",
"Mohamed Mohana",
"Lee Chia Chun",
"Sophan Wahyudi Nawawi",
"Salem Alelyani",
"Mohamed Mohana",
"Lee Chia Chun"
],
"abstract": "Background: The electrocardiogram (ECG) is a physiological signal used to diagnose and monitor cardiovascular disease, usually using ECG wave images. Numerous studies have proven that ECG can be used to detect human emotions using numerical data; however, ECG is typically captured as a wave image rather than as a numerical data. There is still no consensus on the effect of the ECG input format (either as an image or a numerical value) on the accuracy of the emotion recognition system (ERS). The ERS using ECG images is still inadequately studied. Therefore, this study compared ERS performance using ECG image and ECG numerical data to determine the effect of the ECG input format on the ERS. Methods: This study employed the DREAMER dataset, which contains 23 ECG recordings obtained during audio-visual emotional elicitation. Numerical data was converted to ECG images for the comparison. Numerous approaches were used to obtain ECG features. The Augsburg BioSignal Toolbox (AUBT) and the Toolbox for Emotional feature extraction from Physiological signals (TEAP) extracted features from numerical data. Meanwhile, features were extracted from image data using Oriented FAST and rotated BRIEF (ORB), Scale Invariant Feature Transform (SIFT), KAZE, Accelerated-KAZE (AKAZE), Binary Robust Invariant Scalable Keypoints (BRISK), and Histogram of Oriented Gradients (HOG). Dimension reduction was accomplished using linear discriminant analysis (LDA), and valence and arousal were classified using the Support Vector Machine (SVM). Results: The experimental results indicated that numerical data achieved arousal and valence accuracy of 69% and 79%, respectively, which was greater than those of image data. For ECG images, the highest accuracy for arousal was 58% percent; meanwhile, the valence was 63%. Conclusions: The finding showed that numerical data provided better accuracy for ERS. However, ECG image data which shows positive potential and can be considered as an input modality for the ERS.",
"keywords": [
"Emotion recognition",
"electrocardiogram",
"numerical ECG",
"image ECG",
"DREAMER"
],
"content": "Introduction\n\nMedical professionals have been actively using electrocardiogram (ECG) wave images as a tool for monitoring1,2 and diagnosing3–6 cardiovascular diseases, such as heart attacks, dysrhythmia, and pericarditis, with some reported accuracy of more than 99% in the past decade. Besides monitoring and diagnosing health-related diseases, many studies have proven that human emotions can also be identified using ECG in the form of numerical data.7–10\n\nThe effects of using different types of ECG inputs to recognise emotions by the emotion recognition system (ERS) have yet to be closely studied. In addition, there is no consensus on whether or not the type of ECG input format affects the emotion classification accuracy by the ERS. Most researchers have focused on recognising emotions using ECG numerical data instead of using EGC wave images. To date, research on the use of ECG wave images in identifying emotions is still absent. Therefore, to address this gap, the objective of this study is to compare emotion classification performance using ECG image and ECG numerical data to determine the effect of the ECG input format on the ERS.\n\nEmotions can be seen in two different models put forward by Paul Ekman11 and James Russell,12 namely, the discrete emotion and dimensional emotion models. Ekman, a psychologist, suggested six basic emotions: happiness, sadness, anger, fear, disgust, and surprise. On the other hand, Russell presented a two-dimensional scale of emotions consisting of valence and arousal (Figure 1). Valence refers to positive or negative feelings, and arousal indicates the intensity of the feeling, either high or low. This study used the latter emotion model to classify the subject’s emotions, because 1) the work presented in13 used the same emotion model; hence, allowing benchmarking of the performance, and 2) simplicity of binary classification.\n\nAn electrocardiogram is used to measure electrical activity in the human heart by attaching electrodes to the human body. The standard is a 12-lead ECG system. However, today ECG devices have evolved from bulky nonportable devices to wearable portable devices. The accuracy of the signal by portable devices is comparable to conventional medical devices. This suggests that researchers can use wearable ECG devices for purposes similar to conventional devices, including for studying human emotions. However, most of these devices store the ECG as images instead of raw numerical data.\n\nThe ECG signals have P, Q, R, S, and T waves (Figure 2). Emotional states are associated with autonomic nervous system's (ANS) physiological responses.15 Different emotions influence human heart activities differently; these influences may be hidden in the ECG wave.16 These responses can be detected through ECG by monitoring the main features of ECG, namely, heart rate (HR) and heart rate variability (HRV).\n\nThis study used ECG numerical data obtained from the multimodal database called the DREAMER dataset.13 In the dataset, electroencephalogram (EEG) and ECG signals were recorded from 23 participants during an emotion elicitation session. The emotions were elicited by using 18 audio-visual stimulations. Valence and arousal emotion model was used to classify the elicited emotions. This paper only focuses on the use of ECG. We employed the Augsburg BioSignal Toolbox (AUBT)18 and the Toolbox for Emotional feature extraction from Physiological signals (TEAP)19 to facilitate feature extraction from the ECG numerical data. Then, linear discriminant analysis (LDA) was applied to reduce the dimension of the extracted ECG numerical features.\n\nSince the DREAMER dataset only has numerical data, the data must be converted into the corresponding ECG wave images for comparison purposes. Six different feature extractors, namely, Oriented FAST and rotated BRIEF (ORB), Scale Invariant Feature Transform (SIFT), KAZE, Accelerated-KAZE (AKAZE), Binary Robust Invariant Scalable Keypoints (BRISK), and Histogram of Oriented Gradients (HOG), were applied to the ECG wave images to detect and extract features. The Support Vector Machine (SVM) was used to classify the valence and arousal of both ECG numerical features and ECG image features.\n\nIn the following section, an overview of related works on the ERS is presented. We then describe the selected dataset and explain the proposed methods in detail. This is followed by the results and a discussion and conclusions section.\n\n\nRelated works\n\nResearchers in the emotion recognition field have been proposing multiple approaches using electrocardiogram signals. For instance, Minhad, Ali, and Reaz20 used ECG numerical data to classify emotions of happiness and anger. They achieved 83.33% accuracy using the SVM classification method. Besides, Tivatansakul and Ohkura21 used ECG numerical data from the AUBT dataset to detect emotions for the emotional healthcare system. K-Nearest Neighbour (KNN) successfully classified three emotions (joy, anger, and sadness) with an accuracy 85.75%, 82.75%, and 95.25%, respectively.\n\nKatsigiannis and Ramzan suggested that ERS should use low-cost and off-the-shelf devices to collect ECG signals based on numerical format.13 AUBT and Biosig Toolbox were used to extract the signal features. Classification using SVM with a radial basis function kernel successfully achieved 62.37% for valence and arousal. The MPED database for ERS was proposed by Song et al.22 using ECG numerical data to recognise discrete emotions (joy, humour, disgust, anger, fear, sadness, and neutrality). Attention Long Short-Term Memory (A-LSTM) was used as a feature extractor to extract the frequency and time-domain features from the physiological signal. The A-LSTM was used as a classifier along with SVM, KNN, and Long Short-Term Memory (LSTM). Averagely, A-LSTM achieved better results of 40% to 55% compared to those of other classifiers.\n\nJust as with the widespread use of numerical ECG in human emotion studies, ECG images are also widely used to identify cardiovascular-related diseases. For example, Hao et al.23 used ECG images to detect and classify myocardial infarction (MI). MI is a disease caused by severe cardiovascular obstruction that leads to irreversible injury or even death. KNN and SVM were used in this study and achieved 89.84% and 92.19%, respectively. Besides, Mandal, Mondal, and Roy24 used ECG images to detect ventricular arrhythmia (VA), such as ventricular tachycardia (VT) and ventricular fibrillation (VF) in infants and children. SVM, KNN, and random forest (RF) were used in this study and successfully achieved 93.11%, 92.56%, and 95.36%, respectively.\n\nAlthough much research has been conducted using ECG for ERS, most of them focused mainly on numerical data analysis instead of ECG wave images. However, systems based on ECG images have achieved excellent results in detecting cardiovascular-related diseases. As mentioned before, it remains uncertain whether the ECG input format, numerical value or wave image, affects the emotional classification accuracy in the ERS. Therefore, it is essential to explore the ERS using different input formats of ECG to address this knowledge gap.\n\n\nMethods\n\nThe proposed method consists of three stages: feature extraction, feature dimension reduction, and emotion classification. The data of the present study were obtained in the experiment described in the original study.13 The current study began in September 2020. Matlab version 9.7 was utilized for data conversion and feature extraction, whereas Python version 3.8.5 was used for feature dimension reduction (numerical) and classification. The overall structure of the proposed method is illustrated in Figure 3. The analysis code used in this study is available from GitHub and archived with Zenodo.41\n\nWe built our ERS on a publicly accessible database consisting of ECG signals recorded from 23 participants during emotion elicitation by audio-visual stimuli. The ECG was recorded using the SHIMMER ECG sensor at 256 Hz. Nine emotions: calmness, surprise, amusement, fear, excitement, disgust, happiness, anger, and sadness were elicited using 18 video excerpts.\n\nThe total data amount is 414 data (23 subjects x 18 videos). As previously mentioned, this work is only interested in ECG signals; hence, EEG signals are not included in this study. Additionally, we did not use the dominance rating score, since Russell’s two-dimensional emotional model is adapted here to classify emotions. The summary of the DREAMER dataset is tabulated in Table 1.\n\n1) ECG wave image\n\nThe ECG numerical data was converted into ECG wave images preceding the analysis of ECG wave images using MATLAB version 9.7 (Figure 4). Using Python version 3.8.5, the converted ECG images were then resized to 60% of the original size to reduce the computational time. After resizing, the coloured images were converted into greyscale images. Then, binarization of the image using a threshold was done. Automatic image thresholding, Otsu’s method,25 was used here. Otsu’s method ascertains the optimal threshold values from pixel values of 0 to 255 by calculating and evaluating their within-class variance. This method provides the best performance, as stated in.26\n\nIn total, six different feature extractors were applied to extract features from processed ECG images. The feature extractors are as follows: ORB,27 SIFT,28 KAZE,29 AKAZE,30 BRISK,31 and HOG.32 All of them successfully extracted the ECG features, including the peaks, edges, and corners. However, some feature extractors, such as ORB and SIFT, failed to detect important features, particularly the R-peaks, due to the presence of mass noise,33 which is believed to have affected emotional classification (Figure 5). The extracted images were then given to the classifier (SVM) to classify valence and arousal. This whole process of feature extraction and classification was done using Python version 3.8.5.\n\nNumerical ECG data did not go through any pre-processing process as suggested in13 due to being less susceptible to interference owing to their higher voltage amplitudes. Two open-source toolboxes, namely, Augsburg BioSignal Toolbox (AUBT)18 and Toolbox for Emotional feature extraction from Physiological signals (TEAP),19 were employed to facilitate feature extraction from the ECG signals. Both of them successfully extracted 81 features (Table 2) and 16 features (Table 3) from the ECG signals. The extracted features included heart rate variability (HRV), inter-beat interval (IBI), tachogram power, and statistical features such as mean, median, and standard deviation. The dimension of the features was reduced using linear discriminant analysis, one of the well-known feature reduction methods.34 This process was performed to reduce the computational cost and to improve the separation of emotion classes.35 The extracted features were then given to the classifier (SVM) to classify valence and arousal.\n\nClassification was performed using SVM. The SVM works by separating the class data points and drawing a boundary called the hyperplane between them. Additionally, SVM has a low computational cost and shows excellent performance in classifying emotions, as reported in previous studies.13,36,37 The data was then divided into training and test sets with a ratio of 80:20. The parameters for SVM were tuned using GridSearchCV.38 As we had a small data size, we used 10-fold cross-validation to improve ERS performance. The emotions were determined as follows: high/low valence and high/low arousal, based on the participants’ self-assessment rating.\n\n\nResults\n\nThe experimental results for numerical data showed that the accuracy of arousal achieved using the TEAP feature extractor (69%) was higher than that of the AUBT feature (64%). However, the TEAP feature managed to obtain 67% valence accuracy, while the AUBT feature recorded up to 79%. These results are better than what were recorded in Ref. 11.\n\nThe classification results using ECG wave images recorded an arousal accuracy of 53% to 58%. The highest result was achieved by the SIFT feature, followed by ORB, HOG, KAZE, BRISK, and the AKAZE features. Meanwhile, the highest accuracy for valence was attained by the KAZE feature with 63%, followed by HOG, BRISK, AKAZE, SIFT, and lastly, ORB with 48%, the lowest among other features. The results of this study are presented in Table 4.\n\n* Accuracy of DREAMER reported in the original paper.\n\n\nDiscussion & conclusions\n\nFindings showed that numerical data provided better accuracy for ERS compared to ECG images. In addition, numerical data was easier to handle and process compared to image data. Moreover, the results obtained here using ECG numerical data were even better than those reported by DREAMER.13 This is contributed by the additional processes in our proposed method, the feature reduction using LDA, which was not included in the DREAMER paper. LDA plays an essential role in improving the performance of the emotion recognition system.35,39 On top of that, it is worth noting that the results obtained using ECG image data also showed positive potential and could be considered as an input modality for the ERS. The features extracted by KAZE provided 63% accuracy for valence, which is better than the original work in Ref. 11. Hence, ECG images are recommended for building ERS. ECG images are attractive as the format allows usage of many image-based methods such as image augmentation to increase the data size, the convolution neural networks (CNN), and application of transfer learning from models trained using large data.\n\nHowever, some limitations were found throughout the study and needed to be addressed to achieve better emotion classification results. The first limitation is, as per suggestion by the DREAMER paper, we did not run the pre-process process to the signal leading to the presence of noise in the signal, both ECG data format, which have affected emotion classification, especially for image data. Therefore, the use of filtering and noise reduction in the pre-processing stage should be considered. The second limitation is the data size, which is too small for image learning and classification, leading to lower accuracy.40 In the future, with a larger data size, researchers can consider deep learning techniques for emotion classification using ECG images as a primary modality.\n\nTo conclude, ECG numerical data provided a better performance of emotion classification. In addition, ECG image data that shows positive potential, thus it can be considered an input modality for the ERS in future studies.\n\n\nData availability\n\nThe DREAMER dataset was first presented here: https://doi.org/10.1109/JBHI.2017.2688239 and can be found on Zenodo. Access is restricted and users are required to apply. The decision whether to grant/deny access is solely under the responsibility of the record owner.\n\nAnalysis code available from: https://github.com/nr-isml/ECG-Numerical-Vs.-Image-Data-for-Emotion-Recognition-System\n\nArchived analysis code as at time of publication: https://doi.org/10.5281/zenodo.5542739.41\n\nLicense: Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgements\n\nThe authors would like to thank those who were involved in this experiment, either directly or indirectly.\n\n\nReferences\n\nMena LJ, et al.: Mobile Personal Health Monitoring for Automated Classification of Electrocardiogram Signals in Elderly. Comput. Math. Methods Med. 2018; 2018(Figure 1): 1–9.\n\nWang YH, Chung CG, Lin CC, et al.: The Study of the Electrocardiography Monitoring for the Elderly Based on Smart Clothes. 8th Int. Conf. Inf. Sci. Technol. 2018; pp. 478–482.\n\nUllah A, Anwar SM, Bilal M, et al.: Classification of arrhythmia by using deep learning with 2-D ECG spectral image representation. Remote Sens. 2020; 12(10): 1–14. Publisher Full Text .\n\nTayel MB, El-Bouridy ME: ECG images classification using artificial neural network based on several feature extraction methods. 2008 Int. Conf. Comput. Eng. Syst. ICCES 2008. 2008; pp. 113–115.\n\nMohamed B, Issam A, Mohamed A, et al.: ECG Image Classification in Real time based on the Haar-like Features and Artificial Neural Networks. Procedia Comput. Sci. 2015; 73(Awict): 32–39. Publisher Full Text\n\nWang F, Syeda-Mahmood T, Beymer D: Finding disease similarity by combining ECG with heart auscultation sound. Comput. Cardiol. 2007; 34: 261–264.\n\nSoleymani M, Lichtenauer J, Pun T, et al.: A multimodal database for affect recognition and implicit tagging. IEEE Trans. Affect. Comput. 2012; 3(1): 42–55. Publisher Full Text\n\nAbadi MK, Subramanian R, Kia SM, et al.: DECAF: MEG-Based Multimodal Database for Decoding Affective Physiological Responses. IEEE Trans. Affect. Comput. 2015; 6(3): 209–222. Publisher Full Text\n\nSubramanian R, Wache J, Abadi MK, et al.: ASCERTAIN: Emotion and personality recognition using commercial sensors. IEEE Trans. Affect. Comput. 2018; 9(2): 147–160. Publisher Full Text\n\nSiddharth S, Jung T-P, Sejnowski TJ: Utilizing Deep Learning Towards Multi-modal Bio-sensing and Vision-based Affective Computing. IEEE Trans. Affect. Comput. 2019; 1–1. Publisher Full Text\n\nEkman P: Cognition & Emotion An argument for basic emotions An Argument for Basic Emotions. COGNlTfON Emot. 1992; 6(May 2013): 169–200. Publisher Full Text\n\nRussell JA: A circumplex model of affect. J. Pers. Soc. Psychol. 1980; 39(6): 1161–1178. Publisher Full Text\n\nKatsigiannis S, Ramzan N: DREAMER: A Database for Emotion Recognition Through EEG and ECG Signals from Wireless Low-cost Off-the-Shelf Devices. IEEE J. Biomed. Heal. Informatics. . 2018; 22(1): 98–107. PubMed Abstract | Publisher Full Text\n\nYu LC, et al.: Building Chinese affective resources in valence-arousal dimensions. 2016 Conf. North Am. Chapter Assoc. Comput. Linguist. Hum. Lang. Technol. NAACL HLT 2016 - Proc. Conf. 2016; (no. June): pp. 540–545.\n\nBota PJ, Wang C, Fred ALN, et al.: A Review, Current Challenges, and Future Possibilities on Emotion Recognition Using Machine Learning and Physiological Signals. IEEE Access. 2019; 7: 140990–141020. Publisher Full Text\n\nWen WH, Qiu YH, Liu GY: Electrocardiography recording, feature extraction and classification for emotion recognition. 2009 WRI World Congr. Comput. Sci. Inf. Eng. CSIE 2009. 2009; vol. 4: pp. 168–172.\n\nC. U. First Faculty of Medicine: Electrocardiogram - WikiLectures.2018. [Accessed: 04-Oct-2021]. Reference Source\n\nWagner J: Augsburg biosignal toolbox (aubt). Univ. Augsbg; 2014.\n\nSoleymani M, Villaro-Dixon F, Pun T, et al.: Toolbox for Emotional feAture extraction from Physiological signals (TEAP). Front. ICT. 2017; 4(FEB): 1–7. Publisher Full Text\n\nMinhad KN, Ali SHM, Reaz MBI: Happy-anger emotions classifications from electrocardiogram signal for automobile driving safety and awareness. J. Transp. Heal. 2017; 7(November): 75–89.\n\nTivatansakul S, Ohkura M: Emotion Recognition using ECG Signals with Local Pattern Description Methods. Int. J. Affect. Eng. 2015; 15(2): 51–61. Publisher Full Text\n\nSong T, Zheng W, Lu C, et al.: MPED: A multi-modal physiological emotion database for discrete emotion recognition. IEEE Access. 2019; 7(October): 12177–12191. Publisher Full Text\n\nHao P, Gao X, Li Z, et al.: Multi-branch fusion network for Myocardial infarction screening from 12-lead ECG images. Comput. Methods Programs Biomed. 2020; 184: 105286.\n\nMandal S, Mondal P, Roy AH: Detection of Ventricular Arrhythmia by using Heart rate variability signal and ECG beat image. Biomed. Signal Process. Control. 2021; 68(May): 102692. Publisher Full Text\n\nOtsu N: A Threshold Selection Method from Gray-Level Histograms. IEEE Trans. Syst. Man Cybern. 1979; 9(1): 62–66. Publisher Full Text\n\nTrier OD, Taxt T: Evaluation of Binarization Methods for Document Images. IEEE Trans. Pattern Anal. Mach. Intell. 1995; 17(3): 312–315. Publisher Full Text\n\nRublee E, Rabaud V, Konolige K, et al.: ORB: An efficient alternative to SIFT or SURF. Proc. IEEE Int. Conf. Comput. Vis. 2011; (May): 2564–2571.\n\nShi Y, Lv Z, Bi N, et al.: An improved SIFT algorithm for robust emotion recognition under various face poses and illuminations. Neural Comput. Appl. 2020; 32(13): 9267–9281. Publisher Full Text\n\nAlcantarilla PF, Bartoli A, Davison AJ: KAZE features. Lect. Notes Comput. Sci. (including Subser. Lect. Notes Artif. Intell. Lect. Notes Bioinformatics). 2012; vol. 7577 LNCS(no. PART 6): pp. 214–227.\n\nTareen SAK, Saleem Z: A comparative analysis of SIFT, SURF, KAZE, AKAZE, ORB, and BRISK. 2018 Int. Conf. Comput. Math. Eng. Technol. Inven. Innov. Integr. Socioecon. Dev. iCoMET 2018 - Proc. 2018; vol. 2018-Janua: pp. 1–10.\n\nLiu Y, Zhang H, Guo H, et al.: A FAST-BRISK feature detector with depth information. Sensors (Switzerland). 2018; 18(11). Publisher Full Text\n\nRathikarani V, Dhanalakshmi P, Vijayakumar K: Automatic ECG Image Classification Using HOG and RPC Features by Template Matching.2016; pp. 117–125.\n\nMa Y, Wang Z, Wu C: Feature extraction from noisy image using PCNN. Proc. IEEE ICIA 2006-2006 IEEE Int. Conf. Inf. Acquis. 2006; (no. September): pp. 808–813.\n\nValenzi S, Islam T, Jurica P, et al.: Individual Classification of Emotions Using EEG. J. Biomed. Sci. Eng. 2014; 07(08): 604–620. Publisher Full Text\n\nVelliangiri S, Alagumuthukrishnan S, Thankumar Joseph SI: A Review of Dimensionality Reduction Techniques for Efficient Computation. Procedia Comput. Sci. 2019; 165: 104–111. Publisher Full Text\n\nBulagang AF, Weng NG, Mountstephens J, et al.: A review of recent approaches for emotion classification using electrocardiography and electrodermography signals. Informatics Med. Unlocked. 2020; 20: 100363. Publisher Full Text\n\nZhai J, Barreto A: Stress detection in computer users based on digital signal processing of noninvasive physiological variables. Annu. Int. Conf. IEEE Eng. Med. Biol. - Proc. 2006; (no. May): pp. 1355–1358.\n\nPedregosa F, Varoquaux G, Gramfort A, et al.: Scikit-learn: Machine Learning in Python. J. Machine Learn. Res. 2011; 12: 2825–2830.\n\nHaq S, Jackson P: Multimodal emotion recognition. In: Machine audition: principles, algorithms and systems. Multimodal Emot. Recognit. 2010.\n\nMitsa T: How Do You Know You Have Enough Training Data?. Towards Data Science. 2019. [Accessed: 07-Jun-2021]. Reference Source\n\nnr-isml: nr-isml/ECG-Numerical-Vs.-Image-Data-for-Emotion-Recognition-System: First release (ECG). Zenodo. 2021.Publisher Full Text"
}
|
[
{
"id": "121060",
"date": "21 Feb 2022",
"name": "Umesh Chandra Pati",
"expertise": [
"Reviewer Expertise Computer Vision",
"Image/Video Processing",
"IoT",
"Artificial Intelligence."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper presents a comparison of the Emotion Recognition System (ERS) performance using ECG image and ECG numerical data. DREAMER dataset containing 23 ECG recordings has been used for experimentation. ECG numerical data has been converted to ECG images for comparison. The proposed method consists of feature extraction, dimension reduction, and emotion classification. Arousal and Valence accuracy have been compared using different feature extractors on ECG image and numerical data. ORB, SIFT, KAZE, AKAZE, BRISK, and HOG have been used to extract features from ECG image data whereas TEAP and AUBT have been used to extract features from ECG numerical data. It has been concluded that ECG numerical data provides better performance of emotion classification in comparison to ECG image data.\nThe authors have done a good job in addressing a typical issue. However, there are many aspects that need attention. Hence, the following suggestions should be addressed to enhance the quality of the manuscript.\nLiterature survey is poor. More number of related state-of-the-art works should be cited. There is no citation of the work taking into account both ECG image and ECG numerical data.\n\nIt has been mentioned that the converted ECG images have been resized to 60% of the original size to reduce the computational time. What is the reason for choosing 60%?\n\nThere is no analysis of the computational complexity of the proposed method.\n\nIn Table 4, emotion classification accuracies for both ECG image and ECG numerical data have been provided. Can these accuracy values be accepted in practical applications?\n\nThere is no comparison of the proposed method with state-of-the-art methods.\n\nReferences should be complete in all respect and in a uniform style. A few exceptions are 1, 32, 39, 40.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8274",
"date": "30 May 2022",
"name": "Sharifah Noor Masidayu Sayed Ismail",
"role": "Author Response",
"response": "The paper presents a comparison of the Emotion Recognition System (ERS) performance using ECG image and ECG numerical data. DREAMER dataset containing 23 ECG recordings has been used for experimentation. ECG numerical data has been converted to ECG images for comparison. The proposed method consists of feature extraction, dimension reduction, and emotion classification. Arousal and Valence accuracy have been compared using different feature extractors on ECG image and numerical data. ORB, SIFT, KAZE, AKAZE, BRISK, and HOG have been used to extract features from ECG image data whereas TEAP and AUBT have been used to extract features from ECG numerical data. It has been concluded that ECG numerical data provides better performance of emotion classification in comparison to ECG image data. The authors have done a good job in addressing a typical issue. However, there are many aspects that need attention. Hence, the following suggestions should be addressed to enhance the quality of the manuscript. Thank you for taking the time to review our manuscript. We reviewed the comments and made improvements based on the comments provided accordingly. Literature survey is poor. More number of related state-of-the-art works should be cited. There is no citation of the work taking into account both ECG image and ECG numerical data. We have revised Section Related Works as per the suggestion by adding more related state-of-the-art work citations. The revised part is on pages 5 until 8. We also include the summary information about the existing works that employed 1-D and 2-D ECG input, which is tabulated in Table 2 on pages 6 through 8. Furthermore, the work that considers both ECG images and ECG numerical data is also included in this section. This work can be found on page 6, which reads as follows: \"Additionally, Mandal et al. 5 published a study comparing 1-D and 2-D ECGs for the diagnosis of Ventricular Arrhythmia. They concluded that both ECG inputs are effective at detecting the disease.\" It has been mentioned that the converted ECG images have been resized to 60% of the original size to reduce the computational time. What is the reason for choosing 60%? Thank you for drawing our attention to this. We have improved the explanation of this matter in the manuscript. You can find the text on page 11 that reads as follows: “Due to the fact that the 2-D ECG was converted to a rectangle shape, it is not easy to resize the photos to the standard input image sizes of 224×224 and 299×299. As a result, the converted 2-D ECG was resized to 60% of its original size using Python version 3.8.5. This scale percentage was chosen after considering the quality of the image, the type of feature extractor used, and the computational cost the system can afford.” There is no analysis of the computational complexity of the proposed method. Thank you for pointing out this matter. We have included the analysis of the computational complexity under the result section, tabulated in Table 7, which discussed the time analysis of both inputs used to train and test the ERS model. The analysis was located on page 14: “For comparison purposes, the computation time for both ECG inputs was recorded and reported in Table 7. The average time required to compute 1-D is 1.58 ± 0.07 seconds. In comparison, the average computation time for 2-D is 3377.425 ± 3138.875 seconds. Therefore, according to the observation, 2-D took the longest computation time, whereas 1-D obtained the shortest.” Additionally, the analysis of the computational time was touched on in the Discussion and Conclusion section as follows: “In terms of computational cost, 1-D ECG is better to 2-D ECG since it requires less computation time.” In Table 4, emotion classification accuracies for both ECG image and ECG numerical data have been provided. Can these accuracy values be accepted in practical applications? Thank you for pointing this out. For your information, our results have been updated according to the result of the latest experiment. This result is tabulated in Table 6 on page 13. Based on this result, the accuracy and F1-score achieved for this study are on par with the existing works, which shows that our ERS model can be accepted in practical applications. However, this does not rule out the possibility of improving this result, as there is much more room to improve the ERS performance to develop a more robust ERS in the future. There is no comparison of the proposed method with state-of-the-art methods. A comparison with existing work (DREAMER) has been provided for 1-D ECG. This comparison can be found in the result section on page 15, tabulated in Table 6. However, no existing work using the 2-D ECG of the DREAMER dataset has been reported. Therefore, no comparison can be made. References should be complete in all respect and in a uniform style. A few exceptions are 1, 32, 39, 40. Thank you for bringing our attention to this. We have revised the references and citation part accordingly and completed it in all respects and in a uniform style as per suggestions."
}
]
},
{
"id": "126091",
"date": "16 Mar 2022",
"name": "Marios Fanourakis",
"expertise": [
"Reviewer Expertise Affective computing",
"emotion recognition"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors use the DREAMER dataset to compare the emotion recognition performance of features extracted from the time-series ECG signal versus features extracted from images of the ECG wave signal. An SVM model is used as the classifier.\nOverall, the structure of the report is not coherent, the related work is incomplete, and the motivation for this work is not convincing. Furthermore, many important details are missing about the dataset and the methods used which makes it difficult to trust the results and the comparisons they make with other works.\nDetailed comments:\nStructure: several improvements to be made, information seems to be scattered throughout the article. For example, information about the dataset is present in both the introduction and methods sections. It is best to keep this information in the same section. Same for the related works.\nAuthors should give a brief explanation on what are ECG wave images in the introduction, otherwise readers in the emotion recognition field might confuse them with spectrograms which are more widely used in the field. It may also be better to change the term \"numerical data\" to \"time-series data\" or \"1D data\" (2D being an image).\nTypo on page 3: EGC instead of ECG.\nFrom the references pertaining to the use of ECG images (1-6, 23,24) only half actually use ECG wave images (2,4,23,24). The rest either use time-series or convert the time-series to spectrograms. The ones that do use ECG images, mainly analyze individual beats and not the entire ECG wave in order to detect medical heart issues. For the emotion recognition use-case it is necessary to analyze significantly larger regions of the signal than individual beats.\nIn emotion recognition, it is common to transform the ECG signal into a spectrogram image. The authors do not cite any work mentioning this method.\nAuthors do not include any references to other works that use the DREAMER dataset ECG signals for emotion recognition, here are some:\nWenwen He et al. 2021 Emotion Recognition from ECG Signals Contaminated by Motion Artifacts1 Pritam Sarkar et al. 2020 Self-supervised ECG Representation Learning for Emotion Recognition2\nI also came across another publication of some of the co-authors which would be advantageous to reference:\nMuhammad Anas Hasnul et al. 2021 Evaluation of TEAP and AuBT as ECG’s Feature Extraction Toolbox for Emotion Recognition System3\nIn the Emotion model paragraph (page 3): it is still unclear which model of emotions was used, Ekman or Russell? Authors say \"the latter\" (referring to Russel) but then mention binary classification which may be confusing since the arousal/valence space is continuous making it a regression problem or at least multiclass and not binary. Authors should re-word this part to make it clear.\nReferring to wearable ECG devices, the authors state: \"However, most of these devices store the ECG as images instead of raw numerical data\". No references or other market analysis is provided to show that this is the case. The use of ECG wave images for emotion recognition is not properly motivated. I fail to see any advantage of using ECG wave images over the time-series data unless ECG time-series data is not available.\nHow was the data annotated in the DREAMER dataset? Were they continuous annotations or a single annotation per video clip? This is very relevant to include in the article. A few more words about the dataset are needed like a short description of the experimental protocol.\nArousal/valence rating values are ranging from 1 to 5 in the DREAMER dataset. The authors never explain how they split them into two classes (high/low) for the binary classification.\nAuthors do not include sufficient information on how the time-series ECG data was converted to an image (resolution, compression, windowing), or how the data was treated in general. Did the authors use the entire ECG signal for each video? Was there any windowing? Since the authors did not properly summarize the dataset (how were the videos annotated?) it is difficult to grasp or guess on how the data was processed.\nNone of the cited literature used any of the image feature extraction methods that the authors used, and the authors did not discuss their reasoning for why they selected those image feature extraction methods and not the ones established in the ECG image analysis literature that they cited. Some more illustrations of these features may be useful besides the one in Figure 5 in order to convince the readers.\nSupport vector machine: It is not clear what preprocessing steps were applied to the data. For example in the DREAMER dataset baseline they only use the last 60s of data for each film clip.\nData was divided 80:20 and 10-fold cross-validation was used. The authors do not specify exactly how the data was split (see DREAMER dataset paper section V as an example). From reading this part, I can only assume that all data from all participants was used for each fold (general model), something that is diverging from how the data was split in the DREAMER dataset paper (they made models for each individual participant). Therefore any comparisons to the results of the DREAMER baseline are invalid.\nResults: If the classes are unbalanced (as the DREAMER dataset paper indicates) accuracy is not valid on it's own, include f1 score, and/or Cohen's Kappa.\nDiscussion: \"Ref. 11\" has nothing to do with the statement in that paragraph. LDA was actually applied in the DREAMER dataset paper and they reported that there were no significant differences in performance.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8275",
"date": "30 May 2022",
"name": "Sharifah Noor Masidayu Sayed Ismail",
"role": "Author Response",
"response": "The authors use the DREAMER dataset to compare the emotion recognition performance of features extracted from the time-series ECG signal versus features extracted from images of the ECG wave signal. An SVM model is used as the classifier. Overall, the structure of the report is not coherent, the related work is incomplete, and the motivation for this work is not convincing. Furthermore, many important details are missing about the dataset and the methods used which makes it difficult to trust the results and the comparisons they make with other works. Thanks for taking the time to review our manuscript. We have revised the manuscript based on your comments and suggestions accordingly. Structure: several improvements to be made, information seems to be scattered throughout the article. For example, information about the dataset is present in both the introduction and methods sections. It is best to keep this information in the same section. Same for the related works. Thanks for pointing this out. We agree with your suggestion and have attempted to address the issues. Therefore, we have revised each section as per suggestions by revising the information written in the manuscript accordingly. The revised part can be found on pages 3 until 13. Authors should give a brief explanation on what are ECG wave images in the introduction, otherwise readers in the emotion recognition field might confuse them with spectrograms which are more widely used in the field. It may also be better to change the term \"numerical data\" to \"time-series data\" or \"1D data\" (2D being an image). Thank you for drawing our attention to this. As you mentioned, we have added an explanation of what ECG wave images are in the Introduction section that reads as follows: “Fundamentally, ECG is used to measure electrical activity in the human heart by attaching electrodes to the human body. Due to the continual blood pumping action to the body, the electrical activity of the heart can be found in the sinoatrial node. The electrocardiogram signal is composed of three basic components: P, QRS, and T waves (Figure 1). P waves are produced during atrium depolarization, QRS complexes are produced during ventricular depolarization, and T waves are produced during ventricle recovery. Despite this, majority of the portable devices record the ECG signal as images (2-D images) in a PDF file rather than as raw numerical data (1-D data) 16 – 18. The example of a PDF-based 2-D ECG is depicted in Figure 2. Due to this problem, researchers were required to convert the PDF file of the ECG into 1-D data before performing further emotion analysis, adding complexity to the pre-processing process. On this account, given the positive results obtained in monitoring and diagnosing cardiovascular-related diseases, the efficacy of 2-D ECG in emotion studies also warrants further investigation.” Additionally, we also added Figure 2 that shows the snippet of the 2-D ECG from the PDF file. This figure can be found on page 4. Furthermore, as per suggestion, we have changed the terms \"numerical data\" to \"1D ECG\" and \"wave images\" to \"2-D ECG\". Typo on page 3: EGC instead of ECG. Thank you so much for catching these glaring and confusing errors, which we have now corrected. From the references pertaining to the use of ECG images (1-6, 23,24) only half actually use ECG wave images (2,4,23,24). The rest either use time-series or convert the time-series to spectrograms. The ones that do use ECG images, mainly analyze individual beats and not the entire ECG wave in order to detect medical heart issues. For the emotion recognition use-case it is necessary to analyze significantly larger regions of the signal than individual beats. Based on your comment, we have revised our Related Works section and corrected them accordingly. Additionally, we added the summary of existing works that use 1-D and 2-D ECG input with their purposes, tabulated in Table 1. The revision of these issues can be found on page 4 until 8. In emotion recognition, it is common to transform the ECG signal into a spectrogram image. The authors do not cite any work mentioning this method. Thanks for pointing this out. We agree with your comments. Therefore, we have revised our Related Works section and provided improvements through the fourth paragraph on page 6: . “Despite rising popularity among medical practitioners in assessing patients' cardiac disease, 2-D ECG remains inadequate compared to 1-D ECG usage as a type of input in emotion recognition studies. As a result, the number of studies employing 1-D ECG in ERS is higher than that utilizing 2-D ECG in ERS. However, rather than employing a printout-based 2-D ECG, emotion researchers classified human emotions using 2-D ECG spectral images. For example, 15 determines the R-peaks of the electrocardiogram prior to generating the R-R interval (RRI) spectrogram. Following that, CNN was used to classify the emotions, with an accuracy rate greater than 90%. Elalamy et al. 30 used ResNet-50 to extract features from a 2-D ECG spectrogram. Then, Logistic Regression (LR) was employed as a classifier and achieved an accuracy of 78.30% in classifying emotions.” Additionally, in Table 1, the ECG input was listed as either 1-D or 2-D ECGs, where 2-D was further categorised into standard 2-D ECG or spectral 2-D ECG. Authors do not include any references to other works that use the DREAMER dataset ECG signals for emotion recognition, here are some: Wenwen He et al. 2021 Emotion Recognition from ECG Signals Contaminated by Motion Artifacts Pritam Sarkar et al. 2020 Self-supervised ECG Representation Learning for Emotion Recognition I also came across another publication of some of the co-authors which would be advantageous to reference: Muhammad Anas Hasnul et al. 2021 Evaluation of TEAP and AuBT as ECG’s Feature Extraction Toolbox for Emotion Recognition System. Thank you for the paper suggested. We have added the reference according to your recommendation, which you can find on page 6 as follows: “Additionally, numerous other researchers also used the ECG signals from the DREAMER dataset to perform emotion recognition. For instance, 1-D ECG data from the DREAMER dataset is utilized by Wenwen He et al. 24 that suggested an approach for emotion recognition using ECG contaminated by motion artefacts. The proposed approach improved classification accuracy by 5% to 15%. Additionally, Pritam and Ali 25 also employed 1-D ECG from the DREAMER dataset to develop the self-supervised deep multi-task learning framework ERS, which consists of two stages of learning: ECG representation learning and emotion classification learning. The accuracy gained in this study was greater than 70%. Hasnul et al. 12 also used the 1-D ECG by DREAMER dataset to compare the performance of two feature extractor toolboxes. They noted that the dataset's size and the type of emotion classified might affect the suitability of the extracted features.” In the Emotion model paragraph (page 3): it is still unclear which model of emotions was used, Ekman or Russell? Authors say \"the latter\" (referring to Russel) but then mention binary classification which may be confusing since the arousal/valence space is continuous making it a regression problem or at least multiclass and not binary. Authors should re-word this part to make it clear. Thank you for pointing this out. The reviewer is correct; the original phrase is confusing. Therefore, we have removed this part to avoid any further confusion. Furthermore, this concern has been changed and revised to make it more straightforward and understandable. The revised text was located in the experimental setting subsection under the Method section on page 13: “The scale of self-assessed emotions, which ranges from 1 (lowest) to 5 (highest), was classified using a five-point scale with middle-point thresholds (an average rate of 3.8). As a result, scales four and five were assigned to the high class, while the remaining scales were assigned to the low class.” Referring to wearable ECG devices, the authors state: \"However, most of these devices store the ECG as images instead of raw numerical data\". No references or other market analysis is provided to show that this is the case. The use of ECG wave images for emotion recognition is not properly motivated. I fail to see any advantage of using ECG wave images over the time-series data unless ECG time-series data is not available. Thank you for drawing our attention to this, and we agree with the comments. Therefore, we have cited the necessary references and revised the statement as per the suggestion. The revised text can be found on page 4 as follows: “Previous research on human emotions has primarily relied on either direct analysis of 1-D data 12 – 14 or the conversion of 1-D data to a 2-D spectral image 15 prior to identifying the emotions. Despite this, majority of the portable devices record the ECG signal as images (2-D images) in a PDF file rather than as raw numerical data (1-D data) 16 – 18. The example of a PDF-based 2-D ECG is depicted in Figure 2. Due to this problem, researchers were required to convert the PDF file of the ECG into 1-D data before performing further emotion analysis, adding complexity to the pre-processing process. On this account, given the positive results obtained in monitoring and diagnosing cardiovascular-related diseases, the efficacy of 2-D ECG in emotion studies also warrants further investigation.” How was the data annotated in the DREAMER dataset? Were they continuous annotations or a single annotation per video clip? This is very relevant to include in the article. A few more words about the dataset are needed like a short description of the experimental protocol. Thank you for bringing this issue to our attention. The short description of the DREAMER dataset has been improved to address this issue. The revised text was located in the Method section under a subsection called \"The dataset (DREAMER\") on page 8: “This study used ECG signals from Katsigiannis and Ramzan 13 called DREAMER. The DREAMER dataset is a freely accessible database of electroencephalogram (EEG) and electrocardiogram (ECG) signals used in emotion research. However, EEG signals were removed from this study because the primary focus is on ECG signals. The ECG was recorded using the SHIMMER ECG sensor at 256 Hz and stored in 1-D format. The DREAMER dataset contains 414 ECG recordings from 23 subjects who were exposed to 18 audio-visual stimuli designed to evoke emotion. Each participant assessed their emotions on a scale of 1 to 5 for arousal, valence, and dominance. However, because this study was primarily concerned with arousal and valence ratings, participants' evaluations of dominance were discarded.” Arousal/valence rating values are ranging from 1 to 5 in the DREAMER dataset. The authors never explain how they split them into two classes (high/low) for the binary classification. Thank you for bringing this to our attention. We have improved this part by adding an explanation of how we categorise emotions into two classes. The explanation can be found on page 13: “The scale of self-assessed emotions, which ranges from 1 (lowest) to 5 (highest), was classified using a five-point scale with middle-point thresholds (an average rate of 3.8). As a result, scales four and five were assigned to the high class, while the remaining scales were assigned to the low class.” Authors do not include sufficient information on how the time-series ECG data was converted to an image (resolution, compression, windowing), or how the data was treated in general. Did the authors use the entire ECG signal for each video? Was there any windowing? Since the authors did not properly summarize the dataset (how were the videos annotated?) it is difficult to grasp or guess on how the data was processed. We agree with this comment. Therefore, we improved the explanation part of pre-processing the 2-D ECG. The improvised text can be found in the first and second paragraphs of subsection 2-D ECG on page 11. “The duration of the ECG recording varies according to the duration of the video (average = 199 seconds). As Katsigiannis and Ramzan proposed, this study analysed the final 60 seconds of each recording to allow time for a dominant emotion to emerge 13. Following that, 1-D ECG was pre-processed using a simple MATLAB function by 34 to eliminate baseline wander caused by breathing, electrically charged electrodes, or muscle noise. The signal was then divided into four segments corresponding to 15 seconds each. Then, using MATLAB version 9.7, the 1-D ECG was transformed into a 2-D ECG (Figure 4). The image has a width of 1920 pixels and a height of 620 pixels. Due to the fact that the 2-D ECG was converted to a rectangle shape, it is not easy to resize the photos to the standard input image sizes of 224×224 and 299×299. As a result, the converted 2-D ECG was resized to 60% of its original size using Python version 3.8.5. This scale percentage was chosen after considering the quality of the image, the type of feature extractor used, and the computational cost the system can afford. The coloured images were converted into greyscale images. Then, binarization of the image using an Otsu's automatic image thresholding method 35 was done. This method ascertains the optimal threshold values from pixel values of 0 to 255 by calculating and evaluating their within-class variance 36” None of the cited literature used any of the image feature extraction methods that the authors used, and the authors did not discuss their reasoning for why they selected those image feature extraction methods and not the ones established in the ECG image analysis literature that they cited. Some more illustrations of these features may be useful besides the one in Figure 5 in order to convince the readers. Thank you for pointing this out. Cite literature either using their own algorithm to detect peaks on PQRST waves or automatically extracting ECG features using a deep learning system. However, we had included our reason for employing these image feature extraction methods, which we believed could add a valuable contribution to the state-of-the-art. Additionally, we removed Figure 5 and replaced it with the description of each feature extractor to help convince the readers. The revised text can be found on pages 11 and 12: “The area of interest for 2-D ECG is laying on the PQRST waves, making the peaks detector the best approach to be employed. Therefore, six different feature extractors that could extract peaks, edges, or corners were applied to extract features from 2-D ECGs using Python version 3.8.5: 1. ORB 37: ORB features are invariant to rotation and noise because they are a combination of Features from Accelerated Segment Test (FAST) detection and Binary Robust Independent Elementary Features (BRIEF) description methods. 2. SIFT 38: SIFT identifies feature points by searching for local maxima on the images using Difference-of-Gaussians (DoG) operators. The description approach generates a 16x16 neighbourhood around each identified feature and sub-blocks the region. SIFT is also rotation and scale invariant. 3. KAZE 39: KAZE is based on the scale of the normalised determinant of the Hessian Matrix, with the maxima of detector responses being captured as feature points using a moving window. Additionally, KAZE makes use of non-linear space via non-linear diffusion filtering to reduce noise while keeping the borders of regions in images. 4. AKAZE 40: AKAZE is a more sophisticated version of KAZE that is based on the Hessian Matrix determinant. Scharr filters were employed to enhance the quality of the invariance rotation, rendering AKAZE features rotation- and scale-invariant. 5. BRISK 41: While searching for maxima in the scale-space pyramid, BRISK detects corners using the AGAST algorithm and filters them using the FAST Corner Score. Additionally, the BRISK description is based on the recognised characteristic direction of each feature, which is necessary for rotation invariance. 6. HOG 42: HOG is a feature descriptor that is used to compute the gradient value for each pixel. The image shape denoted the edge or gradient structure derived using a high-quality local gradient intensity distribution.” Support vector machine: It is not clear what preprocessing steps were applied to the data. For example, in the DREAMER dataset baseline they only use the last 60s of data for each film clip. Thank you for this comment. The pre-processing part can be found in the Methods section under the 1-D ECG and 2-D ECG subsections. The pre-processing for 1-D ECG can be read as follows: “The AUBT and TEAP feature extractors were included with the Low Pass Filter (LPF), a filter meant to reject all undesirable frequencies in a signal. The LPF was one of the most widely used filters before the computation of statistical features for physiological signals 31, 32. As a result, automated 1-D ECG pre-processing utilizing LPF was performed in this study to reduce muscle and respiratory noise in ECG signals.” Whereas the pre-processing for 2-D ECG can be read as follows: “The duration of the ECG recording varies according to the duration of the video (average = 199 seconds). As Katsigiannis and Ramzan proposed, this study analysed the final 60 seconds of each recording to allow time for a dominant emotion to emerge 13. Following that, 1-D ECG was pre-processed using a simple MATLAB function by 34 to eliminate baseline wander caused by breathing, electrically charged electrodes, or muscle noise. The signal was then divided into four segments corresponding to 15 seconds each. Then, using MATLAB version 9.7, the 1-D ECG was transformed into a 2-D ECG.” Data was divided 80:20 and 10-fold cross-validation was used. The authors do not specify exactly how the data was split (see DREAMER dataset paper section V as an example). From reading this part, I can only assume that all data from all participants was used for each fold (general model), something that is diverging from how the data was split in the DREAMER dataset paper (they made models for each individual participant). Therefore, any comparisons to the results of the DREAMER baseline are invalid. Thank you for pointing this out. We have addressed this issue by adding a new subsection under Method, namely, Experimental Setting. This subsection is located on pages 13 and 14, and can be read as follows: “The hyperparameters for SVM were tuned using an exhaustive parameter search tool, GridSearchCV, from Scikit-learn that automates the tuning procedure 45. This study tuned only the parameters with a high and relative tuning risk and left the remainder at their default values because they are the least sensitive to the hyperparameter tuning process, as suggested by Weerts, Mueller, and Vanschoren 46. The dataset was split into a reasonable proportion of training and testing sets to evaluate the model's performance on new unseen data. This study used a stratified train-test split of 80:20 for the training and testing sets. This strategy guarantees the dataset's exact proportions of samples in each class are preserved. Additionally, as we had a small dataset size, this study applied KFold Cross-Validation, with the number of folds set to 10, the most commonly used number in prior research to improve ERS performance.” Additionally, the summary of the experimental setting values has been tabulated in Table 5 on page 14. Results: If the classes are unbalanced (as the DREAMER dataset paper indicates) accuracy is not valid on its own, include f1 score, and/or Cohen's Kappa.. Thank you for your suggestions. As per your recommendations, we have included the F1-score along with the accuracy to address the unbalanced class distribution issue. This result can be found in Table 6 on page 14. Discussion: \"Ref. 11\" has nothing to do with the statement in that paragraph. LDA was actually applied in the DREAMER dataset paper and they reported that there were no significant differences in performance. Thank you for your great observations. We have revised that part as needed. Regarding the LDA, we agree with you. However, as far as we know, LDA was used for classification purposes in the DREAMER dataset paper but not for dimension reduction."
}
]
},
{
"id": "121059",
"date": "16 Mar 2022",
"name": "Md. Asadur Rahman",
"expertise": [
"Reviewer Expertise Biomedical Signal Processing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper titled “Evaluation of electrocardiogram: numerical vs. image data for emotion recognition system” looks interesting. Although it is a short paper, I found it interesting and am positive about this work, but it should go through some modification:\nFigure 2 should be redrawn, only providing the reference is not enough to present a figure or image in the article.\n\nThe ECG signals used in this work contain some baseline wandering. It should be removed before further analysis. A simple technique with Matlab code is described in Rahman et al (2019)1 to remove baseline wander. I am expecting a result comparing the emotion recognition rate before and after the baseline wander removal from the ECG signal.\n\nIn addition to that, is it possible to use LSTM to the ECG time series to find the accuracy of the emotion recognition from ECG signals?\n\nPlease provide detailed information about transforming the signal to image conversion.\n\nThe reference-related comparison and discussion should be completed in the result and discussions. If possible, avoid referencing in the Conclusion section.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8276",
"date": "30 May 2022",
"name": "Sharifah Noor Masidayu Sayed Ismail",
"role": "Author Response",
"response": "The paper titled “Evaluation of electrocardiogram: numerical vs. image data for emotion recognition system” looks interesting. Although it is a short paper, I found it interesting and am positive about this work, but it should go through some modification: We appreciate your feedback and suggestions. We have revised the manuscript as needed. Figure 2 should be redrawn, only providing the reference is not enough to present a figure or image in the article. Thank you for your suggestions. As per your recommendations, we have redrawn the figure and an additional note has been added in the legend. As several modifications were made to the manuscript, Figure 2 was originally changed to Figure 1. This figure can be found on page 4. The ECG signals used in this work contain some baseline wandering. It should be removed before further analysis. A simple technique with MATLAB code is described in Rahman et al (2019)1 to remove baseline wander. I am expecting a result comparing the emotion recognition before and after the baseline wander removal from the ECG signal. Thank you for your suggestion. We did use the method suggested as cited accordingly. However, your expectation of having a result comparing the emotion recognition before and after the baseline wander removal from the ECG signal is inappropriate for our work because the focus of this paper is to compare emotion classification performance using 1-D and 2-D ECGs to investigate the effect of the ECG input format on the ERS. In addition to that, is it possible to use LSTM to the ECG time series to find the accuracy of the emotion recognition from ECG signals? As far as we know, it is possible to use LSTM on the ECG time series to find the accuracy of emotion recognition from ECG signals. The work by Song et al. used LSTM for the same purpose as your concern. Below is the paper, which you can take a look at. We hope it answers your question. T. Song, W. Zheng, C. Lu, Y. Zong, X. Zhang, and Z. Cui, “MPED: A multi-modal physiological emotion database for discrete emotion recognition,” IEEE Access, vol. 7, no. October, pp. 12177–12191, 2019. Please provide detailed information about transforming the signal to image conversion. Thank you for pointing this out. We have revised the 2-D ECG subsection, where the pre-processing process until the transformation from 1-D to 2-D is explained in detail. This subsection can be found on pages 11 and 12, which can be read as follows: “The duration of the ECG recording varies according to the duration of the video (average = 199 seconds). As Katsigiannis and Ramzan proposed, this study analysed the final 60 seconds of each recording to allow time for a dominant emotion to emerge 13. Following that, 1-D ECG was pre-processed using a simple MATLAB function by 34 to eliminate baseline wander caused by breathing, electrically charged electrodes, or muscle noise. The signal was then divided into four segments corresponding to 15 seconds each. Then, using MATLAB version 9.7, the 1-D ECG was transformed into a 2-D ECG (Figure 4). The image has a width of 1920 pixels and a height of 620 pixels. Due to the fact that the 2-D ECG was converted to a rectangle shape, it is not easy to resize the photos to the standard input image sizes of 224×224 and 299×299. As a result, the converted 2-D ECG was resized to 60% of its original size using Python version 3.8.5. This scale percentage was chosen after considering the quality of the image, the type of feature extractor used, and the computational cost the system can afford. The coloured images were converted into greyscale images. Then, binarization of the image using an Otsu's automatic image thresholding method 35 was done. This method ascertains the optimal threshold values from pixel values of 0 to 255 by calculating and evaluating their within-class variance 36” The reference-related comparison and discussion should be completed in the result and discussions. If possible, avoid referencing in the Conclusion section. Thank you for bringing this to our attention. We found your comments extremely helpful and have revised them accordingly. The revised text can be read as follows: “The results indicate that both inputs work comparably well in classifying emotions. This finding is demonstrated by the fact that the best valence performance was obtained using a 1-D ECG, and the best arousal performance was acquired using a 2-D ECG. Additionally, ERS with 1-D ECG was combined with dimensionality reduction, called LDA. The presence of LDA improved the ERS performance in valence emotion but not in arousal. In terms of computational cost, 1-D ECG is better to 2-D ECG since it requires less computation time. However, it is worth mentioning that the results obtained using 2-D ECG demonstrated potential for use as an input modality for the ERS. Additionally, 2-D ECGs are appealing because the format enables the use of a variety of image-based methods such as image augmentation to increase the data size, convolution neural networks (CNN), and the application of transfer learning from models trained using large data. To summarise, the ERS performance of the two ECG inputs is comparable since both yield a promising outcome for emotion recognition.”"
}
]
}
] | 1
|
https://f1000research.com/articles/10-1114
|
https://f1000research.com/articles/11-585/v1
|
27 May 22
|
{
"type": "Research Article",
"title": "Determinants of unintended pregnancy among women attending antenatal clinic at Kenyatta National Hospital.",
"authors": [
"Rose Ojuok",
"Dr. Daniel Nyamongo",
"Dr. Joseph Mutai",
"Dr. Daniel Nyamongo",
"Dr. Joseph Mutai"
],
"abstract": "Background: Unintended pregnancy predisposes women of child-bearing age to risk factors like maternal deaths, poor child outcomes, mental illness because of stress, risky abortion, and vertical transmission of HIV. According to the Kenya Demographic Health Survey in 2014, 34% of the pregnancies were unintended and in the year 2020 it rose to 41.9% (Monitoring, 2020). Determinants of unintended pregnancy among women attending antenatal clinics in Kenya is diverse and is poorly understood due to no representative information. The objective of the study was to determine the factors associated with unintended pregnancy among women attending antenatal clinic particularly their individual factors, family planning practices and health facility-based factors. Method: A cross-sectional study design. Data was collected using a structured administered questionnaire from 227 participants. The proportion and determinants of unintended pregnancy was derived using bivariate analysis and multivariate logistic regressions. Results: In this study, a third (29.9%) of the pregnant women reported that their existing gravidity was unintended. Individual factors such as age less than 25 years [AOR 8.1 (95% CI 1.4-48.6)), p=0.001], use of contraceptive method [AOR 7.9 (95% CI 2.5-25.0), p<0.001] and the woman being the sole decision-maker on when to get pregnant [AOR 3.8 (95% CI 1.3-11.2), p=0.014] were significantly associated with unintended pregnancy. Conclusion: The study area had quite a significant proportion of unintended pregnancy underscoring the need for health facilities to enhance targeted contraceptive counselling during antenatal and postnatal clinics. Reinforcing effective utilization of family planning services in the pursuit to decrease unintended pregnancy not only in Nairobi but also in Kenya.",
"keywords": [
"Determinants",
"unintended pregnancy",
"family planning",
"18-49 years pregnant women"
],
"content": "Introduction\n\nWorldwide, women upon reaching a childbearing age are at risk of experiencing a pregnancy that is unintended or intended. A pregnancy is unintended if it occurs when a child is not desired (unwanted) or not anticipated at that particular time (mistimed) (Ameyaw et al., 2019). Globally, 210 million pregnancies take place annually out of which about 75-80 million are unintended (Ali, Tikmani, et al., 2016). In Africa, out of 49.1 million pregnancies, unintended pregnancies were 39%. Sub-Saharan Africa record about 14 million unintended pregnancy annually (Ameyaw et al., 2019). Presently, developed and developing countries share in this problem of unintended pregnancy though the prevalence is greater in the former than the latter (Singh et al., 2010). As from 1995-2008, unintended pregnancy reduced by 20% with developed countries having 29% decrease compared to developing countries that had 20%.Despite the reduction in these rates, the existence of unintended pregnancy was still comparatively elevated (Ali & Ali, 2014).\n\nOver the years, globally, there has remained a decline in the number of unintended pregnancy especially between 2010 and 2014 with its prevalence reducing from 30% to 16% (Ameyaw et al., 2019). In Kenya, the prevalence of unintended pregnancy was at 43% according to the KDHS 2008-2009 among married women (Ikamari et al., 2013) and at 34.4% in 2014 (Ameyaw et al., 2019). Unintended pregnancy is a public health problem that cuts across all the countries in the world due to its negative health and socio-economic outcomes to the mother, family, and society in general. It predisposes women of child-bearing age to risk factors like risky abortion, maternal mortality, poor child outcomes, mental illness as a result of stress and vertical transmission of HIV (Ameyaw et al., 2019). It affects adolescents or teenagers, married and unmarried women of reproductive age, and because of the humiliation or dishonor that sometimes it comes with, particularly teenagers or young women become obliged to undertake unsafe abortion. Out of the unintended pregnancy that occurs in Kenya, 14% of them end up in unsafe abortions claiming 2600 women and girls’ lives annually (Mumah et al., 2014). The key influencing factor for risky abortion which has led to high maternal mortality and morbidity in Kenya is unintended pregnancy (Obiero & Mwai, 2018). A report by Allan Guttmacher Institute (2012) indicates that unsafe abortion is prevalent in East Africa especially in Kenya where it is restricted and stigmatized. Unsafe abortion claims 500 women lives per 100,000 (Hussain, 2012).\n\nUnintended pregnancy has adverse maternal and neonatal outcomes which include death and disease related to induced and unsafe abortions, poor and delayed utilization of maternal health care service, poor child birth outcomes, low physical maternal health and poor maternal mental health (Exavery et al., 2014). Kenya seeks to guarantee that every gravidity is planned, every birth safe and each young person reaches their potential by the year 2030 guided by the Sustainable Development goals. This they will achieve by putting an end to unmet need for contraception and preventable maternal deaths hence will positively impact on inadvertent pregnancy (UNFPA, 2015).\n\nThere are studies that have been done in the past to evaluate the prevalence, predictors and correlates of unintended pregnancy like in Sub-Saharan Africa (Ameyaw et al., 2019), narrative review of this problem in developing countries (Ali, Tikmani, et al., 2016), Ethiopia (Hamdela et al., 2012), Tanzania (Calvert et al., 2013), Nigeria (Sedgh et al., 2006), Ghana (Nyarko, 2019) and Kenya (Ikamari et al., 2013) (Mumah et al., 2013). With wide spread search on the work that has been done on this problem in Kenya, it was evident that women of childbearing age in slum and non-slum settlement had high prevalence of unintended pregnancy irrespective of their income status or wealth index of the household and educational accomplishment. Despite the accessibility of effective methods of contraceptives, incorrect and inconsistence use and contraceptive method failure also contribute to unintended pregnancy.\n\nDeterminants of unintended pregnancy among women of reproductive age attending antenatal clinics in Nairobi, Kenya is diverse in addition is poorly understood due to no representative information. Unintended pregnancy has extreme side effects for the mother and child and the best point for government, supporting public health partners and stakeholders to intervene is at this point. The proportion of women attending antenatal clinics in Kenya is said to be about 94%, this gives health care providers an opportunity to assess adequately case by case the type of pregnancies that these women have. This study sought to find out the level of unintended pregnancy among women attending antenatal care in Nairobi and the associating factors.\n\n\nMethods\n\nA cross-sectional study design was conducted to assess the prevalence and determinants of unintended pregnancy among expectant women aged 18-49 years old attending antenatal clinic at Kenyatta National Hospital. It excluded any woman aged below 18 years, in labor or had complications, declined to consent and those who were unable to communicate (who could not hear, speak, or mentally challenged). Kenyatta National Hospital is the largest Level 6 referral hospital in Nairobi, Kenya and offers services to people from various parts of the country and its environs. According to the facility daily registry, about 1200 women attend the antenatal clinic every month at Kenyatta National Hospital antenatal clinic.\n\nAll women attending the Kenyatta National Hospital antenatal clinic during the time of study were the study population.\n\nThe Fisher et al 1998 formula n=(Z2 p q)÷d2 was applied with assumption of; 24% of the population proportion had prevalence of unintended pregnancy in Nairobi (Ikamari et al., 2013), 95% confidence interval, marginal error of 5% (0.05) to calculate the sample size. The target population was less than 10,000 hence used nf = n/1+(n/N). Sample size was 227 pregnant women.\n\nSystematic sampling method was used to choose study participants from the antenatal clinic registration book that contains a list of all the pregnant women (sample frame) visiting the ANC clinic. The sampling fraction K was calculated by dividing the anticipated number of pregnant women who visited the ANC clinic monthly which was approximately 1200, by the calculated sample size (227). The study participants were selected at every ‘Kth’ intervals which was 5. So after every five pregnant women, one study participant was recruited for the study by the nurse after triaging till the sample size was obtained (Daniel & Cross, 2013).\n\nTo create an unintended pregnancy as the outcome variable, a dichotomous outcome was created by coding participant’s response on whether they wanted to become pregnant then (if yes, it was intended or wanted) (0) or wanted to become pregnant later (mistimed) or did not want children (unwanted) (1). The pregnancy was categorized into two groups: the intended and unintended (mistimed and unwanted). The predictor variables were the individual factors like age, marital status, educational level, work status, religion, occupation, and facility-based factors. Likert scale for rating was used to determine the facility-based factors associated with unintended pregnancy. The responses were rated ranging from one to six which stood for strongly disagree, disagree, slightly disagree, slightly agree, agree, and strongly agree, respectively. The first three represented fifty percent negative response and the latter three stood for fifty percent positive response. Practices on family planning was also determined in the study as the intervening variable to determine the use of contraceptive, types that they preferred and where they sought the family planning services. The response rate of the study was good and various variables like socio-demographics, family planning practices and respondents’ perspectives on health care services were examined at the same time.\n\nKenyatta National Hospital/ University of Nairobi Ethics and Research Committee (KNH/UON ERC) reviewed and permitted this study to be done at the Kenyatta National Hospital antenatal clinic. The KNH/UON ERC approval number was P421/05/2019. There were two nurses at the triage one of whom was a research assistant responsible for guiding the eligible participants into a private room for the consenting process.\n\nInformed consent was obtained from the eligible study participants prior to enrolling them into the study. The written informed consent was translated into Kiswahili. During the consenting process, the written informed consent was explained in detail either in Kiswahili or English depending on the language that was comfortable to the participant. Anonymity and confidentiality were maintained throughout the data collection, management, and dissemination.\n\nIn the design and execution of this study, great effort was set into undertaking a trial run, keeping the data collection protocol simple and easy to administer, communicating details of the study to the participants to lessen the occurrence of missing data. Quantitative data entry was done using a Microsoft Office excel 2010 thereafter coding and analysis based on Statistical Package for Social Sciences (SPSS) version 21. Descriptive and bivariate analysis was used primarily to check the proportion of unintended pregnancy among the predictor variables. Multivariate logistic regression was further used to determine the association between unintended pregnancy and sociodemographic factors, practices on family planning and health facility-based factors. Variables with substantial association were identified based on OR (odds ratio) with 95% confidence interval (CI) and those having association with the dependent variable with a p-value less than 0.05 were entered to Multivariate Logistic regression for controlling possible effects of confounders during analysis.\n\n\nResults\n\nTable 1 presents selected individual factors, facility-based factors and practices of currently women attending antenatal clinic at Kenyatta National Hospital. Majority (78.4%) of the women were aged between 25 and 39 years old. Most of the women (86.8%) lived in the urban areas, 58.6% had post-secondary education and 83.3% were married or cohabiting while 16.7% were not living with a spouse. Partner’s level of education was mainly post-secondary in 63% and a half (50.7%) of the women were employees in the private sector. Of all the study participants, 80.7% were multiparous with 62.8% of them having had more than three births. 29.9% of the pregnancies were unintended out of which 83.8% were mistimed and 16.2% were unwanted pregnancy. 70% of the pregnancies the women had been intended.\n\nTable 2 shows that 29.9% of the pregnancies were unintended out of which 83.8% were mistimed and 16.2% were unwanted pregnancy. 70% of the pregnancies the women had were intended. Contraceptive use before the current pregnancy was reported among 42.3% of the women. The most popular method among them was pills (40.6%) followed by injections 26%. Long term reversible contraceptives (LARC) like IUD and Implants were used by 16.7% and 11.5% of the respondents, respectively. A substantial proportion (41%) said they did not use contraceptives even when they did not intend to get pregnant while 17.2% practiced traditional contraceptive methods. In terms of decision-making for pregnancy, 77.1% said they both (respondent and the sexual partner) made the decision while 20.7% said it was dependent on the woman. Regarding contraceptives utilization, the decision was made by 48.5% of the women and 41.0% of the study participants involved their sexual partners in decision making.\n\nTable 3 shows that out of all the study participants, 73.6% of them sought the family planning services from health facilities. 24.2% of the women had never accessed Family Planning services. For those who sought the services, 26.4% accessed them once a year while 30% looked for the services whenever they needed. Most (46.7%) of the women lived in closed proximity to a health care facility. Health talks were useful in informing on family planning according to 91.6% of the women and 63.4% said they accessed the services from the nearest health facility.\n\nAs shown in Table 4, there was an incresed risk of unintended pregnancies among women aged below 25 years compared to the 35+ years, OR 5.2 (95% CI 2.0-13.2), p<0.001. Those who were not married were twice more likely to report unintended pregnancies, OR 2.9 (95% CI 1.4-5.8), p=0.003. Other demographic factors such as rural or urban residence, woman’s or partner’s level of education, occupation and religion were not associated with pregnancy intentions.\n\nGravidity was significantly associated with pregnancy intentions with gravida 1 more likely to have unintended pregnancies [OR 2.8 (95% CI 1.4-5.9), p=0.004] compared to those with gravida 3 or more (OR1.0). However, parity did not show any significant association with pregnancy intentions.\n\nIn addition, the women who used contraceptive methods prior to the current pregnancy were more likely to report unintended pregnancies, OR 2.9 (95% CI 1.6-5.2), p<0.001. In relation to decision making for pregnancy and Family Planning use, there was a higher likelihood of unintended pregnancies in relationships where the woman was the only decision maker on when to get pregnant [OR 4.9 (95% CI 2.5-9.6), p<0.001] and FP use [OR 4.1 (95% CI 2.0-8.0), p<0.001] compared to those with both partners involved.\n\nUnintended pregnancies was likely to be reported among women who never sought FP services from health facilities [OR 4.4 (95% CI 1.8-10.6), p=0.001] and those who sought the services only when they felt they needed it [OR 3.3 (95% CI 1.4-7.8), p=0.005]. Also, the women with unintended pregnancies thought health talks were not educative on FP, OR 3.6 (95% CI 1.4-9.5), p=0.005.\n\nTable 5, shows a multivariate logistic regression revealing that ages less than 25 years [aOR 8.1 (95% CI 1.4-48.6), p=0.022], prior use of family planning methods [aOR 7.9 (95% CI 2.5-25.0), p<0.001, the woman independently deciding on when to get pregnant [aOR 3.8 (95% CI 1.3-11.2), p=0.014], never seeking FP service from a health facility [aOR 4.4 (95% CI 1.0-19.6), p=0.050] and the attitude that health talks are not useful in informing on FP [aOR 5.6 (95% CI 1.1-27.6), p=0.033] were suggestively associated with unintended pregnancy. Marital status and gravidity of the women were not independently related with occurrence of unintended pregnancies.\n\n\nDiscussion\n\nThis study sought to find out the proportion and determinants of unintended pregnancy in among women attending antenatal clinic. Our finding revealed that 29.9% of these women had unintended pregnancy. This proportion of women was slightly lower compared to the proportion of unintended pregnancy in Kenya from reports from other studies like in 2012 was at 40% (Mumah et al., 2013), 34.4% (Ameyaw et al., 2019) and 41.9% (Monitoring, 2020). This means that about 29.9% of women attending antenatal clinic are at risk of having unintended pregnancy and further more exposed to the severe health implications associated with it.\n\nIn this study, younger women were at a higher risk of unintended pregnancies with those aged below 25 years were 8 times likely to report unintended pregnancy compared to those aged 35 years and above. Similar findings were reported in a previous study in Nairobi that showed younger women having a greater possibility of getting unintended pregnancies (Ikamari et al., 2013). This may be because the younger women were more exposed to frequent sexual intercourse with lower utilization or higher failure rates of contraceptives (Habib et al., 2017).\n\nMarital status did not have association with unintended pregnancies in this research despite those who were not married showing a higher risk. This significant finding was lost when the results were adjusted for other characteristics including age. This was explained by the general trend that majority of the unmarried women were younger in age which came out as an important factor associated with unintended pregnancies. Studies in Malaysia and South Africa have reported that unintended pregnancies were higher in women who were not married (Yusof et al., 2018; Haffejee et al., 2018).\n\nStudies elsewhere and in a population in Kenya have shown increased risk of unintended pregnancies among women with higher parity. Unintended pregnancies were more likely in women with para 4 and above in Tanzania (Exavery et al., 2014). A study in Kenya showed 2.5 fold risk of unintended pregnancies among women with parity of three and above (Ikamari et al., 2013). However, this study did not find any association between parity and occurrence of unintended pregnancies.\n\nThe association between lower gravidity and the pregnancies being reported as unintended but was lost when adjusted for other significant characteristics. Younger women had lower numbers of previous pregnancies hence age was independently associated with unintended pregnancy thus eliminating gravidity. According to this study, other demographic factors such as rural or urban residence, partner’s level of education, occupation and religion were not significantly associated with pregnancy intentions.\n\nDecisions to use of contraceptive methods was determined by the pregnancy intentions of the woman and partly the sexual partner. About two-fifths of the women in this study reported use of contraceptive methods in the period before the current pregnancy. This was comparable to the proportion reported in a survey in Kenya where 42.6% of the women used at least a method of contraceptive to avoid pregnancy (KDHS 2014). Only 59% of the women in this study said they use contraceptives to avoid pregnancies. Pills and injectables were the most utilized methods in this study and this is quite similar to the Kenya national demographic survey report that showed that injectables was the most preferred contraceptive methods with a quarter of the women using the method (KDHS 2014). In 2018, a survey also indicated that 47.2% of women aged 15-49 years use injectables and pills as their preferred contraceptive methods (Monitoring, 2020).\n\nIn addition, this study found that the decision to use contraceptives was dependent mainly on the woman while conception intentions were discussed in most circumstances between the two partners. The relationships in which the woman was the sole decision-maker regarding conception had a 4-fold risk of unintended pregnancies. This is comparable to the findings of a study that was carried out in Bangladesh where women who discussed their intent of using contraceptives with their sexual partners showed less prevalence of unintended pregnancy likened to those who did not discuss at all (28.4% vs 31.1%) (Kamal & Islam, 2011). This could be attributed to the lack of a common goal within the relationship hence conflicting intentions. In certain societies the social norm limits women freedom to make choices and are fully dependent on their male sexual partners or spouses. So in certain relationships men make decision on health seeking behavior of the sexual partner or spouse including use of contraceptives (Ali, Ali, et al., 2016).\n\nOur study showed that utilization of contraceptives before pregnancy predicted occurrence of unintended pregnancies. Women who used contraceptives had an eight-fold risk of unplanned pregnancies. At the same time, women having unintended pregnancies were 4 times more likely to have never sought family planning services in a health care facility. This means the women utilizing contraceptive methods were not receiving adequate efficacy because lack of expert advice on the uptake and incorrect use of the methods. Other researchers have found that unintended pregnancies were related to lack of use of contraceptives as well as incorrect use or failure of the methods (Kassie et al., 2017).\n\nIn Kenya, family planning programs greatly impact on unintended pregnancy because the quality of care is determined by accessibility and availability of contraceptives. 80% of the pregnant women agreed that the nurses and doctors explained to them reproductive health issues and handled them with a lot of confidentiality. 63% of the women who experienced unintended pregnancy thought that they experienced that because of family planning failure (7%), mistake (34.9%) and 34.9% again could not explain why. This could also be supported by the fact that those who reported unintended pregnancies thought the health talks in the clinics were not meeting their need regarding family planning. This attitude could impact on their healthcare-seeking behavior. This study found out that women who never sought family planning services had a four-fold increased chance of unintended pregnancies but distance to Family Planning facility had no significant association. Kenya family planning programs in collaboration with Ministry of Health and other Reproductive health stakeholders need to continue with the Family planning 2020 campaigns on the scaling up of long-term reversible methods of family planning.\n\n\nConclusions\n\nIn conclusion, despite the high level of education, majority living in town and the fact that most of these women attend antenatal clinic when pregnant, the proportion of unintended pregnancy is significantly high. Age below 25 years, the woman being the only decision maker on when to conceive, never seeking Family Planning (FP) service from a health facility, attitude that health talks are not useful in informing Family Planning and women who get pregnant while using contraceptives are likely to report the pregnancy as unintended. There is need towards integrating Sustainable family planning health education and promotion with antenatal care services to increase awareness of consequences of unintended pregnancy, factors associated with it and how to prevent it through modern family planning.\n\nThe small sample size may affect the application of these findings to the whole general population. There may have been some response bias influenced by social desirability bias that inclined the women to report their pregnancy as intended even though it was not, leading to an under- estimation of the burden of unintended pregnancies.\n\n\nData availability\n\nFigshare. Determinants of unintended pregnancy among women attending antenatal clinic at Kenyatta National Hospital. DOI: https://doi.org/10.6084/m9.figshare.19403879.v1 (Ojuok et al., 2022).\n\nThis project contains the following underlying data:\n\n- A cross-sectional study design was used. Data was collected using a structured and interviewer guided questionnaire from 227 participants. The prevalence and determinants of unintended pregnancy was calculated with bivariate and multivariate logistic regressions.\n\n- This data sought to find the prevalence of unintended pregnancy among the study population and the determinants of unintended pregnancy.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAli SA, Ali SA: Unmet need for contraception and unintended pregnancies among women of reproductive age group: A situation analysis. El Mednifico Journal. 2014; 2(3): 259. Publisher Full Text\n\nAli SA, Ali SA, Khuwaja NS: Determinants of Unintended Pregnancy among Women of Reproductive Age in Developing Countries: A Narrative Review. Journal of Midwifery and Reproductive Health. 2016; 4(1): 513–521. Publisher Full Text\n\nAli SA, Tikmani SS, Qidwai W: Prevalence and determinants of Unintended Pregnancy: Systematic Review. July. 2016.\n\nAmeyaw EK, Budu E, Sambah F, et al.: Prevalence and determinants of unintended pregnancy in sub-Saharan Africa: A multi-country analysis of demographic and health surveys. PLoS One. 2019; 14(8): e0220970. PubMed Abstract | Publisher Full Text\n\nDaniel WW, Cross CL: Biostatistics: A foundation for Analysis in the Health Sciences. 2013. Publisher Full Text\n\nExavery A, Kanté AM, Njozi M, et al.: Predictors of mistimed, and unwanted pregnancies among women of childbearing age in Rufiji, Kilombero, and Ulanga districts of Tanzania. Reproductive Health. 2014; 11(1): 1–9. PubMed Abstract | Publisher Full Text\n\nGrenier L, Suhowatsky S, Kabue MM, et al.: Impact of group antenatal care (G-ANC) versus individual antenatal care (ANC) on quality of care, ANC attendance and facility-based delivery: A pragmatic cluster-randomized controlled trial in Kenya and Nigeria. PLoS One. 2019; 14(10): e0222177–e0222118. PubMed Abstract | Publisher Full Text\n\nHabib MA, Raynes-Greenow C, Nausheen S, et al.: Prevalence and determinants of unintended pregnancies amongst women attending antenatal clinics in Pakistan. BMC Pregnancy Childbirth. 2017; 17(January): 156. PubMed Abstract | Publisher Full Text\n\nHamdela B, Mariam AG, Tilahun T: Unwanted pregnancy and associated factors among pregnant married women in Hosanna town, Southern Ethiopia. PLoS One. 2012; 7(6) Publisher Full Text\n\nHussain R: Abortion and unintended pregnancy in Kenya. Issues Brief (Alan Guttmacher Inst.). 2012; 2008(2): 1–4. Publisher Full Text\n\nIkamari L, Izugbaru C, Oghako R: Prevalence and determinants of unintended pregnancies in Nairobi, Kenya. BMC Pregnancy Childbirth. 2013; 13(1): 2014. PubMed Abstract | Publisher Full Text\n\nLiterature Review, Conceptual Framework and Methodology Background Characteristics of Women:n.d.\n\nMonitoring, P: Pma2020/kenya. 2018. 2020. (December 2018), 2018–2019.\n\nMumah J, Kabiru C, Mukiira C, et al.: Unintended Pregnancies in Kenya: A Country Profile. April. 2013; 110.Reference Source\n\nNyarko SH: Unintended Pregnancy among Pregnant Women in Ghana: Prevalence and Predictors. J. Pregnancy. 2019; 2019: 1–8. Publisher Full Text\n\nObiero BO, Mwai D: Determinants of Unintended Pregnancy in Kenya. International Journal of Academic Research in Economics and Management Sciences. 2018; 7(1). Publisher Full Text\n\nOjuok R, Dr Mutai J , Dr Nyamongo D : Determinants of unintended pregnancy among women attending antenatal clinic at Kenyatta National Hospital. figshare. Dataset. 2022. Publisher Full Text\n\nSedgh G, Bankole A, Oye-Adeniran B, et al.: Unwanted pregnancy and associated factors among Nigerian women. Int. Fam. Plan. Perspect. 2006; 32(4): 175–184. Publisher Full Text\n\nUNFPA: Kenya Annual Report 2015. 2015.\n\nUNFPA: Summary report of the assessment of UNFPA’s advocacy campaign to end preventable maternal and Newborn mortality in Kenya. 2016; 1–20."
}
|
[
{
"id": "148558",
"date": "13 Sep 2022",
"name": "Ayodele. O. Arowojolu",
"expertise": [
"Reviewer Expertise Public health Nutrition and clinical nutrition",
"Contraception and reproductive health issues."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe title is appropriate and relevant to the study carried out. It predicts the content and type of study.\n\nThe abstract is structured, reflecting the introduction, methodology, results, and conclusion of the study. The keywords are relevant.\n\nThe introduction is clearly and accurately presented and does cite the current literature.\n\nThe study design is appropriate, and the work has academic merit.\n\nThe details of the methods show that the study is a survey using a structured questionnaire (of unknown source). However, it is uncertain if this was self-administered or not. (The authors dwelt more on the process of obtaining consent from the participants by the assisting nurses).\n\nSample size calculation used appropriate formula, but no correction was made for attrition during the study. Fortunately, no attrition occurred during the study.\n\nThe sampling technique is systematic using recorded antenatal case record as the sample frame with calculated sampling interval.\n\nThe statistical analysis and its interpretation are appropriate. The section is well described and should allow replication by others. However, the analysis will be richer if a stepwise multivariate logistic regression is performed in addition, to determine the influence of the relevant variables in predicting the outcome measure (unintended pregnancy). All the source data underlying the results are available to ensure full reproducibility of data.\n\nThe results are clearly presented in the text and tables with correctly labeled titles. Statistical measures and results are well shown.\n\nThe discussion of all the findings of the study according to the stated objectives is adequate and related to previous studies in the literature with which appropriate comparisons are made. The validity of the result findings is discussed along with adequate explanation of the factors associated with them.\n\nThe conclusions drawn are adequately supported by the results provided. The recommendation of family planning health education and improvement of facilities, as well as promotion of antenatal care services usage in the community, so as to increase awareness of consequences of unintended pregnancy and its prevention is appropriate.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "153526",
"date": "26 Oct 2022",
"name": "Chitkasaem Suwanrath",
"expertise": [
"Reviewer Expertise Maternal fetal medicine. Obstetrics and Gynecology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis research is interesting and useful for developing country where unintended pregnancy is prevalent.\nThe title is appropriate and reflects the study design as well as prediction of potential factors associated with the unintended pregnancy.\n\nThe abstract is well written. The background states the magnitude of the problem and gap of knowledge. Methods, results and conclusions are appropriate and concise. However, I would suggest to delete the word \"such as\" in line 3 of Results. Since there are only 3 significant factors.\n\nkeywords: in my opinion, \"18-49 years\" should be deleted.\n\nIntroduction: It is well written, reflecting the magnitude of the problem in regions with high prevalence of unintended pregnancy as well as the authors' country. Gap of knowledge is stated. Literature review is appropriate and relevant to the study.\n\nMethods: Study design is appropriate. Sample size calculation is correct. Sampling technique is clearly described. Data analysis is well explained.\n\nResults: All relevant outcomes are presented. However, please do not replicate the results in the text if they are already in the tables, just summarize which factors are statistically significant.\n\nDiscussion are appropriate, summarized significant findings and compared with relevant previous studies. It is well explained for associated factors with unintended pregnancy.\n\nConclusions are concise with good recommendation.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-585
|
https://f1000research.com/articles/11-584/v1
|
27 May 22
|
{
"type": "Research Article",
"title": "COVID – 19 and psychiatry teaching during the outbreak of the pandemic at the Eduardo Mondlane Medical School",
"authors": [
"Maria Salomão Pedro",
"Antonio Palha",
"Maria Ferreira",
"Antonio Palha",
"Maria Ferreira"
],
"abstract": "Background: The COVID-19 pandemic had a considerable impact on the lives of the world's population, which led to the closure of educational institutions including in Mozambique. In March 2020, the state emergency forced students and professors to change in-person classes to online learning because of the pandemic.\n\nObjectives: To access students’ capacities in terms of technological resources to participate in the 5th-year online classes of the Eduardo Mondlane University Medical School and the difficulties they encountered throughout the year. Additionally, psychological symptoms associated with confinement and how that affected participation in psychiatry and mental health classes were assessed.\n\nMethods: A cross sectional social online questionnaire survey was conducted among 32 students enrolled in the 5th-year psychiatry and mental health classes of the Eduardo Mondlane University Medical School during May and June 2021.\n\nResults: A total of 47 students were invited to participate in this survey, of which 32 students (68%) participated. Of the participants, 16.7% reported the presence of psychological symptoms associated with confinement. All students could participate in online classes using cell phones, computers, and tablets. However, 34.4% did not have a laptop. In this study, 87.5% of the respondents reported poor internet quality, and 12.5% of students did not have internet and had to join colleagues to participate in classes and to interact with the members of their groups. Most of the students (90.6%) were not prepared or knew how to use google classroom, Skype, and Zoom, before the lockdowns.\n\nConclusions: The study suggests that the abrupt and radical change from in-person teaching and learning methods to remote online methods showed the weaknesses of students in terms of resources (computers, tablets, internet) and knowledge for the implementation of online classes. Psychological symptoms were present but did not affect student participation in remote psychiatry and mental health classes.",
"keywords": [
"Medical education",
"Teaching of Psychiatry",
"COVID-19",
"psychological and economic influence."
],
"content": "Abbreviations\n\nCOVID-19: Coronavirus disease 2019\n\nTvCabo: Tv Network by cable\n\nUEM: Eduardo Mondlane University\n\nWEF: World Economic Forum\n\nWHO: World Health Organization\n\n\nIntroduction\n\nIn March 11,2020, COVID-19, caused by SARS COV 2, was declared a pandemic by the World Health Organization (WHO).1 Till date, this disease has infected more than 435 million people and caused the death of more than 5 million.2 It brought challenges to the health, economic, financial, educational and tourism sectors, among others, which had to reinvent and change the work and functioning paradigm of institutions.3\n\nIn Mozambique, on March 20, 2020, the President of the Republic of Mozambique, Filipe Jacinto Nyusi, in a declaration to the nation, determined the closure of schools from pre-primary to higher levels to reinforce measures to prevent the spread of the coronavirus pandemic.4 The Ministry of Health announced the first case of SARS COV 2 infection diagnosed in Mozambique on March 22, 2020.5 On March 31, 2020, the President of the Republic declared a State of Emergency,6 which was approved by the Assembly of the Republic on March 31, and promulgated on the same date through Article No.11/2020 which refers to the “suspension of classes in all public and private schools, from pre-school to university education”.6 This presidential decree was followed by two others, extending the State of Emergency for 30 days in succession, starting on May 1, and the third, published on May 29, which extends the State of Emergency until June 30, 2020.7,8\n\nThe education sector, perhaps, is the one that has brought the most debate, due to its negative impact on the suspension of classes from daycare centers, primary secondary schools, universities to higher institutes because of the lack of technological resources and the gaps in the use of technological means by teachers and students.9 Most professors in the universities and technical institutes had no online teaching experience. Associated, there was a cash-flow reduction due to the drastic decrease in income caused by the non-payment of regular fees by part of the students blocking institutions from being able to modernize and adapt to the “new normal”.9\n\nThe Ministry of Science, Technology, and Higher Education issued the official letter 169/MCTESTP/GM/2020 on March 21.10 The letter instructed subordinate institutions to draw up operating plans to ensure the continuity of classes through ICTs (emails, WhatsApp, google classroom, Zoom meetings, and other platforms).\n\nThe Eduardo Mondlane University (UEM), through the Magnificent Rector, issued several guidelines and appeals, following the recommendations of the Ministry of Science, Technology and Higher Education, the last being the V Exhortation of May 22, which states11:\n\n1. The continuity of the administrative enforcement measures inherent to the State of Emergency, approved by Decree No. 12/2020, of 2 April, which includes, among others, efforts to prevent and control COVID-19 and to ensure personal protection.\n\n2. The application of the knowledge of researchers and professors in the different areas of expertise to support communities and national institutions in solutions for the prevention and mitigation of the new coronavirus pandemic.\n\n3. Regular evaluation of online platforms by students and teachers to guarantee the continuous improvement of the distance learning process.\n\n4. The intensification of strategic use of the resources that UEM has been allocating, namely the video conference laboratories and computer equipment, the bibliographic material remotely available, and the different online platforms to improve the teaching and learning process (V Exhortation, Prof. Orlando Quilambo).11\n\nUEM carried out several training courses for teachers and recommended using Moodle, Google Classes, and Zoom platforms for interaction with students, having a permanent support service for teachers and students, resuming classes in progress. Evaluations to be carried out from May 2020.\n\nGiven the short-term measures taken in March 2020, the changes negatively impacted regular classes. This research aimed to identify if the suspension of classroom lessons would have a psychological and economic influence on the participation in online learning of the discipline of psychiatry and mental health of 5th year students at the Eduardo Mondlane Medical School. The objectives were to assess the availability and the ability of students in using technological and computer means to participate in online learning, and the difficulties that they encountered throughout the semester right after the outbreak of the COVID-19 pandemic. Additionally, this study explored the existence of psychological symptoms associated with confinement that possibly affected participation in online classes.\n\n\nMethods\n\nEthical approval: The institution Ethics Committee of the Faculty of Medicine did not regard this project as medical or health professional research according to law, as such ethical approval was not needed.\n\nInformed written consent with details of ethical issues (confidentiality, anonymity, and beneficence) was obtained from all the participants of this study and participants answered the survey on a personal device (e.g., computer, phone). The questionnaires did not include questions about sensitive personal data. All procedures were conducted in accordance with the principles of the Declaration of Helsinki. Participants received no monetary compensation.\n\nDuring May and June 2021, a cross-sectional study was conducted on students enrolled in psychiatry and mental health classes at the Eduardo Mondlane University Medical School. This study used an online survey, produced on Google forms. The questionnaire was comprised of 27 multiple- choice questions, six of which were on the demographic characterization of the sample (Questions 1 to 6) and the others related to the topic under discussion (Availability of equipment and technology, state of mind, motivation, teaching preferences, and recommendations to improve classes). Of these 21 questions, seven were semi-open (7, 8, 13, 16, 18, 19, 20), and the last three (25, 26, and 27), were open (Underlying data)12\n\nParticipants were sent a link to access information and to complete the survey via WhatsApp.\n\nData were analyzed using Statistical Package for Social Science (SPSS) version 24 (SPSS Inc., Chicago, IL, USA). All continuous variables were expressed as proportions (%).\n\n\nResults and discussion\n\nOf the 47 students that were enrolled in the 5th year psychiatry and mental health course at the Eduardo Mondlane University, 32 (68%) participated in this study. Half of the participants (16) were aged between 23 and 25 years, a quarter (8), aged between 20 and 22 years, seven or just under a quarter, aged between 26 and 28 years and one was above 29 years of age. The results indicated that 19 students (59.4%) were female, and 13 (40.6%) were male, in a class with a predominance of females. Regarding the place where they lived, 24 students (75%) lived in Maputo City, near the Faculty, and eight (25%) of students lived in Maputo province, more than 20 kilometers away from the school (Three in Tchumene, two in Matola, one in Fomento, one in Intaca and one in Marracuene). In total, 18 students lived with their nuclear family (56.3%), six (18.8%) lived with family members, five (15.6%) lived in a university residence, and three (9.4%) lived alone. All students lived in houses with water and electricity.\n\nWhen asked about their emotional state at the time of the survey, one (3.4 %) reported being depressed, four (13.3 %) indicated being sad, and the majority (27, (83.3%)) stated that they felt good. Pragholapati (2020), when referring to the impact of COVID-19 on students, says that their mental health is greatly affected when they face a public health emergency and need attention, psychological assistance, and support from the community, family, and institutions dedicated to mental health.13 The results of that study agree with other studies, which show that lockdown of educational institutions and not attending classes developed anxiety and depression disorders among students. A survey conducted by Basheti (2021) reports that students were significantly affected mentally during the pandemic, with many experiencing borderline symptoms of abnormal anxiety (22.4%) and depression (33.8%).14\n\nRegarding equipment needed to participate in online classes, 20 students (65.6 %) had a computer, and 12 (34.4 %) did not have a computer. Considering the ownership of tablets, 23 students (71.9%) had tablets, and nine (28.1%) did not. All students had a cell phone with IOS or an android system. For participation and access to classes, 23 the students (71.9%) used computers and cell phones, while the rest only used cell phones; 21 (65.5%) used a combination of computer, tablet, and mobile phone to study after participating in online classes (Underlying data)15 All students had a mobile network for internet access, and eight students (25%) also used the internet from specific internet providers (TvCabo, UEM). In this study, 29 students (90.6%) were not prepared or knew how to use Google classroom, Skype, and Zoom. Despite this lack of preparation, 31 students (96.9%) participated in classes. The main difficulties in accessing the classes were due to poor internet quality, which was reported by 28 (87.5%) students or lack of internet, as mentioned by four students (12.5%). These were the same problems stated for the lack of interaction with the group (Poor internet quality (87.5%) or lack of internet (12.5%)) (Underlying data).16\n\nRegardless of the unavailability of tablets and computers and internet access being a concern for the faculty, students could participate in classes using a combination of computer, tablet, and cell phone and private networks. The quality of the internet network was a concern. Armstrong-Mensah et al. (2020) conducted a study at the University of Georgia which found that class participation rates were high, despite concerns about the quality of the internet. As online teaching will continue there is a need to find alternative ways for students to participate in class in Mozambique.17 In terms of time devoted to study, one-third of the students only dedicated themselves to individual study twice a week, and 43.8% studied on alternate days—approximately 32% of the students engaged in studying regularly. Half of the students interacted with their peers on alternate days.\n\nIn the present study, approximately 30% of students dedicated their days to studying, and this lack of motivation was due to the isolation. Tan (2020) indicates that due to the isolation, distancing and closure of educational institutions students must change their individual and group study methods and find means of study that best adapt to their realities.18 The change would help them find ways to improve concentration for personal study, improve interaction with colleagues, find other activities that help with motivation. Additionally, it is important for teachers to be available online. As for the methodology to improve the understanding of the content taught, universities need to organize training sessions to prepare teachers to be more effective in conveying the study content through online platforms.10 Regarding the information and work assigned to the students, all mentioned that the files and clinical cases were duly prepared and guided the individual study and the group study sessions.\n\nIn this study the perception of students after a few months of virtual teaching at the Faculty of Medicine of the Eduardo Mondlane University was assessed. Despite the challenges that the COVID-19 pandemic brought, students showed a great ability to adapt to the new reality, and they made an effort to maintain the level of learning. The study participants mentioned many positive and highlighting aspects that can be use in future studies (Underlying data).19\n\nIt was possible to find psychological symptoms associated with confinement that affected class participation in five students (16.7%), but most of them (27) managed to deal well with the lockdown (6).\n\nThe evolution of the pandemic is uncertain, and it is up to institutions and their students to create online teaching programs and methods using the technology that best suits the reality of the institution and the country to ensure excellent training.\n\n\nConclusions\n\nThe present study evaluated the resources of students to participate in online classes and the type of difficulties faced during the lockdown period.\n\nAccording to WEF, 2020, education has changed dramatically, with the distinctive rise of e-learning, whereby teaching is undertaken remotely and on digital platforms.20\n\nAfter the Declaration of the State of Emergency in Mozambique in March 2020 and the closure of teaching institutions, there was an interest on the part of students and teachers to participate and support online teaching despite the existence of several aspects that affected e-learning. This study acknowledges that the faculty did not have any policy in place for virtual learning methods nor was training provided. Owolabi (2020) states that “the existence of appropriate expertise and methods to develop virtual learning environments in adequate infrastructures and the provision of effective training or workshops on knowledge, skills and attitude of how to teach in the virtual environment would be important to provide quality teaching”.21\n\nZinyemba et al. (2021) found that there was a disparity between the students who lived in rural areas and due to their circumstances had no internet and the ones who lived in urban areas, near Wi-Fi spots.22 This study indicates that the students who resided outside Maputo City were the ones who complained the most about the quality of the internet and had to travel long distances in order to participate in online classes.\n\nMukhtar (2020) mentions that online learning modalities encourage student-centered learning which were easily manageable during lockdown situation.23 The results of this study showed that these fifth-year students seemed to adapt quickly to the sudden shift to online education, despite the fact that 11 (34%) of them did not have a computer to participate in classes and used only their cell phones as study device.\n\nLack of direct interaction between students and teachers, a feeling of being alone during studies, unfit housing situations for home office purposes, including insufficient data bandwidth, and a sense of reduced motivation and effort are the most pressing concerns among students.24,25 In this study 21 students mentioned that the State of Emergency, that led to remote classes, preventing them from having contact with colleagues and professors or having internships in the hospitals was the most difficult part of the interruption of face-to-face classes during the first year of lockdown due to the COVID 19 pandemic.\n\nThis study did not find that the psychological impact of the pandemic on students was significant although Guidotti et al. discovered a notable percentage of neuropsychology trainees reported increased personal mental health symptoms (i.e., anxiety/depression; 74/54%) as well as several other personal stressors.26 Huckins et al. and Wayne et al. concluded that compared with prior academic terms, individuals in the Winter 2020 term were more sedentary, anxious, and depressed.27,28\n\nOur study suggests that the abrupt and radical change in teaching and learning methods to remote online methods showed the weaknesses of students in terms of resources (computers, tablets, internet) and knowledge for the implementation of online classes.\n\nEducational institutions and the government should consider investing in public policies for data access networks to improve the quality of the internet provided to the citizens as the “new normal” requires more significant interaction through these platforms.\n\nFinally, there is room for improvement, in approaching the themes and assessing the knowledge and skills of students to make virtual learning environments more effective and, indeed, we can say for sure that the first year of the SARS COV 2 pandemic constituted a teaching opportunity for everyone - teachers, students, and government officials.\n\nTo the best of our knowledge, this is the first study that evaluates the means of participating in remote classes at a medical school in Mozambique, providing a clear understanding of the material conditions of this group and the taking of some immediate measures to improve the virtual model of teaching and learning. On the other hand, the results can be used by the school of medicine and the government as a starting point to improve the quality of teaching and assessment of online methods in Mozambique.\n\nThe limitation of this study was its small sample size since it was confined to the students that were enrolled in Psychiatry and Mental Health classes.\n\nMore research on the subject, with samples that include students from the first to the final year of the medical course and more medical institutions could improve the knowledge about the best teaching approaches for maintaining social distancing to ensure everyone's safety.\n\n\nData availability\n\nZenodo: COVID – 19 and psychiatry teaching during the outbreak of the pandemic at the Eduardo Mondlane Medical School\n\nThis project contains the following underlying data:\n\nData file 1. Survey Questionnaire\n\nDOI: 10.5281/zenodo.653384512\n\nData file 2. Survey answers -Table 1\n\nDOI: 10.5281/zenodo.653385915\n\nData file 2. Survey answers –Table 2\n\nDOI: 10.5281/zenodo.653386516\n\nData file 2. Survey answers -Table 3\n\nDOI: 10.5281/zenodo.653387219\n\nData are available under the terms of the Creative Commons International “No rights reserved” data waiver (CC BY 4.0).\n\n\nAuthor contributions\n\nMSP conceptualized, wrote, prepared for submission and worked in the finalization of the article. APP contributed the critical reading, coherence and editing of the article. MAF was part of the conceptualization process and contributed to the overall writing, editing, and overseeing the coherence and writing of the ideas.",
"appendix": "Acknowledgements\n\nThank you to students of the 5th year of the medical course at Eduardo Mondlane University, 2020, the professors of the discipline of Psychiatry and Mental Health, Professor Doctor João Salomão and Professor Doctor SeverinoNgoenha.\n\n\nReferences\n\nWHO: WHO Director-General’s opening remarks at the media briefing on COVID-19-11 March 2020. Geneve:WHO;2020; 1–9.Reference Source\n\nWHO:WHO dashboard.Reference Source\n\nMarotta C, Nacareia U, Estevez AS, et al.:Mozambican adolescents and youths during the covid-19 pandemic: Knowledge and awareness gaps in the provinces of sofala and tete. Healthcare. 2021; 9(3).\n\nFica atento website.\n\nPrimeiro caso de covid 19 Moçambique.\n\nda República P :Decreto Presidencial no 11/2020 de 30 de Março. Vol. I Série, Decreto Presidencial no 11/2020 de 30 de Marco.2020; p. 0–1.\n\nDecreto-Presidencial-n.o-21_2020.pdf.\n\nPresidencia da Republica de Mocambique:Decreto Presidencial 14/2020.2020; 181.\n\nCTA:Impacto da COVID-19 no Ensino Superior em Moçambique e Perspectivas de Retoma. Cta. 2020; 8.Reference Source\n\nMCTES:Medidas-de-Prevenção-da-Pandemia-do-novo-Coronavírus-COVID-19-nas-Instituições-de-Ensino-Superior-públicas-e-privadas.pdf.\n\nReitoria da UEM:Exortação V. Cidade de Maputo.2020.\n\nPedro MR, Palha AP, Ferreira MA:Data File (1) - Survey Questionnaire (Version V0) [Data set]. Zenodo. 2022; p. 2. Publisher Full Text\n\nPragholapati A:Covid-19 Impact on Students.2020; 1–6.\n\nBasheti IA, Mhaidat QN, Mhaidat HN:Prevalence of anxiety and depression during COVID-19 pandemic among healthcare students in Jordan and its effect on their learning process: A national survey. PLoS One. 2021; 16(4 April): e0249716–e0249716. PubMed Abstract | Publisher Full Text\n\nPedro MR, Palha AP, Amélia FM:Data file 2. Survey answers - Table 1 (Version V0) [Data set]. Zenodo. Publisher Full Text\n\nPedro MR, Palha AP, Ferreira MA:Data file 2. Survey answers - Table 2 (Version V0) [Data set]. Zenodo. 2022; 3. Publisher Full Text\n\nArmstrong-Mensah E, Ramsey-White K, Yankey B, et al.:COVID-19 and Distance Learning: Effects on Georgia State University School of Public Health Students. Front. Public Health. 2020; 8(September): 1–10. Publisher Full Text\n\nTan C:The impact of COVID-19 on student motivation, community of inquiry and learning performance. Asian Educ. Dev. Stud. 2021; 10(2): 308–321. Publisher Full Text\n\nPedro MR, Palha AP, Ferreira MA:Data file 2. Survey answers - Table 3 (Version V0) [Data set]. Zenodo. 2022; 3. Publisher Full Text\n\nWorld Economic Forum:The COVID-19 pandemic has changed education forever.2020.Reference Source\n\nOwolabi JO:Virtualising the school during covid-19 and beyond in africa: Infrastructure, pedagogy, resources, assessment, quality assurance, student support system, technology, culture and best practices. Adv. Med. Educ. Pract. 2020; Volume 11: 755–759. PubMed Abstract | Publisher Full Text\n\nZinyemba L, Nhongo K, Zinyemba A:COVID-19 induced online learning: the Zimbabwean experience. Afr. J. Soc. Work. 2021; 11(4): 223–230.Reference Source\n\nMukhtar K, Javed K, Arooj M, et al.:Advantages, limitations and recommendations for online learning during covid-19 pandemic era. Pakistan. J. Med. Sci. 2020; 36(COVID19-S4): S27–S31. Publisher Full Text Reference Source\n\nSelvaraj A, Radhin V, KA N, et al.:Effect of pandemic based online education on teaching and learning system. Int. J. Educ. Dev. 2021; 85(April): 102444. PubMed Abstract | Publisher Full Text\n\nAlmahasees Z, Mohsen K, Amin MO:Faculty’s and Students’ Perceptions of Online Learning During COVID-19. Front Educ. 2021; 6(May): 1–10. Publisher Full Text\n\nGuidotti Breting LM, Towns SJ, Butts AM, et al.:2020 COVID-19 American Academy of Clinical Neuropsychology (AACN) Student Affairs Committee survey of neuropsychology trainees. Clin. Neuropsychol. 2020; 34(7–8): 1284–1313. PubMed Abstract | Publisher Full Text\n\nHuckins JF, da Silva AW , Wang W, et al.:Mental health and behavior of college students during the early phases of the COVID-19 pandemic: Longitudinal smartphone and ecological momentary assessment study. J. Med. Internet Res. 2020; 22(6): e20185. PubMed Abstract | Publisher Full Text\n\nWayne DB, Green M, Neilson EG:Medical education in the time of COVID-19. Sci. Adv. 2020; 6(eabc7110): eabc7110. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "169840",
"date": "18 Jul 2023",
"name": "Ravi Rajkumar",
"expertise": [
"Reviewer Expertise Psychiatry",
"mental health",
"psychopharmacology",
"psychosocial factors associated with pandemics and disasters",
"attachment theory",
"neurobiology of mental illness"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper examines the impact of the COVID-19 pandemic on the educational experience of a group of medical students in Mozambique.\nAs there are relatively few studies of this nature from the geographical region in question, the current study is valuable as a source of original results.\nThere are certain aspects of the paper that would benefit from correction or clarification:\nIntroduction: This section could be improved by coverage of the following two issues:\nGeneral details of readiness / infrastructure availability for online education in Mozambique and neighbouring countries, including any challenges specific to this country (e.g., Internet coverage and quality, unreliable electricity supplies, high cost of materials, economic hardship among students)\n\nImpact of the COVID-19 pandemic in Mozambique (in general, in terms of cases, deaths, prevalence, mortality / fatality rates) and the specific medical college in question (e.g., was it used as a centre for the treatment of COVID-19 cases, did students have to take up additional duties / responsibilities in caring for patients with COVID-19 during the pandemic?)\nMethodology: As this study has made use of a single, semi-structured questionnaire, more details of its development are required. On what basis were the items selected (e.g., expert opinion, literature review of prior studies from other countries, discussions with students or other stakeholders)? Was any attempt made to validate the instrument (e.g., through review by an independent expert, or through a pilot study in a smaller number of students)? What other tools / questionnaires have been used in earlier studies in this population during the COVID-19 pandemic, and what are the advantages / disadvantages of the questionnaire used in the current study compared to these?\nData analysis: The authors have chiefly presented descriptive statistics and no attempts at examining correlates / relationships between each variable of interest were presented. Could any of these associations be worth examining (e.g., relationships between sociodemographic characteristics and quality / availability of Internet access, relationships between difficulties in attending online classes and mental health status)? As most work in this field includes both descriptive and analytical components, this is a significant limitation of the current study.\nSample size / selection: The sample size of n = 32 seems low for a study of this kind. Why did the authors select only students attending a mental health / psychiatry course? As the issues being examined by the authors are not specific to mental health / psychiatry training and are generally applicable to online education as a whole, could a larger number of students have been included?\nResults & Discussion: This section could be improved by presenting the key study findings in 2-3 tables. The text in this section should ideally summarize the most important results and not contain an excess of numerical data. This section could be improved by discussing similar studies of medical / healthcare students from other low- and middle-income countries (or at least other African countries) and comparing them with the results of the current study. The limitations of the current work should also be discussed frankly.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "270027",
"date": "05 Jun 2024",
"name": "Manar Al-Azzam",
"expertise": [
"Reviewer Expertise psychiatric mental health"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for allowing me the opportunity to review this journal submission and to provide feedback. This article aimed to access students’ capacities in terms of technological resources to participate in the 5th-year online classes of the Eduardo Mondlane University Medical School and the difficulties they encountered throughout the year. Additionally, psychological symptoms associated with confinement and how that affected participation in psychiatry and mental health classes were assessed. .\nTherefore, I believe that this study is working to address gaps in the literature. However, despite the work the authors are doing to address this gap, I have some concerns related to the study and the document. I review these concerns below.\nFeedback:\nLiterature Review:\nThe authors need to restructure the literature review to better make the case for why the data they are gathering is useful. Though there may be relatively little data collected about patients in the studied area.\n\nMethods:\n\nMore data is needed about the data collection process. When was the study conducted? The sample size is too small, resulting in the sample being underpowered. The authors have not mentioned how they decided the needed sample size. What were the inclusion and exclusion criteria? More information is needed about the instruments, were they adopted? Did the authors develop them? What are the geometric information about the instruments? what type of statistical analysis tests were used?\n\nDiscussion\n1. The structure of the discussion should be revised. The authors should not restate specific data but should rather address big ideas. This will be easier to do when the literature they cite in the discussion is actually reviewed in the literature review section first.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-584
|
https://f1000research.com/articles/11-582/v1
|
27 May 22
|
{
"type": "Research Article",
"title": "Color translation from monoscopic photogrammetry +ID Methodology into a Polyjet final 3D printed facial prosthesis.",
"authors": [
"Rodrigo Salazar-Gamarra",
"Andrés Cárdenas-Bocanegra",
"Uri Masch",
"Cícero André Da Costa Moraes",
"Rosemary Seelaus",
"Jorge Vicente Lopes Da Silva",
"Luciano Lauria Dib",
"Andrés Cárdenas-Bocanegra",
"Uri Masch",
"Cícero André Da Costa Moraes",
"Rosemary Seelaus",
"Jorge Vicente Lopes Da Silva",
"Luciano Lauria Dib"
],
"abstract": "Background: The artistic techniques necessary to fabricate facial prostheses mainly depend on individual skill and are not a resource easily reproduced. Digital technology has contributed to improved outcomes, often combining analog and new digital techniques in the same workflow. Methods: This article aims to present an innovative workflow to produce a final colored 3D printed and facial prosthesis by UV-map color translation into colored resin 3D printing. A modified +ID Methodology was used to obtain 3D models with the calibrated 3D printable patient’s skin color. No hands-on physical molding, manual sculpture, or intrinsic silicone coloration was used. Results: The outcome resulted in acceptable aesthetics, adaptation, and an approximate color match after extrinsic coloration. The patient reported good comfort and acceptance. Conclusions: A direct resin 3D printed prosthesis may be a viable alternative, especially for rapid delivery as an immediate prosthesis or an option when there is no experienced anaplastogist to manufacture a conventional prosthesis.",
"keywords": [
"3D printing",
"color",
"head and neck neoplasms",
"prosthesis design",
"maxillofacial prosthesis"
],
"content": "Introduction\n\nThe customized production of facial prostheses is a worldwide challenge due to multiple factors. Lack of formal education programs, a steep technical learning curve with associated high costs, the working time and labor-intensive nature of the work, lack of reliable supply chain for materials, and limited health system coverage are among the many challenges. Among the maxillofacial prosthodontics and anaplastology services, the most significant challenges from the fabrication perspective are the processes of molding, sculpture, and coloration reproduction. The technique-specific processes that mainly rely on individual artistic capabilities represent a scarce clinical resource.1,2\n\nIn the past two decades, digital technology has been progressively overcoming some of these challenges being a source of innovation for techniques, methods, and biomaterials, combined with conventional methods for optimizing the efficiency and outcomes of facial prosthetic rehabilitation.3–8 Some workflows have been proposed combining different hardware & software tools for a) data acquisition (CT scans, MRI, laser, structured light or photogrammetry scanners), b) 3D modeling resources (mirrored anatomy, digital manual sculpting, digital donors or digital libraries, etc.) and c) 3D manufacture methods like 3Dprinting (FDM, SLA, DLP, LCD, Polyjet, SLS, etc.) or CNC milling machines.7,9–12\n\nDue to the high cost of some of these resources, one of the recent trends is achieving digital results using more accessible resources. In that sense, the authors previously proposed a complete workflow for 3D accessible facial prosthesis, called Plus ID Methodology (+ID). It uses monoscopic photogrammetry from smartphone captures, open-source software, and low-cost 3D printers.3,7\n\nMore recently, efforts about direct 3D printing of facial prosthetic materials and semi-final devices have been evolving. Physical and chemical optimization of the elastomeric material properties have been tested for suitable additive manufacture production for facial prosthetics.13,14 Also, authors have published reports on 3D printed nasal and auricular prosthesis as semi-final devices in medical-grade silicone, multi-material consistency silicone, and flexible resin to produce interim prosthesis. However, enhancements and limitations were recognized in terms of technology, ideal characteristics of the materials proposed, biocompatibility, margin adaptation, and desired combined properties as one unique solution.5,6,15\n\nIn a parallel line, the industry of resin 3D printing has been advancing in color 3D printing. VRML files allow carrying the voxel-color information from UV-Map JPG files in a common language for additive manufacturing, as CMYK works for 2D printing. The monoscopic photogrammetry 3D models obtained by +ID are suitable for calibration and export into VRML files. They adequately communicate with a specific resin 3D printer compatible with color 3D printing, like the Stratasys J750®.\n\nThe possibility of using color translation from accessible 3D scanning and computer graphic tools to overcome color reproduction with greater automation, and less manual work, is promising for a more productive and practical solution for future patients and professionals in facial prosthetics.\n\nThe purpose of this publication is to contribute an innovative methodology and multi-material color resin 3D printing technique as a proposed combined specific workflow of digital resources to obtain a resin full-color 3D printed facial prosthesis for an orbital prosthesis by full-color Polyjet 3D printing.\n\n\nMethods and results\n\nA 56-year-old man from our PlusID Maxillofacial Prosthetics department at the Universidade Paulista (UNIP) was due to renew his old prosthesis and voluntarily agreed to participate in the present study after reviewing ethical considerations and signing the informed consent. The research was given ethics committee approval N° 2.509.955 by the ethics committee “Associacao Unificada Paulista De Ensino Renovado Objetivo” CAAE 83301517.7.0000.5512 regulated by the Brazilian Platform.\n\nThe +ID Methodology was used to obtain the 3D model of the facial prosthesis. (The +ID Methodology refers to the combined use of smartphones and open-source software features to produce the desired 3D model of the prosthesis.) After clinical and functional evaluation, a delimitation of the margins of the prosthesis were defined, joined by a clinical measurement of the largest diameter of the area, performed with an electronic caliper for further scaling of the model (Figure 1). No less than 1000 lux was used to illuminate the subject by indirect natural light in the scene, measured by a smartphone (Samsung Galaxy Note 8) app (Light Meter – Lux & Kelvin, Trajkovski Labs). No part of the anatomy of the face was cut out from the captures (the ears and the tip of the nose must be included). The coverage of the face of the patient was no less than approximately 80% of the screen. This “close-up” display determined the distance between the camera and the subject, focusing on the desired anatomical region; the more face coverage, the more data available for registration with each capture (Figure 2). Optical deformations were compensated for mathematically by orthographic projections in the open-source software for 3D modeling (OrtogOnBlender v2.80). A specific series of 39 photographs (3 different heights, 13 angles per height) were captured in this subject-operator setup (Figure 3). A fiduciary color element (VITA-PAN® Dental Shade A2 L83 A1 B22) was placed within the capture area, a photo was then taken using the smartphone’s built-in camera, with all filters deactivated.16 Files should be JPG. Captures were downloaded into a Dell computer (Model: G5 i7, 32gb ram, graphics card rtx2060) and loaded into +IDonBlender add-on to execute a monoscopic photogrammetry process selecting the OpenMVG+OpenMVS photogrammetry option, with D factor in 6 and Smooth factor at 16. After ten minutes on a computer with optimized features (i7 9th Generation Intel Processor with 16Gb Ram and Geforce RTX/Nvidia graphic cards), an OBJ file (3D file) linked to the JPG file (Texture map/UV Map) of the subject’s face was obtained3 (Figures 4 and 5).\n\n(Written informed consent for publication of the patient’s details and publication of the identifiable image in Figure 1 was obtained from the patient).\n\nAppropriate focus is important to optimize data registration and to avoid blurry zones that may compromise the result. (Written informed consent for publication of the patient’s details and publication of the identifiable image in Figure 2 was obtained from the patient).\n\nThe angle between photo 1 and 13 has an angle of approximately 120 degrees with the point of interest to ensure accuracy beyond the frontal region of the face.\n\nNotice that the delimitations of the prosthesis, decided and drawn clinically before the photo captures, were appropriately reproduced and will be helpful to transport the clinical needs of the 3D modeling tools. (Written informed consent for publication of the patient’s details and publication of the identifiable image in Figure 4 was obtained from the patient).\n\nThis UV map wraps the 3D model (OBJ), aligned with the MTL in order to obtain full color aligned to the 3D geometry. (Written informed consent for publication of the patient’s details and publication of the identifiable image in Figure 5 was obtained from the patient).\n\nThe healthy unaffected left orbit was used and mirrored over the defect (Figure 6). 3D sculpting tools, Boolean operations, and the application of multiresolution and displacement modifiers were used to ensure reproduction of the fit, adaptation, and realistic skin detail.3 The JPG of the color texture map,17 including the fiduciary color element, was calibrated according to LAB color tools of Adobe Photoshop® 2020, v21.0.6, image editing software, using the fiduciary element color space coordinates as a target. The final size, form, and color of the 3D model information were exported into a VRML file, which carries information on color, transparency, brightness, texture and is compatible with the CMYKW format of 3D printers.\n\nThe prosthesis looks gray because the UV-Map was hidden, allowing the mesh to be shown. (Written informed consent for publication of the patient’s details and publication of the identifiable image in Figure 6 was obtained from the patient).\n\nThe VRML file was imported into the GrabCAD Print® software v1.33 of the Stratasys® J750 3D printer. The software automatically identifies the color-per-voxel information of the VRML file and shows an approximate representation of the colors in the workbench. When selecting the color resins, the user must choose between “Absolute” or “Relative” color gamut approximation. We used “Absolute” because it creates a mathematical approximation from the RGB to the CMYKW color expression for those RGB colors out of the CMYKW gamut expression. The selected and loaded resins into the printer in this case were VeroFlexBlack, VeroFlexClear, VeroFlexCyan, VeroFlexMagenta, VeroFlexWhite, VeroFlexYellow and support resin FullCure705 (Figure 7). Additionally, the flexible resin Agilus® was used for the base of the printed model, although due to the concentration of rigid colors, the final result was as expected, obtaining a prosthesis of high hardness. The time spent to 3D print the prosthesis was six hours and twenty-two minutes in high quality (14 microns in layer Z). The total resin used was 113 grams divided into 99 g of support resin FullCure705, 13 g of VeroFlexBlack, 13 g of VeroFlexClear, 14 g of VeroFlexCyan, 18 g of VeroFlexMagenta, 36 g of VeroFlexWhite, and 19 g of VeroFlexYellow, automatically estimated by GrabCAD Print® v1.33, using the chosen settings. The “Matte surface” was selected aiming to get a regular surface finishing for the whole part. The support material was easily removed by using some hand tools and water. The mechanism of the Polyjet 3D printer allows a layer-by-layer unique mixture of resins based on the voxel-color 3D printing, which provides an outcome of a full-color multi-material 3D printed prosthesis (Figure 8).\n\n(Written informed consent for publication of the patient’s details and publication of the identifiable image in Figure 7 was obtained from the patient).\n\nRadika light cured translucent resin was applied on the eyeball structures to enhance the glaze effect. (b) Perspective of the clean 3D full color printed facial orbital prosthesis before arrangement on the patient. Radika light cured translucent resin was applied on the eyeball structure to enhance the glaze effect. (Written informed consent for publication of the patient’s details and publication of the identifiable image in Figure 8 was obtained from the patient).\n\nFollowing printing and finishing the 3D model, a few manual modifications were required in the laboratory including the manual bending of a 1 mm gap at the external right side margin adjusted with a heat gun. This was explained by the patient’s weight loss between the data acquisition process and the prosthesis installation date. Also, a slight extrinsic coloration to compensate for the color reproduction of CMYKW color expression of the 3D printer was used and afterward sealed with a thin layer of a dispersion of medical-grade Type A silicone to coat the resin prosthesis. Enhanced adhesion was obtained with a platinum primer (A304), and Bonding Enhancer (A-321) was used according to the manufacturer’s recommendations (Factor II®, Lakeside AZ USA). Matting dispersion (Factor-II®) was used according to manufacturer recommendations to avoid a shiny silicone surface. A thin layer of translucent photopolymerizing resin (Radika® Dentsply Sirona®, Pennsylvania USA) was used to achieve the shiny surface of the ocular component.\n\nThe full-color resin 3D printed facial prosthesis was delivered on a subject with an orbital deformity. Two appointments of 20 and 45 minutes were needed to deliver the final prosthesis. Prosthetic adhesive (B-204 Pros-Aide Adhesive, Factor II) was used to attach the prosthesis to the skin. There were no concerns about weight/adhesive retention.\n\nNo physical impression, direct molding, sculpture, or intrinsic silicone coloration were needed. Similarly, no separate ocular prosthesis was necessary because it was also 3D printed with the final prosthesis. No complications were observed up to the submission of this article, which was four months after prosthesis installation (Figure 9).\n\n(Written informed consent for publication of the patient’s details and publication of the identifiable image in Figure 9 was obtained from the patient).\n\n\nDiscussion\n\nReproducing a patient’s skin color into a 3D printed facial prosthesis is a complex and challenging process. The manifestation of data as a physical embodiment is defined under the term “data physicalization”18 or “physical visualization”.19 Moreover, the physicalization of a direct 3D printed facial prosthesis has several challenges. Nevertheless, color information can be obtained by the point-based rendering of geospatial data obtained from photogrammetry methods. These visualization maps allow a user to gather insights through perception and computer-aided interaction20,21 Multiple integrations of acquisition technologies, software, and digital fabrication methods have benefited facial prosthesis production around its diverse context worldwide.2,3,7,22 Ultimate trending technologies have been low-cost1,7,16,23,24 and accessible workflows, as well as direct 3D printing of prosthesis.5,13–15\n\nResins for 3D printing have a different nature compared to medical grade silicone, and more studies should be conducted to understand them for this purpose. The multi-material characteristic of the latest Polyjet versions of 3D printers has much to offer to the complex composition of skin consistency and color reproduction because it can process it up to a voxel-color pigmentation, thanks to its capacity of jetting drops of approximately 40 pl (1-9 ml) each. Silicone 3D printing is evolving towards multi-material, thanks to a pre-nozzle of the silicone extruder. It was reported using multiple consistencies of silicone in one piece.15 However, while the minimum drop of silicone is not close to resin, it will not be superior in the most delicate reproduction details and will depend on experienced post-processing. Silicone 3D printing demonstrated a 400-micron layer, while Polyjet resin 3D printed up to a 14-micron layer.\n\nBoth resin and silicone 3D printing systems have arguments for evolving their materials, software, and hardware technology. It will be common to see further comparisons in literature while both address their limitations. Our workflow with colorful resin 3D printing considering important technical steps is shared below to contribute to this further discussion.\n\nWhen a photo capture is taken, the gamut of color expression is reduced from the infinite visible light expression into approximately 16.77 million colors. Here is where we start to lose color data information because any digital capture depends on an on-screen display that emits RGB (Red, Green, and Blue) light to express color. Each color channel is expressed from 0 (least saturated) to 256 (most saturated). (2563=16,777’216 colors). Captures could be saved into RAW or JPG files. JPG files are more suitable for ease of storage purposes and faster photogrammetry processing.16\n\nColor reflectance of the skin color of the subject is modified by the illumination of the ambient light. The +ID method recommends indirect frontal natural daylight. A recommended range between 1000 lux and 4000 lux will allow the automated smartphone functions of the camera to have a lower ISO, narrower diaphragm diameter, faster captures, and a better-balanced color temperature. Using a fiduciary color element and UV Map color calibration, we reduced the color discrepancy between the patient and the 3D-colored printed prosthesis. Continuous artificial light also works if it is set up closest to natural light. Manual functions of a smartphone or an SLR camera will have no better output of the 3D model and UV-map because nowadays, automatic algorithms of smartphone cameras optimize capture results. This feature also helps to reduce the micro-movements of the head and facial expressions of the patient, which, if not considered, can result in poor output.\n\nThe resultant photogrammetry 3D model (.blend) has a UV map associated and can be exported into a JPG file for further image calibration. The UV-Map has the information of the face’s color and wraps the surface of the 3D model. Once the prosthesis is 3D designed, to finally produce the 3D printing of the facial prosthesis (physical visualization), the file should be exported into a VRML file due to its compatibility with the CMYKW color 3D printing. Other printers like 3DP technology, which prints in gypsum, can print in color because its catalyzers are in CMYK tones. However, gypsum is not a suitable material for facial prosthetics and is insufficient for realistic color expression.\n\nThe color materials of the Stratasys® J750, at the time of the present publication, can materialize up to five hundred thousand colors in a 3D printed model. In contrast, conventional 2D color printing can express up to the RGB 16.77 million colors. That is why it is currently technically impossible to 2D or 3D print something precisely the same color as the actual subject’s skin. Although this technical limitation exists, the algorithms of GrabCAD Print® allow the user to choose between a Relative or Absolute approximation of the colors, aiming to get 3D printed colors that are the closest possible to the desired ones. That is why a slight layer of extrinsic coloring was applied over the external surface and fully sealed with translucent medical-grade type-A silicone. The extrinsic coloring was a mixture of orange to compensate for the greenish expression of the prosthesis of a dark skin tone of the patient. This procedure was executed to compensate for the technical limitation of the 3D printed colors to express the natural colors of our patient’s skin. This fine detailing may be understood better in further research that compares 3D printed skin color expression. Also, the possibility of using the +ID Methodology allows us to print the whole compound of the characterized eye in the same model of the whole orbital prosthesis. Thus, no separate ocular prosthesis was needed.\n\nPolyjet resins have a non-toxic certification but not a biocompatibility certification from the manufacturers. Other authors faced this challenge when installing a flexible nasal prosthesis manufactured by flexible Polyjet resin in a J750 3D printer.6 We considered the full coverage of the prosthesis with the medical grade type-A silicone after slight extrinsic characterization to prevent any complication. To date, the patient did not show any clinical complications, and more specific studies of Polyjet resins for this application must be conducted to guarantee patient safety in time.\n\nAt the commencement of this research, no flexible color resin was available on the market. A high durometer prosthesis was obtained (approximately 80A Shore) due to the high concentration of pigments to achieve a darker skin color. As long as the available resins for the J750 3D printer allow white flexible resin (30A shore) but rigid (100A Shore), Cyan, Magenta, and Yellow, the darker the skin you need to reproduce the more rigid the prosthesis will become. Clearer skin colors that may need less rigid pigments for reproduction will (likely) produce a more flexible result.25\n\nIn this specific case, the high durometer prosthesis was not an issue due to the almost static tissues and lack of muscular function around the limits of the patient’s prosthesis—due to post-surgical loss of nerve function following tumor resection. A high-functional muscle may present more difficulties with comfort when using a high-durometer prosthesis (darker skin). Once color resins are available, the resultant prosthesis may fit around a more appropriate range of durometers. The flexible base used was Agilus®, the evolution of Tango®.\n\nThe Direct 3D Facial Prosthesis resulted in appropriate adaptation, approximate color matching after extrinsic coloration and was accepted by the patient who reported good comfort in wearing it. No irritation of the skin at the margins was observed up to the publication of this paper, which is four months after delivery of the prosthesis. Silicone was adhered firmly with no debonding areas up to the submission of this paper. This prosthesis was designed to be adhesively retained. The authors expect that successive designs will enable the inclusion of design options for implant retention, including designing the attachment for magnets.\n\nThe manufacture of this 3D facial prosthesis depends on access to a J750® 3D printer with the available CMYKW resins. A J750 3D printer is a professional 3D printer with special requirements about the ambient, calibration, and professionalized handling. The accessible concept is also applied when a local print center can work as a provider, with a relatively low cost of approximately $50–$150, depending on the volume and the resultant grams of resin used.\n\nThe primary purpose of 3D printing in the colorful resin Polyjet technology is the color translation of the patient tissues from the +ID Methodology. Proper computational graphic processes allow this objective, like color calibration, multiresolution and displacement, specific 3D color file exportation, and the proper setup of the printer, model, and mixture of resin loading. This alternative manufacturing method tempts to close the gap in color reproduction while the manufacturers or other 3D printing industries evolve the desired properties of the final prosthesis.\n\nThe aesthetic outcome is not yet able to replace the most skilled maxillofacial prosthodontics or anaplastologists. However, it has the chance to deliver an effortless and outstandingly fast direct colored 3D printed facial prosthesis as a temporary prosthesis or as a definitive one as determined by context. This is the crucial argument and opportunity with this workflow and its evolution: reduced working time, optimized teamwork structure, which includes diversification of technology functions to minimize reliance on individual skill-dependent capabilities, the most difficult to reproduce resource. Thus, we have the opportunity to progress toward a definitive single-step, digital, turn-key solution of facial prosthesis production, always guided by formally trained specialists.\n\n\nConclusions\n\nUsing the +ID Methodology and full-color resin 3D printers allowed us to 3D print a resin-colored orbital final prosthesis. With no conventional molding, sculpture, and only a limited color adjustment, we obtained an acceptable adaptation and color reproduction of the final 3D prosthesis. The patient reported no complications on the usage of the prosthesis up to the time of this publication. The combined use of emerging technologies and biomaterials allows us to expand the limits of healthcare and be one step closer to a reliable, digitally driven, turn-key solution for the delivery of facial prostheses. By adapting our workflow with a more accessible learning curve, there is a more significant opportunity for more reliable provision of holistic care for patients who endure facial mutilation. With the limitations of the present study, further research is needed to determine the indications and opportunities of this digital workflow. An experienced maxillofacial prosthodontics or clinical anaplastologist, inserted into a multi-professional team, will be needed to guide design and production of a medical grade therapeutic device, and ensure appropriate rehabilitative care for the patient.\n\n\nData availability\n\nFigshare: Underlying data for ‘Color translation from monoscopic photogrammetry +ID Methodology into a Polyjet final 3D printed facial prosthesis’. https://doi.org/10.6084/m9.figshare.19609428.v1.17\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nConsent\n\nWritten informed consent for publication of the patient’s details and publication of the identifiable images in Figures 1, 2, 4, 5, 6, 7, 8 and 9 was obtained from the patient.",
"appendix": "Acknowledgments\n\nPlusID Non-Profit Organization and Paulista University (UNIP) for being the institutional authors of the international patent BR1020170174417 - PlusID Methodology for creating accessible 3D printed prosthesis.\n\nTo the “Centro Tecnologico da Informação Renato Archer” as a Public Technological Institution of Brazil for being our principal source of technological support.\n\nTo Stratasys international and their related collaborators for doing the 3D printing tests and optimized the capabilities of their software and hardware through their Headquarters in Israel, Minneapolis, and Demo Center of Buenos Aires at the ITBA.\n\nAppreciation to DDS. Anibal García and DDS. Marcel Barreiro for helping with part of the photo registration included in this article and Jorge Leporati for participating in the testing manufacture.\n\n\nReferences\n\nTetteh S, Bibb RJ, Martin SJ: Maxillofacial prostheses challenges in resource constrained regions. Disabil. Rehabil. 2019; 41: 348–356. PubMed Abstract | Publisher Full Text\n\nFarook TH, Jamayet NB, Abdullah JY, et al.: A systematic review of the computerized tools and digital techniques applied to fabricate nasal, auricular, orbital and ocular prostheses for facial defect rehabilitation. J. Stomatol. Oral Maxillofac. Surg. 2019; 121: 268–277. Publisher Full Text\n\nSalazar-Gamarra R, et al.: Introdução à Metodologia Mais Identidade Proteses Faciais 3D com a utilização de tecnologias accessíveis para pacientes sobreviventes de cancer no rosto. E-book Comunicação Científica eTécnica em Odontologia. 2019; 251–272. Publisher Full Text\n\nKim SH, Shin WB, Baek SW, et al.: Semiautomated fabrication of a custom orbital prosthesis with 3-dimensional printing technology. J. Prosthet. Dent. 2019; 122: 494–497. PubMed Abstract | Publisher Full Text\n\nUnkovskiy A, Spintzyk S, Brom J, et al.: Direct 3D printing of silicone facial prostheses: A preliminary experience in digital workflow. J. Prosthet. Dent. 2018; 120: 303–308. PubMed Abstract | Publisher Full Text\n\nNuseir A, et al.: Direct 3D Printing of Flexible Nasal Prosthesis: Optimized Digital Workflow from Scan to Fit. J. Prosthodont. 2019; 28: 10–14. PubMed Abstract | Publisher Full Text\n\nSalazar-Gamarra R, Seelaus R, da Silva JVL , et al.: Monoscopic photogrammetry to obtain 3D models by a mobile device: a method for making facial prostheses. J. Otolaryngol. Head Neck Surg. 2016; 45: 33. PubMed Abstract | Publisher Full Text\n\nCiocca L, Fantini M, De Crescenzio F , et al.: New protocol for construction of eyeglasses-supported provisional nasal prosthesis using CAD/CAM techniques. J. Rehabil. Res. Dev. 2010; 47: 595–604. PubMed Abstract | Publisher Full Text\n\nJiao T, Zhang F, Huang X, et al.: Design and fabrication of auricular prostheses by CAD/CAM system. Int. J. Prosthodont. 2004; 17: 460–463.\n\nCoward TJ, Scott BJJ, Watson RM, et al.: A comparison of prosthetic ear models created from data captured by computerized tomography, magnetic resonance imaging, and laser scanning. Int. J. Prosthodont. 2007; 20: 275–285. PubMed Abstract\n\nCoward TJ, Watson RM, Wilkinson IC: Fabrication of a wax ear by rapid-process modeling using stereolithography. Int. J. Prosthodont. 1999; 12: 20–27. PubMed Abstract\n\nCheah C, Chua C, Tan K, et al.: Integration of Laser Surface Digitizing with CAD/CAM. Production. 2003; 16: 435–441.\n\nJindal SK, Sherriff M, Waters MG, et al.: Development of a 3D printable maxillofacial silicone: Part I. Optimization of polydimethylsiloxane chains and cross-linker concentration. J. Prosthet. Dent. 2016; 116: 617–622. PubMed Abstract | Publisher Full Text\n\nJindal SK, Sherriff M, Waters MG, et al.: Development of a 3D printable maxillofacial silicone: Part II. Optimization of moderator and thixotropic agent. J. Prosthet. Dent. 2018; 119: 299–304. PubMed Abstract | Publisher Full Text\n\nUnkovskiy A, Wahl E, Huettig F, et al.: Multimaterial 3D printing of a definitive silicone auricular prosthesis: An improved technique. J. Prosthet. Dent. 2020; 125: 946–950. PubMed Abstract | Publisher Full Text\n\nJauregui Ulloa J, Salazar-Gamarra R, Mesquita AMM, et al.: A Digital Method to Fabricate the Ocular Portion of An Orbital Prosthesis with A Smartphone Camera, Color Calibration and Digital Printing. J. Prosthodont. 2021; 30: 91–94. PubMed Abstract | Publisher Full Text\n\nSalazar-Gamarra R, Moraes C, Seelaus R, et al.: color texture map. figshare. Figure.2022. Publisher Full Text\n\nJansen Y, et al.: Opportunities and challenges for data physicalization. Conf. Hum. Factors Comput. Syst. - Proc. 2015; 2015-April: 3227–3236.\n\nJansen Y, Dragicevic P, Fekete JD: Evaluating the efficiency of physical visualizations. Conf. Hum. Factors Comput. Syst. - Proc. 2013; 2593–2602. Publisher Full Text\n\nBader C, et al.: Making data matter: Voxel printing for the digital fabrication of data across scales and domains. Sci. Adv. 2018; 4: eaas8652. PubMed Abstract | Publisher Full Text\n\nCard SK, Mackinlay JD, Shneiderman B: Readings in information visualization: using vision to think. Morgan Kaufman Publishers; 1999.\n\nUnkovskiy A, et al.: Additive Manufacturing: A Comparative Analysis of Dimensional Accuracy and Skin Texture Reproduction of Auricular Prostheses Replicas. J. Prosthodont. 2019; 28: e460–e468. PubMed Abstract | Publisher Full Text\n\nKamio T, et al.: Utilizing a low-cost desktop 3D printer to develop a “one-stop 3D printing lab” for oral and maxillofacial surgery and dentistry fields. 3D Print. Med. 2018; 4: 1–2.\n\nXu Y, et al.: Compatibility of a silicone impression/adhesive system to FDM-printed tray materials-a laboratory peel-off study. Materials (Basel). 2018; 11. PubMed Abstract | Publisher Full Text\n\nCoward TJ, Seelaus R, Li SY: Computerized color formulation for African-Canadian people requiring facial prostheses: A pilot study. J. Prosthodont. 2008; 17: 327–335. Publisher Full Text"
}
|
[
{
"id": "140018",
"date": "30 Jun 2022",
"name": "Rodrigo de Faria Valle Dornelles",
"expertise": [
"Reviewer Expertise Reconstructive Plastic Surgery",
"Microsurgery",
"Cranio-maxillo-facial surgery",
"medical virtual modelling and 3D printing"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the present study, named 'Color translation from monoscopic photogrammetry +ID Methodology into a Polyjet final 3D printed facial prosthesis', the authors approach the rehabilitation of the face through the use of prosthesis in direct 3D printing. The prosthesis was designed and the production workflow described, from photogrammetric capture of surface mesh details with texturing, to hardware parameters, as well as prosthesis configuration, fabrication and post-processing.\nThe study addresses a topic that has been studied so that there are alternative solutions for the rehabilitation of facial defects. Anaplastology employs techniques that are often artistic craftwork and therefore difficult to scale because it depends on skills that are not trivial. This work shows clarity in the description of technical details of a recent alternative using free software, citing the +ID method and also the introduction of possibilities of 3D printing of the prosthesis, not only to obtain the replication of the richness of details of the complex human anatomy, but also with the texturing together with the impression of the piece.\n\nIt is essential to approach in terms of accurate printing parameters and to understand the migration of files in compatible languages so that there is reproducibility of the study. It is interesting to note that there is a demonstration that the technological application of the area, essential for automation, has been sought (1), based on a review that also includes current studies (2). The possibility of using photogrammetry and the accuracy of the method for volumetric evaluation of the three-dimensional mesh has already been established in previous studies (3-4), which shows the possibility of direct adaptation due to the actual size of the prosthesis.\nWhen it is necessary to approach initial studies, without previous parameters, the case description is acceptable, since the innovation proposal has no parallel. The study design is adequate, as it brings the use of technology, which is always evolving with periodic updates, with the proposal to use it with current resources. Opening possibilities in the continuity of improvements, according to the appearance of new tools or materials in the area of 3D printing.\nAcademic validity is established with the application of computer science in an area that until recently was eminently artisanal, time consuming and highly dependent on artistic subjectivity, with this, the alternative presented opens another field of approach. Replicating a study depends on the clarity of the methodology applied, when there is involvement of the computing area, computer configurations, such as processor, video card and RAM memory, are essential for the processes to be adequate. As well as for 3D printing parameters, even if proprietary software is used, such as the GrabCAD Print® software v1.33 of the Stratasys® J750 3D printer. This does not determine the economic viability of new projects, but it makes it possible to repeat the environment where the results were obtained and thus to be able to place new variables or even extract new data. The study described the method clearly, with details of the parameters used.\nAs this is an observational, descriptive study, there was no room for statistical analysis.\nAlthough the capture protocol for photogrammetry had been established in a previous work (5), the variation in the number of photos captured for the present study should have been justified and substantiated. Possible changes, clarified for reasons of adequacy, will allow a better understanding of the difficulties and complexity inherent to any method, providing future collaborative work. The providential and ingenious alternative of covering the prosthesis with medical grade type-A silicone could be better described and added to the methodology, since, while there is no biocompatibility certificate from the manufacturer, other parts must undergo the same finish.\nThe results presented are consistent with the conclusion that Using the +ID Methodology and full color resin 3Dprinters allowed us to 3Dprint a resin-colored orbital final prosthesis is adequate for the initial purpose of the study, which was to contribute with an innovative technology and 3D printing technique in resin with colored multimaterial. The detailing of processing care and parameters evidenced the feasibility of the method.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "242385",
"date": "13 Feb 2024",
"name": "Frank Alifui-Segbaya",
"expertise": [
"Reviewer Expertise 3D Printing",
"Biomaterials",
"and Materials Processing and Characterization"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI have reviewed the manuscript, \"Color translation from monoscopic photogrammetry +ID Methodology into a Polyjet final 3D printed facial prosthesis\" in which the authors present a workflow to produce a 3D printed colored prosthesis. While the scientific elements of the manuscript are minimal, the highly descriptive process could be replicated. The manuscript also contain useful information re: the limitations of using Polyjet technology for the facial prosthesis. Apart from a few typos, the manuscript is well written and contains up to date information and attempts to bridge the gap i.e., aesthetic outcomes of the age-old traditional manufacturing methods vs 3D printing.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-582
|
https://f1000research.com/articles/11-581/v1
|
26 May 22
|
{
"type": "Research Article",
"title": "Chronic obstructive pulmonary disease patients' quality of life and its related factors: A cross-sectional study of the Jordanian population",
"authors": [
"Enas A Assaf",
"Angham Badarneh",
"Ahmad Saifan",
"Nabeel Al-Yateem",
"Angham Badarneh",
"Ahmad Saifan"
],
"abstract": "Background: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death globally, mostly in low- and middle-income countries. It is estimated that 6.5% of Jordanians under 50 and 37.5% of those over 70 years of age are affected. The country's air pollution levels surpass recommended levels, increasing the disease incidence and burden on individuals and the health system. COPD is a long-term, severe, and exhausting condition. In Jordan, patients are highly dependent and frequent users of the healthcare services; therefore, their Quality of Life (QoL) is highly influenced by the health care they receive. The QoL of COPD patients must be studied to devise interventions that can help patients cope with this disease and for healthcare systems to improve their service. Method: A cross-sectional correlational study of 200 COPD patients. The Arabic WHO Quality of Life Questionnaire Short Form was used to collect data.\n\nResults: The mean COPD patient QoL score was 10.66 (SD=1.58), showing poor QoL perception. The physical domain had the lowest perceived QoL (10.232, SD=1.912), while the environmental domain had the highest (10.948, SD=1.636). Unmarried, non-smokers, and employed had better QoL (M=11.04, M=10.92, M=12.04). Age categories 50-61 exhibited greater mean QoL than age category 61 or higher (M=11.44, M=10.84, M=10.08). Private health services are characterized by short waiting times, availability of different diagnostic and treatment services, and skilled staff was related to better QoL. Conclusions: QoL for COPD patients seems to be an area requiring urgent attention from Health service providers and planners. Patients should be adequately supported and cared for to have a good QoL. In Jordan, COPD patients' QoL is highly influenced by lack of physical activity, emotional distress, and anxiety. Therefore, better health care services is needed to address all these areas adequately.",
"keywords": [
"Chronic Obstructive Pulmonary Disease",
"COPD",
"Quality of Life",
"QoL",
"Jordan",
"Quantitative study",
"Survey design",
"Cross-sectional study."
],
"content": "Introduction\n\nChronic Obstructive Pulmonary Disease (COPD) is prevalent worldwide. The World Health Organization has reported the disease as the third leading cause of death globally, causing 3.23 million deaths in 2019, with Over 80% occurring in low- and middle-income countries (LMIC).1 In Jordan, COPD has a prevalence rate of 6.5% in patients under 50 years of age and 37.5% in patients aged ≥70 years, which is much higher than the reported international prevalence rate, especially for the latter age group.2\n\nCOPD causes persistent and progressive respiratory symptoms, including difficulty in breathing, cough, and thick viscous mucus secreted within the respiratory passages. It also exacerbates during physical exercise and exertion.3–6 It is usually caused by prolonged exposure to dangerous chemicals and particles and by individual variables such as early experiences that affect lung development and heredity. Tobacco smoke exposure, indoor air pollution, occupational dust, gases, and chemicals all contribute significantly to the chance of developing COPD.\n\nEarly diagnosis and treatment, especially assistance for smoking cessation, are necessary to slow the progression of symptoms and minimize flare-ups.7 As COPD advances, patients increasingly struggle to do routine everyday activities, frequently due to dyspnea. In addition, since the COVID-19 pandemic, there may be a significant financial burden because of the reduced workplace and home productivity and medical care costs. During flare-ups, patients with COPD may notice an increase in their symptoms which may require further treatment at home or admission to the hospital for emergency care, as severe flare-ups can be fatal.7\n\nThere is an association between COPD and many other diseases, such as cardiovascular, lung cancer, osteoporosis, skeletal muscle, cachexia, gastrointestinal, metabolic, other respiratory illnesses, and mental health issues such as anxiety and depression.8 The correlation between COPD symptom load and anxiety and depression is important, as the combination of these disorders can worsen the disease course, duration, and outcome.9\n\nStudies have shown that COPD negatively correlates with the Quality of Life (QoL),10–17 and this correlation worsens as the severity increases. Kushwaha et al. (2020) reported “impaired” life processes and health-related quality of life among patients with COPD.18,19\n\nIn Jordan and in the Middle East region, there is a lack of national or regional studies about the extent of the COPD disease in the country and the service offered for these patients. Most studies and evidence come from developed countries. Also, available epidemiological data significantly underestimate the entire frequency of COPD because the disease is typically not identified until it is clinically evident and moderately progressed.20–22 Furthermore, the causing and the exacerbating factors for COPD are also common in Jordan; for example, environmental toxins, pollutants, smoking habits, and occupational chemicals exposures that are trigger for respiratory illnesses have been reported to be much higher than the accepted international standards.23–25\n\nA recent study in Jordan26 investigated uncertainty, anxiety, and the Health-Related Quality of life (HRQoL) among COPD patients and found higher levels of these variables among their study participants. Although important, the finding lacked details about these issues since the HRQoL was one variable measured in the study, among others.\n\nCOPD is a long-term, severe, and exhausting condition. Patients are highly dependent and frequent users of the healthcare services; therefore, their Quality of Life (QoL) is an important consideration to measure and improve. In addition, their QoL is expected to be highly influenced by the health care services they receive. In Jordan, the QoL of patients with COPD must be studied to devise interventions that can help patients cope with this disease and for healthcare systems to improve their services.\n\nTherefore, this study will focus on QoL and assess its different domains such as physical, psychological, social interaction, and environmental. Additionally, this study will help identify the concerns of COPD patients about their QoL; and the main determinant factors affecting it.\n\n\nStudy objective\n\nThe objective of this study is to assess chronic obstructive pulmonary disease patients’ quality of life and its related factors within the Jordanian population.\n\n\nMethods\n\nThe study design was cross-sectional correlational. The study was conducted in the outpatient clinics in four hospitals in Jordan, from different sectors (public, private and educational) and in different cities (i.e., Amman, Irbid, Zarqa). The study was conducted between April 2021 and May 2021.\n\nThis study included 200 participants. All COPD patients aged 18 and over who attended the thoracic clinic were invited to the study. The exclusion criteria for participation were patients with other comorbidities, and individuals with mental health problems that prevent them from consenting to participitation in the study.\n\nThe sample size was calculated using the G*power software version 3.1 (RRID:SCR_013726) based on the following parameters: ANOVA test, alpha 0.05, the medium effect size of 0.25, power of 0.8, number of groups 4. The included sample size (n=200) was enough to achieve these parameters.\n\nA self-administered questionnaire was used in this study; the questionnaire consisted of two parts: social-demographic questions (10 questions) and the Arabic World Health Organization QoL Instrument (Arabic -WHOQoL-BREF27) (See Underlying data).28 The tool included 26 Likert-type questions with answers ranging from 1 (disagree/not at all) to 5 (completely disagree/extremely). The questions assessed an individual’s perceptions of his/her well-being and health over the past two weeks. The questionnaire contained four domains which were: physical health (7 items), psychological health (6 items), social relationships (3 items), and environmental health (8 items).\n\nThe questionnaire is well-known and widely used and translated into different languages. Moreover, it has been validated with different populations and different illnesses; hence it is useful for cross-cultural and cross-disease comparisons.27,29,30\n\nIn the outpatient pulmonary clinic, the researcher obtained the list of patients attending the clinic, and patients with COPD were identified by the doctor and were asked to participate in the study. A suitable place was chosen to collect the data in coordination with the head nurse. The participants were given the questionnaires and the needed instructions, and the researcher remained there to answer any questions and collect the filled questionnaires.\n\nDescriptive statistics were used to describe sample characteristics, individual items, and the mean scores for the subdomains and the whole scale. Tests of associations, differences, and correlations were also used to assess the relationship or associations between the study variables and compare the sample subgroups’ scores. These tests were selected based on the type of variables and the normality assessment of the continuous variables. The used tests included Chi-Squared tests, t-test, ANOVA tests, Man Whitney, Kruskal Wallace, and Pearson or Spearman Correlation tests. The p-value was set at 0.05.\n\nApproval was obtained from the Institutional Review Board (IRB) of Applied Science Private University (IRB # 2020-2021-2-1) prior to data collection. Patients that agreed to participate in the study gave written informed consent after receiving an explanation of the study’s purposes, duration, risks, and benefits and their role in the study. They were informed that they could withdraw from the study anytime they wanted.\n\n\nResults\n\nAs demonstrated in Table 1, majority of participants were male (n =149, 74.5%), married (n=102, 51.0%), retired (n=147, 73.5%), smoker (n=105, 52.5%), and have university degree (n=176, 88.0%) (See Underlying data).28 The participants in the age group 51-60 years were greater (n=86, 43%) than the age group of ≤50 years (n= 34, 17%), and those ≥61years old (n=80, 40%). Patients with low monthly income were higher (n=113, 56.5%) than those with moderate and high income (n=87,43.5%). Regarding respiratory symptoms, 94% (n=188) had a persistent cough, 2% (n=4) had sputum, 68% (n=136) had wheezing, and 90% (n=180) had shortness of breath. In addition, the duration of COPD ranged from one month to 23 years, with a median of eight years. In this study, 34% of participants (n= 68) were recruited from educational hospitals, 33% (n=66) were recruited from private hospitals and finally, 33% (n=66) were recruited from governmental hospitals.\n\nThe results in Table 2 showed that the Mean for the total score of QoL was 10.68 out of a maximum possible score of 20 (SD=1.6). Comparing the four domains of QOL, the environmental domain was the highest with a mean score of 10.96 (SD=1.64), while the physical domain was the lowest with a mean score of 10.24 (SD=1.92) (See Underlying data).28\n\nAs shown in Table 3, the t-test has shown a statistically significant mean difference in QoL between smokers (M=10.28, SD=1.44) and non-smokers (M=11.072, SD=1.63) in favor of the non-smokers who had a higher mean (p≤0.001). Similarly, a statistically significant difference was found between unmarried (M=10.92, SD=1.36) and married (M=10.4; SD=1.52) in favor of unmarried participants who had a higher score mean (p=0.024), while the QoL was not statistically significant among the other independent variables (gender, income, educational level).\n\nANOVA and post hoc test (Scheffe) were conducted to assess the effect of the employment status (employed, not employed, retired) and age (≤50, 51-60, ≥61) on QoL perceptions. Regarding the employment status, there was a significant mean difference score (p≤0.001). The post hoc results showed that the employed have a statistically significant higher mean of QoL than those not employed and retired (M=12.04, SD=2.00; M=10.32, SD=1.4; M=10.48, SD=1.4; respectively). On the other hand, there was no statistical mean difference between not employed and retired (M=10.32, M=10.48, p=0.876), respectively).\n\nIn the same context, one-way ANOVA showed a statistically significant mean difference in QoL between three mean age groups (p≤0.001). The post hoc test (Schefee) showed that the participants’ age category of ≤50 years had a statistically significant higher mean of QoL than the age category of ≥61 years (M=11.44, M=10.08, p≤0.001, respectively) and age category of 51-60 years had higher mean than age category of ≥61 (M=10.84, M=10.08, p≤0.001, respectively).\n\n\nDiscussion\n\nAt present, Jordan has a high incidence of Pulmonary and Cardiovascular diseases. Unfortunately, the reality of the health care systems in this country is that they provide suboptimal services that cannot provide much-needed care and attention for these patients.\n\nThe results of this study demonstrated that perceived QoL among Jordanian patients is low and reflects a poor perception of QoL. Similar results were reported internationally and triggered interventions to improve patients’QoL. For example, studies in South korea and Portugal have shown that the HRQoL was impaired in patients with COPD and other respiratory illnesses, and it further deteriorated with increase in disease severity.29,31\n\nThe physical domain had the lowest perceived QoL. Several studies have also reported the physical environment among the domains with the lowest perceived QoL.11,26,32 This domain relates mainly to the patients’ physical abilities to perform tasks, which were impaired due to shortness of breath and other symptoms of the disease.33 Therefore, it would be imperative that healthcare professionals focus a good portion of their efforts on mitigating the physical effects of COPD on their patients to improve their quality of life through pre-planned and targeted interventions.\n\nThe current study also found that COPD patients are experiencing severe negative emotions in the psychological domain, such as anxiety and depression. This has led to a decreased QoL; this was consistent with the study by Lim et al. (2017),34 who found that symptoms like anxiety and depression caused a lower level of QoL in COPD patients. A previous study in Jordan saw that the perceived QoL among COPD patients was highly related to feelings of uncertainty and anxiety.26 Those feelings might have heightened during the COVID-19 pandemic as fear and anxiety from infection, and severe course of illness peaked.35 Patients with COPD or similar complex and long-term conditions are vulnerable to mental health issues,35 yet in Jordan, they do not receive any form of psychological support interventions. The health system in Jordan focuses on physical health rather than mental or psychological health. Therefore, this seems to be a huge gap that needs to be addressed quickly by the healthcare service planners.\n\nMedical treatment enables COPD patients to function in daily life; in Jordan, especially during the pandemic, there is the issue of medical treatment availability. This further contributes to the lowered QoL perception. Similarly, Ciążyńska et al. (2020) study reported the unavailability of medical treatment for COPD patients and how that severely impacts their perceptions of QoL.12\n\nThis study showed that personal and sexual relationships in the social domain were among the patient’s second mean score level of perceived QoL. Kurpas and colleagues (2016) reported that social relationships increase the QoL because patients do not experience loneliness and lack support.36 However, participants in the study seem to be also struggling with assuming a regular social interaction and their personal and sexual relationships. COPD seems to have also affected this area of their life, resulting in lower perceptions of QoL. During the recent COVID19 pandemic, social interaction was limited, thus adding more challenges to COPD patients. Evidence indicated that the situation with COPD patients was worsening as many people refrained from visiting these patients to prevent COVID transmission; People were allowed to contact one another during Covid-19 by phone calls or internet. However, physical interaction was not allowed.37 In addition, poor sexual relations (as part of the social domain) lead to a decrease in the QoL for these patients due to some of the symptoms of the disease, which, in turn, may reduce the quality of their sexual relationships and thus their QoL. This finding was consistent with a review study conducted by Merghati-Khoei and her colleagues.38\n\nWhen comparing the subgroups of the study, for example, those treated in private vs. governmental vs. educational hospitals, and those in different age groups, it was found that the QoL was different. Patients treated in private hospitals, who were non-smokers, unmarried, and employed have better QoL perceptions. These are all indicators of the main factors that may affect the perception of QoL for these patients in Jordan, probably internationally as well.5,11,14,15,18,33,39 Therefore, these constitute reasonable goals for the healthcare service providers and planners to target to improve the QoL perceptions among patients with COPD.\n\n\nConclusions\n\nThis study assessed the current state of QoL of Jordanian patients with COPD and identified the factors that affect it. The results indicated that the perceived QoL of COPD patients in Jordan is low and requires immediate interventions. The goal of the interventions should be to improve the healthcare service provided for these patients and thus their perceived QoL. The areas that may be targeted to achieve this goal include:\n\n1. To give equal importance to the provision of a psychosocial and mental health support service to the patients.\n\n2. Upgrade the services provided for these long-term healthcare users, as good quality service (i.e., in private hospitals) is associated with a better perception of QOL.\n\n3. Initiate with patients smoking cessation interventions and follow its implementation strictly; this will significantly improve the patient’s QOL.\n\n4. Coordinate with other governmental bodies to ensure these patients’ equal and appropriate employment opportunities. This will improve their QOL without exhausting them and putting a burden on their physical health.\n\n5. Finally, provide extra support for married patients as it seems that despite the social benefits of marriage, it is also associated with additional responsibilities that may burden COPD patients and decrease their QOL.\n\n\nLimitations and generalizability\n\nThis study collected data through a valid and reliable questionnaire and from an adequate sample size. While the data collected is useful, it may lack depth and details. A qualitative approach may have yielded more useful and in-depth data.\n\nThe study is well positioned to be generalizable to the Jordanian population. While it may not be generalizable beyond that, neighboring countries with the same economical, sociocultural and health system contexts may learn from the results of this study.\n\n\nData availability statement\n\nHarvard Dataverse: “COPD Patients’ Quality of Life and its Related Factors: A cross-sectional study of the Jordanian population”, https://doi.org/10.7910/DVN/UED6YA.28\n\nThe data set contains the underlying data:\n\n‐ English_Australian_WHOQOL-BREF.pdf: Study questionnaire\n\n‐ COPD QOL.tab: This file contains the socio-demographic and QoL variables.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAuthors contributions\n\nEnas Assaf & Angham Badarneh: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Original Draft Preparation; Ahmad Saifan & Nabeel Al-Yateem: Supervision, Writing – Final Draft Preparation, Writing – Review & Editing.",
"appendix": "Acknowledgments\n\nThe researchers would like to thank all patients who participated in this study. Also, the authors acknowledge the support provided by the Applied Sciences Private University in facilitating the research study. Finally, the researchers would like to acknowledge the hospitals which facilitated this study on their premises.\n\n\nReferences\n\nOrganization WH: Chronic obstructive pulmonary disease (COPD). Updated.2021.\n\nAdeloye D, Song P, Zhu Y, et al.: Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis. Lancet Respir. Med. 05/2022 2022; 10(5): 447–458. PubMed Abstract | Publisher Full Text\n\nBarnes PJ, Burney PGJ, Silverman EK, et al.: Chronic obstructive pulmonary disease. Nat. Rev. Dis. Primers. 2015 Dec 3 2015; 1: 15076. Publisher Full Text\n\nPrevention CfDCa: Chronic Obstructive Pulmonary Disease (COPD)|CDC. Updated 2021-03-29T05:21:53Z.\n\nKhassawneh BY, Samrah SM, Jarrah MI, et al.: Prevalence of undiagnosed COPD in male patients with coronary artery disease: a cross-sectional study in Jordan. Int. J. Chron. Obstruct. Pulmon. Dis. 2018; Volume 13: 2759–2766. PubMed Abstract | Publisher Full Text\n\nVogelmeier CF, Criner GJ, Martinez FJ, et al.: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary. Am. J. Respir. Crit. Care Med. 2017 Mar 1 2017; 195(5): 557–582. PubMed Abstract | Publisher Full Text\n\nHan M, Stoller J, Finlay G: Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging - UpToDate. Updated.2022.\n\nNegewo NA, McDonald VM, Gibson PG: Comorbidity in chronic obstructive pulmonary disease. Respir. Investig. 2015; 53(6): 249–258. Publisher Full Text\n\nMiravitlles M, Ribera A: Understanding the impact of symptoms on the burden of COPD. Respir. Res. 2017 Apr 21 2017; 18(1): 67. PubMed Abstract | Publisher Full Text\n\nAhmed MS, Neyaz A, Aslami AN: Health-related quality of life of chronic obstructive pulmonary disease patients: Results from a community based cross-sectional study in Aligarh, Uttar Pradesh, India. Lung India: official organ of Indian Chest Society. 2016 Mar-Apr 2016; 33(2): 148–153. PubMed Abstract | Publisher Full Text\n\nCheruvu VK, Odhiambo LA, Mowls DS, et al.: Health-related quality of life in current smokers with COPD: factors associated with current smoking and new insights into sex differences. Int. J. Chron. Obstruct. Pulmon. Dis. 2016; 11: 2211–2219. PubMed Abstract | Publisher Full Text\n\nCiążyńska M, Pabianek M, Szczepaniak K, et al.: Quality of life of cancer patients during coronavirus disease (COVID-19) pandemic. Psycho-Oncology. 2020 Sep 2020; 29(9): 1377–1379. PubMed Abstract | Publisher Full Text\n\nPaap MCS, Bode C, Lenferink LIM, et al.: Identifying key domains of health-related quality of life for patients with chronic obstructive pulmonary disease: the patient perspective. Health Qual. Life Outcomes. 2014 Jul 9 2014; 12: 106. PubMed Abstract | Publisher Full Text\n\nParekh TM, Bhatia S, Cherrington A, et al.: Factors influencing decline in quality of life in smokers without airflow obstruction: The COPDGene study. Respir. Med. 2020 Jan 2020; 161: 105820. PubMed Abstract | Publisher Full Text\n\nPati S, Swain S, Patel SK, et al.: An assessment of health-related quality of life among patients with chronic obstructive pulmonary diseases attending a tertiary care hospital in Bhubaneswar City, India. J. Family Med. Prim. Care. Sep-Oct 2018; 7(5): 1047–1053. PubMed Abstract | Publisher Full Text\n\nTabar NA, Alshraideh JA: Correlates and predictors of health-related quality of life among patients with COPD: an integrative review. Open Journal of Nursing. 2019; 09(12): 1203–1225. Publisher Full Text\n\nWu M, Zhao Q, Chen Y, et al.: Quality of life and its association with direct medical costs for COPD in urban China. Health Qual. Life Outcomes 2015 May 14 2015; 13: 57. PubMed Abstract | Publisher Full Text\n\nKushwaha S, Singh SK, Manar M, et al.: Health-related quality of life of chronic obstructive pulmonary disease patients: A hospital-based study. J. Family Med. Prim. Care. Aug 2020; 9(8): 4074–4078. PubMed Abstract | Publisher Full Text\n\nRosińczuk J, Przyszlak M, Uchmanowicz I: Sociodemographic and clinical factors affecting the quality of life of patients with chronic obstructive pulmonary disease. Int. J. Chron. Obstruct. Pulmon. Dis. 2018; Volume 13: 2869–2882. PubMed Abstract | Publisher Full Text\n\nPauwels RA, Rabe KF: Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet 2004; 364(9434): 613–620. Publisher Full Text\n\nLindberg A, Bjerg-Bäcklund A, Rönmark E, et al.: Prevalence and underdiagnosis of COPD by disease severity and the attributable fraction of smoking: report from the Obstructive Lung Disease in Northern Sweden Studies. Respir. Med. 2006; 100(2): 264–272. PubMed Abstract | Publisher Full Text\n\nTageldin MA, Nafti S, Khan JA, et al.: Distribution of COPD-related symptoms in the Middle East and North Africa: Results of the BREATHE study. Respir. Med. 12/01/2012; 106: S25–S32. PubMed Abstract | Publisher Full Text\n\nMadanat HN, Cole EC, Barnes MD, et al.: Chronic respiratory illnesses in Jordan: pulmonary physicians’ experiences in risk reduction. Int. Q. Community Health Educ. 2009; 30(2): 141–151. PubMed Abstract | Publisher Full Text\n\nInternational Association for Medical Assistance to Travellers: Jordan General Health Risks: Air Pollution.2022. Accessed 09/03/2022. Reference Source\n\nOrganization WH: Environment and health: Air pollution.2022. Accessed 09/03/2022. Reference Source\n\nAbu Tabar N, Al Qadire M, Thultheen I, et al.: Health-Related Quality Of Life, Uncertainty, and Anxiety among Patients with Chronic Obstructive Pulmonary Disease. F1000Res 2021; 10(10): 420. PubMed Abstract | Publisher Full Text\n\nOrganization WH: WHOQOL-BREF: introduction, administration, scoring and generic version of the assessment: field trial version, December 1996 1996.\n\nAl-Yateem N: Data from: COPD Patients’ Quality of Life and its Related Factors: A cross-sectional study of the Jordanian population.2022. V2. Deposited 2022-05-03 15:01:48.037. Publisher Full Text\n\nCarreiro-Martins P, Gomes-Belo J, Papoila AL, et al.: Chronic respiratory diseases and quality of life in elderly nursing home residents. Chron. Respir. Dis. Aug 2016; 13(3): 211–219. PubMed Abstract | Publisher Full Text\n\nBrzoska P: Assessment of quality of life in individuals with chronic headache. Psychometric properties of the WHOQOL-BREF. BMC Neurol. Jul 3 2020; 20(1): 267. PubMed Abstract | Publisher Full Text\n\nChin PQ, Sheu CC, Tsai JR, et al.: Establishing Quality of Life in Southern Taiwan COPD Patients Using Long-Acting Bronchodilator. Patient Prefer. Adherence 2022; 16: 875–886. PubMed Abstract | Publisher Full Text\n\nAntoniu SA, Petrescu E, Stanescu R, et al.: Impact of fatigue in patients with chronic obstructive pulmonary disease: results from an exploratory study. Ther. Adv. Respir. Dis. 2016 Feb 2016; 10(1): 26–33. PubMed Abstract | Publisher Full Text\n\nKouijzer M, Brusse-Keizer M, Bode C: COPD-related fatigue: Impact on daily life and treatment opportunities from the patient’s perspective. Respir. Med. 2018 Aug 2018; 141: 47–51. PubMed Abstract | Publisher Full Text\n\nLim KE, Kim SR, Kim HK, et al.: Symptom Clusters and Quality of Life in Subjects With COPD. Respir. Care 2017 Sep 2017; 62(9): 1203–1211. PubMed Abstract | Publisher Full Text\n\nElbeddini A, Tayefehchamani Y: Amid COVID-19 pandemic: Challenges with access to care for COPD patients. Res. Soc. Adm. Pharm. 2021 Jan; 17(1): 1934–1937. PubMed Abstract | Publisher Full Text\n\nKurpas D, Szwamel K, Mroczek B: Importance of Social Relationships in Patients with Chronic Respiratory Diseases. Adv. Exp. Med. Biol. 2016; 935: 63–73. PubMed Abstract | Publisher Full Text\n\nHalpin DM, Vogelmeier CF, Agusti AA: Copd & Covid-19. Arch. Bronconeumol. 2021; 57(3): 162–164. PubMed Abstract | Publisher Full Text\n\nMerghati-Khoei E, Pirak A, Yazdkhasti M, et al.: Sexuality and elderly with chronic diseases: A review of the existing literature. J. Res. Med. Sci. 2016; 21: 136. PubMed Abstract | Publisher Full Text\n\nAlumran A, Almutawa H, Alzain Z, et al.: Comparing public and private hospitals’ service quality. J. Public Health. 2021; 29: 839–845. Publisher Full Text"
}
|
[
{
"id": "139163",
"date": "10 Jun 2022",
"name": "Khaldoun Hamdan",
"expertise": [
"Reviewer Expertise Critical care nursing",
"adult care"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMethodology:\nThe sampling technique used was not explicitly identified.\n\nPlease identify the response rate.\n\nThe reliability of the tool was not mentioned in the method part. Please provide supporting references.\n\nResults:\nIn the paragraph related to “QoL among COPD patients” it was stated: The results in Table 2 showed that the Mean for the total score of QoL was 10.68 out of a maximum possible score of 20 (SD=1.6). In the method section, you mentioned that the questionnaire consists of 26 items rated from 1 to 5, it was unclear how the maximum possible score is 20, do you mean the maximum possible TOTAL score for the item? And if as stated for the mean how do you calculate the maximum score for the mean score? Please clarify.\n\nDiscussion:\nIn the first paragraph it was stated “Unfortunately, the reality of the health care systems in this country is that they provide suboptimal services that cannot provide much-needed care and attention for these patients.” It needs supporting references otherwise it will be an opinion.\n\nIn the second paragraph: “The results of this study demonstrated that perceived QoL among Jordanian patients is low and reflects a poor perception of QoL” please add “COPD” before patients to be more specific.\n\nPlease clarify how private hospitals enhance the quality of life for COPD patients, to be more understandable for the international audience.\n\nLimitation: if you used a convenience sampling it should be mentioned in the limitation section\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "139164",
"date": "14 Jun 2022",
"name": "Ibrahim Bashayreh",
"expertise": [
"Reviewer Expertise Nursing",
"Medical and Surgical Nursing",
"Critical care Nursing",
"Nursing education."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study is a quantitative cross-sectional study aimed to assess COPD patients’ quality of life within the Jordanian context and identify the related factors.\nI am pretty familiar with the Jordanian context. Therefore, I agree that this topic is relevant given the high incidence of this disease in the country and the situation of the current services offered to the sufferers. The authors were also able to present these facts and establish the importance of the study in the introduction. In general terms, I found the article well written, organized, flows logically and smoothly, and is not difficult to read and understand.\nThe methods used in the study are also appropriate and can achieve the aim of the study. However, the study could have been improved by adopting a mixed-methods approach, employing the different methods to understand the different dimensions of the experiences of the COPD patients. The data identified in this study is meaningful and valuable but may be limited and superficial. Therefore, I advise the authors to conduct a follow-up study further to reveal the remaining dimensions of the patients’ experiences and generate more robust findings that support the needed change in the service.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "139162",
"date": "27 Jun 2022",
"name": "Nermine M. Elcokany",
"expertise": [
"Reviewer Expertise Critical Care & Emergency Nursing"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, the information presented represents valuable information regarding chronic obstructive pulmonary disease which is a major public health problem internationally and even in Jordan as air pollution is really affecting COPD patients' quality of life.\n\nThe overall study is interesting, well-written, and structured.\nThe authors have collected a detailed complete database on the topic mentioning the significance of the study as well as the global studies conducted on the quality of life of COPD patients with little research on the global level which really reflected the significance of the research problem.\nIntroduction is well presented.\n\nThe authors also wrote a well-implemented methodology although the sampling method is not clearly mentioned so better to clarify it.\n\nThe results section reflects the aim of the study and is well organized. However, regression analysis will be better to find factors that affect QoL of COPD patients.\n\nThe discussion is organized, well written, and has an excellent flow of ideas including recent references.\n\nI recommend approving this manuscript and further study is needed to explore other factors that affect the quality of life of COPD patients.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-581
|
https://f1000research.com/articles/11-580/v1
|
26 May 22
|
{
"type": "Research Article",
"title": "A re-analysis of data from Sullins, Rosik, and Santero (2021): are sexual orientation change efforts (SOCE) helpful for those who don't change?",
"authors": [
"Walter R. Schumm"
],
"abstract": "Background. Sullins, Rosik, and Santero (2021) evaluated a convenience sample of 125 men who had undergone sexual orientation change efforts (SOCE) and they made their data available for independent analysis.\n\nMethods: Data from Sullins et al. (2021) were reanalyzed in ten new ways. Several new typologies and variables were created. Paired sample t-tests, correlations, regression analyses, repeated measures analyses with time x group interactions, and chi-square tests were used to evaluate ten novel hypotheses. Results: Using parametric statistics, we found similar results to Sullins et al. (2021) where they had used nonparametric statistics. Regression analyses found that lower initial SSI and higher SSB predicted more change. Using a new typology for marital status, it was found that those who became engaged/got married during SOCE had the largest gains in OSB compared to other categories of marital status.\n\nUsing the typology of change, it was found that some men who became stronger for SSA, SSI, and SSB nevertheless reported high levels of helpfulness for SOCE. Harms from SOCE seem to be minimal compared to the positives reported for young adults. SOCE effectiveness did not appear to change with time since therapy, lending less support to a recall bias argument. Congruence between SSA and SSI, may, in some cases, reduce the apparent effectiveness of SOCE Conclusion: While the sample’s results cannot be generalized outside of highly religious men with initially higher levels of SSA and SSB than SSI, these results differ from many contemporary assertions that SOCE cannot ever be effective and is inherently harmful, or that SSA is inherently immutable. Therefore, calls to ban SOCE legally appear to be founded upon incomplete or inaccurate data and thus premature, while more higher quality research is yet needed regarding SOCE.",
"keywords": [
"sexual orientation change",
"SOCE",
"marriage",
"ex-gay",
"harms",
"immutability",
"gay",
"lesbian",
"bisexual"
],
"content": "Introduction\n\nThe general purpose of this report is to explore the data of Sullins, Rosik, and Santero (2021) in more depth. Their data set is one of the larger ones available for independent analysis and it also has a plethora of measures. Given the controversy surrounding SOCE (American Psychological Association, 2021; Freedman, 2020; Haldeman, 2022; Przeworski et al., 2021; Rosik & Popper, 2014; Sprigg, 2021), independent analysis of such data sets may be especially important. Some criticisms of SOCE are quite strident. Salway et al. (2020) described SOCE as “pseudoscientific practices intended to suppress or deny unwanted feelings of sexual attraction to members of the same gender/sex”, that the “failure rate of SOCE has been estimated at ≥97%” and that SOCE was “associated with numerous negative health outcomes including self-hatred, depression, and suicidal ideation and suicide attempts” (p. 503). Goodyear et al. (2021) argue that “the impacts of [SOCE] are predominately negative and severe, to the point of being life threatening.” (p. 4) such that they approve of international attempts to ban SOCE. Likewise, Kinitz et al. (2021) report that SOCE involves “a set of scientifically discredited practices” associated with “significant adverse health and social outcomes” (p. 1). Bradshaw et al. (2015) assume that sexual attraction is immutable, and that sexual orientation has a biological origin (p. 409), although many would disagree on both counts. On the other hand, some research has found few significant or substantial differences between SSA individuals who reject an LGB identity and those who accept an LGB identity (Rosik, Lefevor, & Beckstead, 2021). Karten and Wade (2010) found a significant and substantial (eta-squared of.57) reported decrease in homosexual feelings and behavior in their study of 117 men. Jones and Yarhouse (2011) found effect sizes ranging between 1.67 and 4.25 (Table 1, p. 414, my calculations) for reductions in same-sex sexual attraction, fantasy, and infatuation, while Pela and Sutton (2021, p. 74, my calculations) found effect size decreases over two years for SOCE subjects of 0.28 for SSA and 0.52 for SSI, suggesting that same-sex attractions (and identity) might not be “immutable”. Whitehead and Whitehead (1999) conclude from their extensive review of the literature that “it is clear that sexual orientation is fluid, not fixed, so that it is impossible to argue it is genetically pre-determined. There is a good possibility that various degrees of change will happen with the right support, including therapy of various kinds. The problem in the present social climate may be finding such support” (p. 228).\n\nBecause some have cited Sullins et al. (2021) as one of the “two strongest studies methodologically” (Sprigg, 2021, p. 30) of the 79 he reviewed and because it was not cited as evidence by the American Psychological Association (2021; Haldeman, 2022), it may be especially important to take a second look into this particular data set. It is not uncommon for scholars to claim that SOCE is based on flawed assumptions, religious bias, might do harm, and is ineffective (del Rio-Gonzalez et al., 2021; Haldeman, 2022). It appears that even most conservative scholars recognize that some subjects have been harmed by SOCE or at least some unprofessional versions of so-called SOCE, but few therapeutic approaches appear to be exempt from being harmful to a few subjects (Rosik & Popper, 2014; Sprigg, 2021). The situation is further complicated by severe backlash often taken against conservative scholars (Rosik & Popper, 2014, p. 231). Nevertheless, some research seems to have found SOCE to be effective for some subjects with low levels of harm (Jones & Yarhouse, 2011). Regardless of their politics, most scholars and professional therapists are opposed to forms of SOCE that are involuntary, punitive, or that amount to torture (Drescher, 2022). Glassgold (2022, p. 20) has made a clear distinction between older, more aversive forms of SOCE and more modern, recent “verbal” approaches. Even Haldeman (2022) recognizes that his APA book did not address what he has called “more recent iterations of SOCE” or “conversion therapy lite” (p. 8). Accordingly, careful analysis of the most recent iterations of SOCE should be viewed as especially important.\n\nThere were several more specific objectives for this reanalysis of their data. In terms of measurement, I wanted to create new variables that might better explain the results and allow the use of scales rather than merely single items as variables. In terms of analyses, I wished to focus on possible effects of SOCE in terms of effect sizes, expressed as Cohen’s d. With N > 100, it might be possible to attain statistical significance in the absence of large effect sizes; without clear indications of effect sizes, SOCE might be granted credibility too easily. Furthermore, I wanted to take advantage of repeated measures analyses of variance, thus permitting a test of any interactions between apparent changes over time and other between-subjects grouping factors. I also wanted to see which, if any, prior factors were predictive of overall outcomes. Would a client’s initial situation be predictive of later outcomes? Even if research found that SOCE was helpful on average for some subjects, that might not help the therapist much for that new client who has just walked in the door with his/her own unique set of circumstances. Finally, I wanted to create a variable that might allow approximation of a control group for this data set and check if indeed changes in sexual orientation variables would parallel client reports of the degree of helpfulness of their SOCE. In other words, therapists might be rated as more or less helpful on other factors than perceived change in sexual orientation variables; therapy might be rated highly even if there were no changes in apparent sexual orientation. Thus, one ought not to assume that “more change” would equal “more helpful SOCE”; rather such an idea should be tested empirically.\n\n\nMethods\n\nThe participants in this study were recruited through an online survey administered pursuant to the doctoral dissertation of Paul Santero (2011) at Southern California Seminary, which, as Sullins et al. (2021) have noted, “contains a more complete description of the survey methods, administration, and question wording.” (p. 3). Sullins et al. (2021) also reported that participants were “contacted through religious organizations and therapist networks who offered services including talk therapy, retreats, and support groups that serve this population” (pp. 3-4). The original participants included 25 men from countries outside the United States, but those men were not included in the analyses here or in Sullins et al. (2021). Respondents were distributed across the United States: west coast (24.0%), mountain west (27.2%), southwest (6.4%), south (8.8%), northeast (4.8%), east coast (14.4%), central (3.2%), with one response “having lived all over the USA” with no missing data for that information. The percentages here for location differ from those reported in Sullins et al. (2021) because two variables concerning residence were merged into one variable to eliminate apparent missing data. For example, in one case, the primary variable was not answered but the second variable answer was “Utah”, which was counted as “mountain west.” No women were among the 125 participants studied here, although 8 women had participated originally. Most of the sample was white (91%) and 73% had a college education or higher, while 58% reported a household income above $50,000. With respect to religious attendance, 88% reported weekly or more often.\n\nFor the items and scales used in this report, Appendix A lists the mean, median, standard deviation, minimum, maximum, and total number of non-missing cases. All data used here were obtained from the data set provided by Sullins et al. (2021). The data set did not include any measures of social desirability response bias; however, a more detailed discussion of different forms of social desirability measurement is available elsewhere (Schumm, 2015).\n\nGenerally, multi-item scales are preferable to single item measures, at the very least because of the potential for increased measurement reliability in terms of internal consistency. There were three questions that concerned sexual behavior, kissing, and daydreaming about sex for both heterosexuality and homosexuality as well as prior to SOCE and during/after SOCE, a total of 12 items. Items about desiring emotional intimacy were added to each of the four scales to see if an additional, but possibly unrelated item, would improve reliability. Adequate-to-fair Cronbach alphas were obtained as follows: prior same-sex sexuality, 0.68; prior heterosexuality, 0.76; post same-sex sexuality, 0.68; and post heterosexuality, 0.79. Adding the fourth item changed the reliabilities, respectively, to 0.58 (a decrease), 0.76 (no change), 0.76 (an increase), and 0.82 (an increase).\n\nThere were 10 items that asked how helpful different forms of SOCE had been, with answers from not at all/none, slightly, moderately, markedly, and extremely. The forms of SOCE listed included psychiatrist, psychologist, social worker, mental health counselor, pastoral counselor, religious peer group, nonreligious peer group, weekend retreat, personal study, and mentoring. Some subjects used only one form of SOCE while others used multiple forms. To create an overall measure for each client, regardless of how many forms they had used or experienced, the highest rating given to any of the ten forms of SOCE was used to create one overall measure of SOCE helpfulness. Taking the opposite approach, using the worst results to create a scale, would have overlooked forms of SOCE that had been effective for the subjects – someone might try a lot of things to find help, but even if some don’t help, the one(s) that did help, would hopefully be those that mattered the most. For the 123 subjects who answered at least one of the helpfulness questions, the percentage results were none (1.6%), slightly (8.9%), moderately (11.4%), markedly (19.5%), and extremely (58.5%), with the values coded from 1 to 5, respectively. The mean score for overall helpfulness was 4.24 (SD = 1.07) with a median of 5.0. The item was significantly skewed, -1.27 (SE of skew = 0.22) with the distribution of responses more strongly favorable than unfavorable. Furthermore, a trinary measure was created by recoding the none/slightly, moderately/markedly, and extremely responses into three groups, which was intended to provide a type of control group (SOCE was not effective, as perhaps no treatment control group would have been) along with two levels of relative SOCE effectiveness. The results for this new item reflect what Sullins et al. (2021) concluded – that some subjects were not benefitted by SOCE but that the majority did seem to report beneficial outcomes.\n\nSexual orientation is usually expressed or described in terms of attraction, behavior, and identity. Would it be possible to develop a typology of sexual orientation of subjects prior to SOCE? Using median splits for sexual attraction, same-sex sexual behavior, and sexual identity, a typology of the three aspects of sexual orientation prior to SOCE was created. Six of the eight possible combinations were obtained for 123 subjects: low behavior, low attraction, and low identity (7.3%); low behavior, high attraction, low identity (30.9%); low behavior, high attraction, high identity (21.1%); high behavior, low attraction, low identity (4.1%); high behavior, high attraction, low identity (15.4%); and high behavior, high attraction, high identity (21.1%). A one-sample Chi-squared test (df = 5) of 36.2 indicated that the types were not equally distributed (p < .001).\n\nMarital status was assessed for the time prior to SOCE and after/during SOCE. Sullins et al. (2021) reported that the men in their study were more likely to be single than in the United States in general but less likely to be divorced; their study seemed to assume that all marriages were heterosexual. Some subjects were single, married, or divorced/widowed before SOCE; some got married from the single state; some were divorced from the married status after/during SOCE. A new item was created with four categories: single (before and later), married (before and later), got married (changed from single to married), and divorced/widowed (either stayed in that category or changed to that category). The percentages of subjects (N = 125) in each category, respectively, were 52.8%, 26.4%, 15.2%, and 5.6%.\n\nRespondents reported the number of SOCE sessions for each of the types of SOCE listed, which included sessions with a psychiatrist, a psychologist, a social worker, a mental health counselor, a pastoral counselor, with an ex-gay support group, and with a nonreligious support group. To create a summary variable, the maximum number of sessions for any of the types of SOCE was noted. In other words, if pastoral counseling involved 30 sessions and mental health counseling involved 50 sessions, the coding would be for 50 sessions. For two subjects, none of the seven types of counseling sessions were used. Thus, the breakdown for maximum number of sessions for the most used type of counseling was none (1.6%), 1-10 (4.8%), 11-25 (8.8%), 26-50 (16.0%), 51-100 (29.6%), 101-200 (12.0%), and more than 200 (27.2%). The logic was that the most used type was probably the one that subjects felt was most useful and therefore those number of sessions probably were most related to any favorable outcomes. Another measure of the maximum number of sessions was created by crediting the variable with the upper limit of each category and crediting ratings of over 200 sessions with a score of 250. While that approach might seem to overestimate the number of sessions, it is counterbalanced by the fact that many SOCE participants had sessions in multiple therapeutic approaches.\n\n\nResearch questions\n\nThe first research question concerned finding the Cohen’s d effect sizes for most of the key before/after variables dealing with different aspects of sexual orientation, to be analyzed with paired samples t-tests (Table 1).\n\nThe second research question concerned how changes would occur in sexual orientation (attraction, identity, same-sex sexual behavior, and different-sex sexual behavior) as a function of a typology of pre-SOCE sexual orientation conditions. In other words, would certain combinations of sexual attraction, behavior, and identity be associated with lesser or greater changes in sexual orientation during or after SOCE? Paired samples t-tests were used to detect apparent change over time for each of six conditions from the pre-SOCE sexual orientation typology (Tables 2–7).\n\nThe third research question concerned whether pre-SOCE levels of same-sex sexual attraction, identity, and behavior, as well as marital status would predict overall level of reported helpfulness of SOCE in positive or negative directions, to be analyzed using ordinary least squares regression.\n\nThe fourth research question concerned how marital status might moderate changes in sexual attraction, identity, or behavior (both same-sex and different-sex), using a repeated measures analysis of variance using marital status as a between-subjects factor. To assess the changes in terms of effect sizes, paired samples t-tests will also be performed for each pair of outcome variables for each level of marital status (Table 8).\n\nThe fifth research question involved predicting the reported helpfulness of SOCE as a linear and/or quadratic function of the maximum number of sessions, using the curve estimation program of SPSS’s version 26.0 linear regression program.\n\nThe sixth research question concerned a possible interaction effect between our trinary measure of reported helpfulness of SOCE as a between-subjects variable and change over time for our four key measures of sexual orientation, using repeated measures analyses of variance, with a focus on observing how effect sizes would change as a function of the three levels of reported helpfulness (Tables 9 through 12).\n\nThe seventh research question concerns how the reported helpfulness of SOCE would be related to the reported changes in both sexual attraction and sexual identity in terms of degree and consistency, using a chi-square test to compare levels of helpfulness against a typology of changes.\n\nThe eighth research question reflects a concern from some that SOCE results might be a function of recall bias or recency bias; recall bias might lead respondents to report more favorable results the longer the time since therapy while recency bias might lead them to report more favorable results the more recent therapy.\n\nThe ninth research question concerns congruence of sexual attraction and sexual identity before and after SOCE. Sullins et al. (2021) found that measures of sexual attraction, identity, and behavior became more congruent after SOCE; Bondy (2021) found congruence of attraction and identity to be related to less effective outcomes of SOCE in his study of 156 participants. As noted by Bondy (2021, p. 93), identity theory may need further consideration (Schumm, 2020). Because previous SOCE studies have included a number of persons who report same-sex attraction but less or no same-sex sexual orientation identity, one could anticipate that more participants would report higher same-sex attraction than sexual orientation identity both before and after SOCE; based on Sullins et al. (2021), one might expect a stronger correlation after SOCE than before for those two variables. When comparing the two variables before and then after SOCE, one might expect a significant difference using paired samples t-tests. Furthermore, the difference before SOCE might be less than after SOCE. It is possible that high congruence of SSA and SSI (before and/or after SOCE) might be associated with greater resistance to SOCE.\n\nThe tenth research question focused on the participants ages 18 to 25. Some have claimed that SOCE is very harmful for minors and this age group was the closest we could come to assessing SOCE’s potential impact on minors, since some had been in therapy for some time. Notably, Ryan et al. (2020) used a sample of youth ages 21 to 25 to assess retrospective accounts of SOCE, an older age than used here. The goal was to compare positives and harms attributed to SOCE in the areas of self-esteem, depression, suicidality, and social functioning and then to assess on a case-by-case basis how positives and harms compared for each of the four outcomes.\n\nPaired samples t-tests, linear regression, Chi-squared tests, and repeated measures analyses of variance will be used to evaluate these research questions, using SPSS version 26 (RRID: SCR 002865). An open access alternative is JASP (RRID: SCR 015823); however, numerous alternative free website sources for statistical analysis have been listed elsewhere (Schumm et al., 2021).\n\n\nResults\n\nSullins et al. (2021) reported nonparametric tests to compare client conditions before and after SOCE. Here, t-tests with Cohen’s d as a measure of effect size are reported. While all the variables used, including the scales, had significantly non-normal distributions, t-tests are generally robust with respect to such violations. However, the main point of the analyses here was to provide a widely recognized measure of effect size that also considered the correlated nature of the variables being compared to avoid underestimating the true effect sizes involved. Cohen (1992) indicated that an effect size of 0.50 or greater would be “visible to the naked eye of a careful observer” (p. 156), though Funder and Ozer (2019) noted that even small effect sizes (d = 0.20) were important (also see VanVoorhis & Morgan, 2007). Results are presented in Table 1.\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nIt appears that the effect sizes detected range from 0.24 to 0.94, falling into the small to large effect size range. Same-sex sexual behavior decreased by more than twice as much as the increase in different-sex behavior (0.56 versus 0.24). Of the three main components of sexual orientation, attraction appeared to decrease the most (0.94) while same-sex sexual behavior (0.56) and same-sex sexual identity (0.60) appeared to decrease by about the same amount. Desired heterosexual emotional intimacy increased by about the same amount (0.68) as desired same-sex emotional intimacy decreased (.63). By Cohen’s (1992) definition, same-sex sexual attraction decreased to a large extent (≥ .80) while the other two aspects decreased by medium size effects (≥ .50). By Cohen’s definition, all three effects would be observable to a trained naked eye.\n\nSullins et al. (2021) compared SOCE scores before and during/after but did not assess a typology of pre-SOCE sexual orientation. Tables 2-7 display the results obtained for apparent changes in four key aspects of sexual orientation: attraction, identity, same-sex behavior, and different-sex behavior.\n\nTables 2-7 predicting basic changes as a function of a typology of six pre-SOCE conditions.\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nIn Table 2, the low/low/low group was small, and these subjects reported higher levels of heterosexual behavior than homosexual sexual behavior prior to SOCE. Homosexual behavior was very low before SOCE. Both sexual attraction and sexual identity were, on average, in the lower bisexual to heterosexual range. Though not significant with a two-tailed test (p < .10) due to the small sample size, decreases in homosexual sexual attraction and identity were in Cohen’s medium range (both 0.67). If one were to assume that SOCE would only decrease same-sex factors, such that a one-tailed test would be appropriate, then the results for sexual attraction and sexual identity would be statistically significant (p < .05).\n\nIn Table 3, pre-SOCE sexual attraction scores were high while same-sex sexual behavior was lower and lower than different-sex sexual behavior; sexual identity fell between the levels for sexual attraction and sexual behavior. Sexual identity changed little with SOCE for this group while sexual attraction changed substantially (d = 0.78, p < .001); the next largest effect size was for heterosexual behavior increasing (d = 0.33, p < .06), a small-to-medium effect that was not quite significant at the. 05 level. These subjects were probably more concerned about their levels of same-sex sexual attraction than anything else and, if so, the results suggest that their expectations were met, at least to some extent.\n\nIn Table 4, the subjects initially were high on same-sex attraction and identity but lower on same-sex sexual behavior. While same-sex sexual behavior changed little with SOCE, changes in both attraction and identity were well above the limit for large effect sizes (≥ .80) per Cohen (1992) with 0.95 for attraction and 1.07 for identity, both significant (p < .001). Changes in either same-sex or different-sex sexual behavior were not significant (p < .05), although their effect sizes were in the small-to-medium range (0.25 to 0.37).\n\nIn Table 5, the subjects before SOCE were lower on attraction and identity (being in a low bisexual range) but higher on same-sex sexual behavior. With only five cases, only the changes in sexual behavior were significant or near significant, even though the effect sizes were well over the limit for large effect sizes per Cohen (1992), at a remarkable 4.07 for homosexual behavior and 1.10 for heterosexual sexual behavior. Effect sizes for attraction and identity were, respectively, nearly large (0.73) and in the small-to-medium range (0.35), though not significant statistically. It is possible that these subjects entered SOCE with more concern with their sexual behavior than with their attractions or identities; hence, the SOCE may have focused more on behavior than the other factors.\n\nIn Table 6, the subjects began higher on same-sex sexual attraction than on identity or behavior; however, in terms of change, effect sizes were very large for both same-sex sexual attraction (1.36) and for gay sexual behavior (1.82), both significant at p < .001. Smaller changes occurred for heterosexual behavior (0.28) and for identity (0.72, p < .01). Notably, same-sex sexual behavior was at a higher level (d = 1.84) than different-sex behavior before SOCE but was lower than heterosexual behavior during/after SOCE (d = 0.17).\n\nIn Table 7, subjects entered SOCE with higher scores on all three aspects of homosexual sexuality. While changes in heterosexual sexual behavior were minimal (0.16), there were very large changes in sexual attraction (1.11, p < .001), sexual identity (1.18, p < .001), and in sexual behavior (1.75, p < .001). While homosexual behavior remained higher than heterosexual behavior at both time points, it declined from an effect size advantage of 3.88 to only 0.34, less than a tenth of the initial effect size difference.\n\nIncluding prior sexual attraction, sexual identity, and same-sex sexual behavior as independent variables led to a non-significant overall degree of explained variance. After deleting sexual attraction as one of the independent variables, the adjusted R-squared was 0.04, with F(2, 199) = 3.52 (p = .033), with significant or near-significant results for the independent variables, prior same-sex sexual behavior (b = .17, p = .06) and sexual identity (b = -.19, p < .04). This would indicate that prior conditions had relatively little impact on therapeutic outcomes as reported by the subjects in this study, although there was a slight tendency, for higher levels of prior same-sex behavior (controlling for sexual identity) and lower levels of prior same-sex sexual identity (controlling for same-sex behavior) to predict slightly higher levels of reported therapeutic helpfulness.\n\nSullins et al. (2021) also indicated that marital status played an important role in SOCE outcomes but I wanted to test that hypothesis more carefully, using a repeated-measures design and establishing a more detailed breakdown of marital status, including four categories: never married (N = 66), married (N = 33), got married or engaged (N = 19), and was divorced/widowed and stayed divorced/widowed or got divorced (N = 7).\n\nThe primary concern was whether there would be an interaction effect between apparent change in sexual orientation variables and this new version of marital status. For sexual identity, the interaction effect was not significant (p = .393). The main effect of marital status was not significant (p < .07). For sexual attraction, the interaction effect was not significant (p = .246) while the main effect of marital status was significant (p < .01). For same-sex sexual behavior, the interaction effect was not significant (p = .07) while the main effect of marital status was significant (p = .01). However, in terms of heterosexual sexual behavior, the main effect of time was less significant (p = .04) than the interaction term (p < .001) while the main effect of marital status was also very significant (p < .001). Therefore, the detailed results for heterosexual sexual behavior are presented in more detail (Table 8).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSullins et al. (2021) did not appear to have developed or used the two measures featured with our fifth research question. The curve estimation program under regression in SPSS was used to predict the perceived helpfulness of SOCE from the two measures of the maximum number of SOCE sessions. For the ordinal measure of sessions, the linear and quadratic model featured F(2, 120) = 4.51, p < .02 with an adjusted R-squared of 0.054. The linear standardized beta coefficient was 1.00 (p = .01) while the quadratic beta was -.84 (p < .03). The pattern suggested that maximum overall helpfulness peaked between 51-100 and 101-200 sessions. For the ratio measures of sessions, the linear and quadratic model featured F(2, 120) = 5.00 (p < .01), with an adjusted R-squared of 0.062. The linear standardized beta coefficient was 1.32 (p = .003) while the quadratic beta coefficient was -1.21 (p = .006). The pattern suggested that the maximum helpfulness peaked at about 160 sessions. For both measures, the stronger increase in helpfulness occurred between no sessions and the maximum while the decrease in helpfulness was not as strong after the maximum.\n\nAs noted in the introduction, it remains an open question if better SOCE ratings for providers will reflect change in sexual orientation. Perhaps, ratings will increase with increased changes in the direction of heterosexuality; perhaps, the reverse might occur. There are three groups with respect to client-rated helpfulness: none or slightly (N = 13), moderately or markedly (N = 38), and extremely (N = 71), labeled respectively as A, B, and C in the Tables 9 through 12.\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nFor sexual attraction, the mean scores were as in the following Table 9.\n\nFor same-sex sexual behavior, the mean scores were as in the following Table 10.\n\nFor heterosexual sexual behavior, the mean scores were as in the following Table 11.\n\nFor sexual identity, the mean scores were as in the following Table 12.\n\nFor heterosexual sexual behavior, changes from SOCE were small and not significant statistically. However, for the three same-sex sexuality factors, the main effects over time and the interaction between time and the three levels of reported helpfulness were always significant (p < .01). For group A, the reported changes were consistently in a pro-gay direction, suggesting that, on average, changes in that direction were not perceived as helpful in terms of SOCE effectiveness. For groups B and C, greater changes in a heterosexual direction were perceived as more helpful. Both of these results suggest that SOCE’s effectiveness was judged on the basis of its association with desired changes in a heterosexual direction, even though changes in the direction of heterosexual behavior were smaller. For group B, changes tended to be from small-to-large; for group C, changes tended to be large, in terms of Cohen’s (1992) criteria.\n\nA typology was created of the main types of change reported by participants crossed with a five-category measure of reported helpfulness of SOCE. The results are shown in Table 13.\n\nFor all categories, a Chi-square test (df = 56) = 90.96, p = .002, indicating differences among the several categories. Comparing the three subgroup counts, a Chi-square (df = 8) = 36.99, p < .001, r = .45, p < .001. Comparing the two largest subgroups, a Chi-square (df = 4) = 26.38, p < .001, r = .48, p < .001. A comparison of the two smallest subgroups was not statistically significant. A comparison of the largest subgroup with the smallest subgroup yielded a chi-square (df = 4) = 22.76, p < .001, r = .43, p < .001. For this last comparison Cramer’s V = 0.24, which represents a large effect size, as calculated using a website [https://www.statology.org/effect-size-chi-square/]. Notably, while those men who became more gay in general (91.7%) reported at least slight or better degrees of helpfulness of SOCE, a small percentage (8.3%) of that group of men reported that SOCE was not helpful at all.\n\nAny time a respondent reports on past events, there may be recall bias or distortions of memory. Social desirability may contaminate reports of past or current events. Here the question was whether the time elapsed since having experienced SOCE would be associated with ratings of SOCE, which might be expected if recall bias was substantial (Table 14).\n\nResults indicate that neither recall bias nor recency bias are predominant; the negative correlation suggests a slight trend in favor of recency bias. It is possible that both biases are operant but canceled each other out.\n\nBefore SOCE, SSA scores (mean, 5.74; SD, 1.10) were significantly greater (t124 = 6.00, p < .001) than scores for SSI (mean, 4.80; SD, 1.76) with the scores correlated, r = .465, p < .001. After SOCE, SSA scores (mean, 4.14; SD, 1.76) were significantly greater (t123 = 5.62, p < .001) than scores for SSI (mean, 3.60; SD, 1.95) with the scores correlated, r = .839, p < .001. After SOCE, SSA and SSI scores were closer and more highly correlated.\n\nSSASSI congruence were positive when SSA > SSI and negative when SSA < SSI. Before SOCE, the scores ranged between -4 and 6, with a mean of 0.936, a median of zero, and SD = 1.74; after SOCE, the scores ranged between -1 and 4, with a mean of 0.540, a median of zero, and SD = 1.07. Before SOCE, 57.6% of the participants had scores of zero; after SOCE, it was 65.6%. Comparing congruence before versus after SOCE, t123 = 2.95, p = .004, with a mean of 0.895 (SD = 1.69) before and a mean of 0.540 (SD = 1.07) after, indicating that congruence scores decreased after, although remaining highly correlated, r = 0.611 (p < .001).\n\nTo investigate whether or how congruence scores might matter, four subgroups of the total sample were created: no exact (SSI = SSA) congruence before or after SOCE, congruence before but not after, congruence after but not before, and congruence both before and after. Chi-square tests were performed for each of the four groups, crossing our trinary outcome variable versus post-SOCE sexual orientation identity split at bisexual to heterosexual orientation versus the more homosexual sexual identity orientations. None of the tests were significant except for the before and after congruence group. For that group, all the participants who reported no to only slight effectiveness, 100% (N = 11) were homosexually oriented. For those who reported moderate effectiveness, 22.7% (N = 5) were more heterosexually oriented compared to 77.3% (N = 17) who were homosexually oriented. For those who reported extremely effective, the respective percentages were 85.7% (N = 24) and 14.3% (N = 4). The chi-square test (df = 2) = 31.76, p < .001, with r = -0.697 (p < .001). Another way of reporting the results would be that 34.4% (11/32) of those who had stronger and congruent gay identities after SOCE indicated that SOCE was of only slight or no effectiveness compared to 82.8% (24/29) of those who had stronger and congruent more heterosexual identities indicated that their SOCE was extremely effective.\n\nThere were 18 participants between the ages of 18 and 25 at the time of the survey. Of those 18, 55.6% were currently in SOCE, 22.2% had finished SOCE within the past year, 5.6% within one to two years, and 16.7% within the past two to five years. In terms of maximum sessions for the longest type of SOCE, 27.8% had been involved in a maximum of 50 sessions, 33.3% for a maximum of 100 sessions, and 38.9% for a maximum of 200 or more sessions. Thus, it is likely that some of these participants had begun SOCE before age 18 (Tables 15, 16).\n\nFor all four outcomes used here, results were significant (p < .01) and indicated that positive effects of SOCE exceeded negative effects or harms, as reported by the young participants themselves.\n\nA supplementary analysis that was not planned along with the others was to evaluate the relative predictive strength of positive versus negative outcomes with respect to the reported helpfulness of SOCE, as shown in Table 17. In general, positive changes seemed to impact reported helpfulness more than negative changes did. The strongest effect occurred for self-esteem, which also featured the strongest impact of a positive change. Although the results for suicidality were limited by a large amount of missing data, the positive and negative changes were equal in magnitude and the negative change’s impact was the largest for all five outcomes, suggesting that SOCE providers need to be acutely aware of and continue to check on participants’ feelings and intentions in that area and also with respect to changes in depression.\n\nSignificance levels are indicated by *** (p < .001), ** (p < .01), * (p < .05), and + (p < .10).\n\nThis report has many of the same limitations as Sullins et al. (2021). The sample is nonrandom, purposive, did not include women, and the data are over a decade old. The sample included men who were, as Sullins et al. (2021) stated, most often “white, affluent, well-educated, highly religious, and overrepresented the Mormon faith” (p. 14). In addition, our analyses used parametric statistics, but the assumption of normality was violated for most of our variables. However, many of our effect sizes are large enough that even if they were positively biased, they would usually still be of small-to-medium size. In general, more favorable results have been found for SOCE when the subjects were eager for treatment, highly religious, and married or planning to get married, as in this sample; less favorable, even harmful results have been found for SOCE when the subjects were pressured into experiencing SOCE, were not religious, were not married, and were high on same-sex sexual orientation identity at the time of the survey about past SOCE attempts. It is unlikely that these different populations will experience SOCE in the same way; results from one group should not be generalized to the other groups. Sullins et al. (2021) have presented other limitations that would also apply to this research.\n\nData sets held by Bondy (2021) and Pela and Sutton (2021), if released by their authors, might provide similar opportunities for independent analysis. Compared to Sullins et al. (2021), Bondy’s data features a larger sample size (N = 156) and includes more data on SSASSI congruence, extrinsic motivations to try SOCE, and client reported sources of SSA (including 44 reports of child sexual abuse; would those reports correlate with initial levels of SSA?). Bondy found that extrinsic motivations for SOCE predicted poorer ratings of SOCE experience, a result like other areas of counseling (e.g., Schumm & Denton (1979). Pela and Sutton’s (2021) data could be explored by age group to see how the youngest (age 18-25) responded to SOCE, by level of religiosity (did those with more frequent church attendance or citing religion as a reason to change report the most change?), or by level of desire for marriage (did a higher level of desire for marriage seem to affect the reported changes?). Even though the data indicated no average decline in mental health with SOCE, it might be useful to create a typology of those whose mental health did deteriorate, those whose remained similar, and those whose increased substantially and investigate if that typology would be associated with different SOCE motivations or outcomes.\n\n\nDiscussion\n\nSOCE is a controversial intervention. Some scholars have concluded that it is not effective and might even be unethical (Haldeman, 2022; Przeworski et al., 2021). In other controversial areas, however, scholarly consensus has been incorrect (Schumm, 2018). Sullin’s (2022) analysis of SOCE harms found little evidence of harms even when SOCE seemed to have been ineffective and even though the persons who were exposed to SOCE had experienced greater levels of childhood adversity, including having been bullied on account of their sexual orientation than those with no SOCE experience; scholarly “consensus” may be incorrect with respect to SOCE.\n\nHere an attempt was undertaken to independently evaluate a data set previously analyzed by Sullins et al. (2021). Our overall assessment is that Sullins et al. (2021) correctly concluded that SOCE was often effective, though change in this area is very difficult, and that in some cases, SOCE was not effective at creating change. However, our assessment may add further knowledge in the following areas:\n\n(1) Measurement. New measures were introduced, including four scales from the Santero data set, as well as a measure of overall helpfulness of SOCE, a typology of sexual orientation conditions prior to SOCE, a more differentiated measure of marital status, and a measure of the number of sessions of SOCE undertaken.\n\n(2) Comparing a variety of measures of sexual orientation before and during/after SOCE, we found effect sizes from 0.24 to 0.94, all of which were significant statistically (p < .01). Changes in attraction and daydreaming were large (generally > .80) but even changes in attraction and behavior were larger than Cohen’s medium effect size. The smallest effect sizes occurred for heterosexual kissing and sexual behavior, though they were still of small or greater size, still important for social science (Funder and Ozer, 2019).\n\n(3) Among six conditions involving the three aspects of sexual orientation prior to SOCE, it was found that the most consistent results for sexual attraction with three medium and three large effect sizes. Changes in same-sex sexual behavior varied more, with three large effect sizes but also one small effect size change. Changes in sexual identity included two large, two medium, and one small effect size. All the changes were in the expected direction, towards less same-sex interest or activity. The weakest changes occurred in terms of heterosexual behavior with one large effect size and four small effect sizes. In general, SOCE seemed more effective when initial levels of sexual orientation were higher. When levels were higher than others before SOCE, the initially higher levels seemed to change more, with larger effect sizes obtained.\n\n(4) A slight trend was observed for higher levels of identity (controlling for behavior) to be associated with smaller levels of reported helpfulness of SOCE; likewise, a small effect was noted for higher levels of behavior (controlling for identity) to be associated with stronger levels of reported helpfulness of SOCE.\n\n(5) Marital status appeared to interact with changes in heterosexual sexual behavior before and during/after SOCE, with larger changes for those who got married after SOCE began and negative changes for those who were divorced or widowed.\n\n(6) Significant linear and quadratic effects were observed, predicting reported helpfulness from the number of sessions of SOCE, although the level of explained variance was small (0.051) and the peak benefit seemed to be around 150 sessions, though most help occurred per session in the first 50 sessions.\n\n(7) Using three levels of reported helpfulness, it was found that for the 13 subjects who reported changes towards homosexuality their sense of helpfulness was lower while the 109 subjects who reported changes in the other direction reported higher levels of helpfulness. Effect sizes increased across the three groups of reported helpfulness. The smallest and most inconsistent effects were observed for changes in heterosexual sexual behavior.\n\n(8) Similar results were found as above when perceived helpfulness was cross tabulated with typologies of reported changes in terms of size and consistency. High levels of reported helpfulness were obtained when changes occurred as desired, but lower levels occurred when changes were towards homosexuality. However, the results for the subjects who reported changes towards homosexuality were bifurcated – some subjects reported lower levels of helpfulness, but a larger percentage of that group reported high levels of helpfulness, suggesting that even though they didn’t change towards heterosexuality, they still found SOCE very helpful. Perhaps these subjects found helpful affirmation of their homosexual identity through SOCE or, as some critics might surmise, despite SOCE. The percentage of men who became more gay and found SOCE to be not helpful was small (8.3%) compared to those (91.7%) who became more gay but said SOCE was nevertheless slightly, moderately, or extremely helpful.\n\n(9) The self-reported efficacy of SOCE was not significantly related to the time since SOCE, which may suggest that recall bias is not as great as often feared; it’s also possible that recency bias and recall bias cancelled each other out.\n\n(10) Congruence between SSA and SSI was investigated. In most cases, SSA > SSI. Congruence seemed to become greater after SOCE compared to before SOCE. When SSA and SSI were congruent both before and after SOCE, self-reported efficacy was strongly related to sexual orientation.\n\n(11) Self-reported positives for self-esteem, depression, suicidality, and social functioning were significantly greater than negatives. On average, positives were greater than negatives for nearly 70% of the respondents. Only 5.6% of the time were reports of harms greater than the slightly negative level and never rated greater than moderately negative. In this sample, harms appeared to be mostly of a minor nature.\n\n(12) Positive reported changes in SOCE outcomes appeared, in general, to predict reported helpfulness of SOCE more than negative changes did. The strongest overall effect was for changes in self-esteem. The apparent effects of positive and negative changes were nearly equal for suicidality and for depression, which may warn SOCE providers to be careful to assess and prevent adverse changes in suicidality and/or depression among their SOCE participants.\n\nFrom this author’s perspective, there may be at least two “elephants in the living room.” First, there seems to be an assumption by some scholars that if you experience any degree, slight to large, of SSA, then you must adopt a gay, lesbian, or bisexual identity (SSI), assuming (1) there should be absolute congruence or else one risks becomes inauthentic as a human being and (2) that determination is not up to the individual but to a variety of others wielding some sort of social influence. It seems that for some, SOCE is in part about disagreeing with, breaking, or reframing those assumptions (Bondy, 2021). Some religious groups may interpret SSA as a “temptation” rather than an intrinsic part of oneself, relying on the religious premises that everyone (even Jesus) has been tempted to do unusual, strange, even wrong things but that only verbal or nonverbal behavior involves moral culpability (Sutton, 2019). As Karten & Wade (2010) noted, “there are men who are sexually attracted to other men but do not identify as gay; rather, they experience their homosexual orientation and behavior as at odds with who they really are” (p. 86). Furthermore, as the number of persons identifying as nonheterosexual has increased in recent decades (Pellicane & Ciesla, 2022), perhaps a greater number of individuals might describe themselves as mostly heterosexual or somewhat bisexual – and might find SOCE more relevant to their needs than those who would identify as exclusively gay or lesbian.\n\nBasing one’s identity around a particular type of issue might be counterproductive for some, even if it provided self-justification or social justification for others. As an extreme example, believing in a flat earth might provide a person with an identity of sorts and a community of fellow believers, but is basing an identity on an incorrect belief helpful in the long run? An identity might inhibit a person’s perception of their ability to change when presented with more accurate facts. There is some evidence that a stronger identity as gay or lesbian may be associated with SOCE being ineffective, even counterproductive (Karten & Wade, 2010). The data here weakly suggested the same outcome, with a stronger LGB identity predicting less chance of change in attraction or behavior. My hypothesis here is that encouraging persons to assume nearly any identity (gay, Muslim, Christian, transgender, evangelical, tea party, professional, etc.) may be motivated for sociological or political purposes as much or more than for the personal or psychological benefit of those persons. For example, if a person is same-sex attracted but does not want to identify as gay/lesbian, what right would I have to force him (her) to do so or to try to prohibit him (her) from doing so? Should it not be his (her) choice on how to identify? For an SSA person to identify accordingly, may not necessarily be in their best interest (Pela & Sutton, 2021, p. 63; Diamond, 2008). While I think it’s fair to discuss the possible or likely advantages and disadvantages of any given identification, I don’t think it would be right for me to impose my desires about the other person’s potential identifications on them, even if it would make me feel better if they identified in a way I might prefer. Moreover, I am not sure the other person should assume a right to demand that I accept their identification, in part because many of the labels we might attach to ourselves can change over short or long times for a variety of both anticipated and unanticipated reasons.\n\nThe second elephant is something both sides in the debate over SOCE seem to overlook. Lesbian, gay, and bisexual behavior and identity can have many positive advantages, especially from a near-term perspective (Schumm, 2018, pp. 31-46; Schumm, 2020). As one gay youth said, “We have all the fun!” (Russell, 2003, p. 1253) or as a famous actress, Cynthia Nixon, said, “I’ve been straight and I’ve been gay, and gay is better” (Schumm, 2018, p. 39, citing from Diamond & Rosky, 2016, p. 382). A recent study found that lesbian and gay persons, especially those married, had higher socioeconomic status than heterosexual persons (Elwood et al., 2020), at least in California. In my view, these advantages should be openly discussed in SOCE; it may well be that some SOCE subjects may realize that they enjoy and want the advantages of a nonheterosexual lifestyle and should feel free to continue or move in that direction, without apology. Given such numerous advantages, LGB persons may experience guilt from being “over benefitted”, a prediction from social exchange theory, guilt that might account for internalized homophobia or lowered psychosocial health rather than or in addition to sexual minority stress.\n\nIt may also be that the difficulty found in SOCE is due in part to a failure to recognize and consider such advantages, as well as any disadvantages. Even if one believes that SSA is genetic or inborn, it might still be possible that the many advantages of being lesbian, gay, or bisexual work to reinforce those identities and behaviors over time. The advantages might lead a person to become LGB even without SSA as was found for some of the children of lesbian mothers, as detailed elsewhere (Schumm, 2004). In other words, beneficial experiences may reinforce attraction, behavior, and identity. At the same time, there may be some persons who feel that some negatives, perhaps especially long-term risks, of a gay, lesbian, or bisexual lifestyle might outweigh the positives. In general, my view is that when a person weighs short-term versus long-term advantages and disadvantages of a decision, change will be more difficult when the former have many positives and the latter (whether advantages or disadvantages) may not accrue for years, even decades. Even if change of sexual orientation were not possible, such subjects may find professional assistance helpful in evaluating their situation and understanding their own (accurate or inaccurate) perceptions of advantages and disadvantages, from both a short-term and a long-term perspective.\n\nOne possible interpretation of this research is that because SOCE did not lead to all participants attaining a completely heterosexual outcome in terms of attraction, behavior, or identity it must have failed. Such a conclusion may reveal implicit bias in terms of standards used for evaluating “success” in therapy. Using some raw data drawn up in only a few minutes, let’s suppose that a therapist was running a marriage therapy program, using the scores from one spouse to assess change. The data used here used five 1’s, four 2’s, four 3’s, four 4’s, three 5’s, and four 6’s at pre-test, with the following sets of scores for pretest 1’s (7, 2, 3, 4, 5), 2’s (1, 1, 5, 5), 3’s (6, 6, 5, 4), 4’s (5, 3, 5, 6), 5’s (6, 5, 6), and 6’s (7, 6, 6, 7), so anyone is welcome to replicate the analyses. There were 24 spouses assessed at pre-test and post-test on an item whose score ranged between 1 and 7, with higher scores indicating greater marital satisfaction. With the data used, the pre-test mean was 3.33 (SD = 1.79) and the post-test mean was 4.83 (SD = 1.74). The mean difference was 1.50 and the standard deviation of the difference was 1.69. Depending on which website calculator is used, Cohen’s d was between 0.84 and 0.89, a large effect size. The results were very significant, t(23) = 4.23 (p < .001). Using a Wilcoxin signed-ranks test, z = 3.45, p = .001, so the results would be similar using either parametric or nonparametric statistics. It is likely that most therapists would consider the results impressive, both substantial in effect size and very significant statistically.\n\nHowever, SOCE critics could argue that in the raw data only one spouse changed from a 1 to a 7 and only three ended up at a 7 while three scored lower at post-test and three more were unchanged at post-test with many (n = 11) changing by only one or two points in a positive direction (so that the majority of the clients (n = 14) either did not change at all or only changed a “little”. One might claim that of the 24 clients, seven were divorced during or after the program, which might be taken as failure, harm, or success (Moxley et al., 1987). Both explanations of the results are technically correct.\n\nWhile most scientists would present the first set of results and claim “success”, SOCE critics are more likely to take issue with the results by focusing on the second set of results, assuming the outcome measured was sexual orientation (i.e., few (n = 3) clients became completely heterosexual (and most - two of three - of them started as “mostly” heterosexual so their change was small), only one changed from completely gay to completely heterosexual, and most remained more or less bisexual (i.e., started out as bisexual and ended up as bisexual), while three became “more” gay. SOCE critics would probably conclude from the data that SOCE was not effective, despite the “impressive” first set of results. Furthermore, SOCE critics could argue that the program was “harmful” because some clients got “worse”, some did not change at all, and for all the time and expense lost to the participants, a majority got worse or got little benefit from the program. Perhaps marital therapy should be banned, given such poor results! It is also interesting that recent research has found a number of interventions (other than SOCE) to be ineffective (Williams et al., 2020), even more harmful than effective, and yet we are unaware of calls for their termination by major professional organizations, or at least not with the same fervor as for SOCE.\n\nWe believe that the same standards should be used for SOCE as for other types of therapeutic interventions rather than carving out a special set of standards for SOCE not used elsewhere for evaluating therapeutic interventions. In other words, we do not think it’s logically coherent to apply different standards statistically just because the outcome measure is different. In other words, SOCE critics are apt to use a double standard or special pleading when evaluating SOCE results.\n\n\nConclusions\n\nWhile the results here confirm those reported by Sullins et al. (2021), they also add to our knowledge about SOCE. For most of the subjects in this study, SOCE appeared to reduce same-sex attractions, identity, and behavior, while SOCE seemed less effective at increasing heterosexual behaviors. A small minority of some subjects did not appear to find SOCE helpful, but most subjects reported greater helpfulness of SOCE to the extent that it did help them reduce same-sex attractions, identity, and behavior. Remarkably, some subjects reported SOCE as very helpful even when their same-sex behaviors, identity, and attractions did not change or when they increased over time. Thus, SOCE may be capable of affirming even increases in same-sex behaviors, identity, and attractions when that is the overall outcome. Harms from SOCE seem to be minimal compared to the positives reported for young adults, reporting on their SOCE experience. SOCE effectiveness did not appear to change with time since therapy, lending less support to a recall bias argument. Congruence between SSA and SSI, may, in some cases, reduce the apparent effectiveness of SOCE, although our limited findings may not replicate. Since the findings here differ from many contemporary assertions that SOCE cannot be effective under any circumstances and is inherently harmful (especially for youth), or that SSA is inherently immutable. In essence, recent criticisms of SOCE (Haldeman, 2022) are beating a dead horse, criticizing former aversive methods condemned even by those researching current “talk” versions of SOCE. In other words, much of the criticism, even condemnation, of older versions of SOCE are irrelevant to current versions of SOCE. Furthermore, even the best therapies can lead to harm to some clients and therapies that have substantial and statistically significant effect sizes may not be successful for many of their clients. Therefore, calls to ban SOCE legally appear to be founded upon incomplete or inaccurate data, as well as biased standards for therapeutic success, and thus are very premature. Future research needs to be done more carefully (Rosik, 2020a,b; Sprigg, 2021) and focus on current versions of SOCE rather than memories of versions of SOCE that may date back a few decades.\n\n\nData availability\n\nA complete data availability statement may be found in Sullins et al. (2021).\n\n\nEthics\n\nAs noted in Sullins et al. (2021, p. 4), “The original study and protocols were approved by the Southern California Seminary Institutional Review Board. Written informed consent was obtained from all study subjects prior to participation (Santero, 2011, p. 154). As a secondary analysis of pre-existing data, the Catholic University of America Institutional Review Board has certified this study as exempt from human subject ethical review under 45 CFR 46.101.” On 25 April 2022, the Committee on Research Involving Human Subjects, Kansas State University, proposal number IRB-11175, declared this research activity exempt under the criteria set forth in the Federal Policy for the Protection of Human Subjects, 45 CFR 104(d), category: Exempt Category 4 Subsection 1, signed electronically by Chair, Dr. Rick Scheidt, 26 April 2022.",
"appendix": "Acknowledgments\n\nSpecial gratitude is extended to Dr. Paul Sullins, Paul Santero, and Christopher Rosik for making the data available for independent analysis; without their prior work with this data and its initial collection, this secondary analysis would have been impossible.\n\n\nAppendices\n\n\n\n\nReferences\n\nAmerican Psychological Association: APA resolution on sexual orientation change efforts. Washington, DC: Author; 1994. February 2021. Reference Source\n\nBondy G: Subjective experiences in sexual orientation change efforts: a mixed-method analysis. J. Hum. Sex. 2021; 12: 89–122.\n\nBradshaw K, Dehlin JP, Crowell KA, et al.: Sexual orientation change efforts through psychotherapy for LGBQ individuals affiliated with the Church of Jesus Christ of Latter-Day Saints. J. Sex Marital Ther. 2015; 41(4): 391–412. PubMed Abstract | Publisher Full Text\n\nCohen J: A power primer. Psychol. Bull. 1992; 112: 155–159. PubMed Abstract | Publisher Full Text\n\nDel Rio-Gonzalez AM, Zea MC, Florez-Donado J, et al.: Sexual orientation and gender identity change efforts and suicide morbidity among sexual and gender minority adults in Colombia. LGBT Health. 2021; 8(7): 463–472. PubMed Abstract | Publisher Full Text\n\nDiamond LM: Sexual fluidity: understanding women’s love and desire. Cambridge, MA: Harvard University Press; 2008.\n\nDiamond LM, Rosky CJ: Scrutinizing immutability: research on sexual orientation and US legal advocacy for sexual minorities. J. Sex. Res. 2016; 53(4-5): 363–391.\n\nDrescher J: Foreword. The case against conversion “therapy”: evidence, ethics, and alternatives. Haldeman DC, editor. Washington, DC: The American Psychological Association; 2022.\n\nElwood WN, Irvin VL, Liu B, et al.: Health-related influences of extending marital benefits to same-sex couples: results from The California Health Interview Survey. Fam. Relat. 2020; 69: 934–943. Publisher Full Text\n\nFreedman E: Critique of the Report of the American Psychological Association Task Force on Appropriate Therapeutic Responses to Sexual Orientation (2009). J. Hum. Sex. 2020; 11: 34–59.\n\nFunder DCOzer DJ: Evaluating effect size in psychological research: Sense and nonsense. Adv. Methods Pract. Psychol. Sci. 2019; 2(2): 156–168. Publisher Full Text\n\nGlassgold JM: Research on sexual orientation change efforts: a summary. Haldeman DC, editor The case against conversion “therapy”: evidence, ethics, and alternatives. Washington, DC: The American Psychological Association; 2022; (pp. 19–50)\n\nGoodyear T, Kinitz DJ, Dromer E, et al.: “They want you to kill your inner queer but somehow leave the human alive”: Delineating the impacts of sexual orientation and gender identity and expression change efforts. J. Sex Res. 2021; 1–11. online advance. PubMed Abstract | Publisher Full Text\n\nHaldeman DC: The case against conversion “therapy”: evidence, ethics, and alternatives. Washington, DC: American Psychological Association; 2022.\n\nJones SL, Yarhouse MA: A longitudinal study of attempted religiously mediated sexual orientation change. J. Sex Marital Ther. 2011; 37: 404–427. PubMed Abstract | Publisher Full Text\n\nKarten EY, Wade JC: Sexual orientation change efforts in men: a client perspective. J. Mens Stud. 2010; 18(1): 84–102. Publisher Full Text\n\nKinitz DJ, Salway T, Dromer E, et al.: The scope and nature of sexual orientation and gender identity and expression change efforts: a systematic review protocol. Syst. Rev. 2021; 10(1): 1–8.\n\nMoxley V, Eggeman K, Schumm WR: An evaluation of the “Recovery of Hope” program. J. Divorce. 1987; 10(1-2): 241–261. Publisher Full Text\n\nPela C, Sutton PM: Sexual attraction fluidity and well-being in men: a therapeutic outcome study. J. Hum. Sex. 2021; 12: 61–86.\n\nPellicane MJ, Ciesla JA: Temporal trends in rates of depression, anxiety, and suicidality among cisgender sexual minority and heterosexual college students. Psychol. Sex. Orientat. Gend. Divers. 2022. online advance.\n\nPrzeworski A, Peterson E, Piedra A: A systematic review of the efficacy, harmful effects, and ethical issues related to sexual orientation change efforts. Clin. Psychol. Sci. Pract. 2021; 28(1): 81–100.\n\nRosik CH: The creation and inflation of prevalence statistics: the case of “conversion therapy.”. J. Hum. Sex. 2020a; 11: 66–86.\n\nRosik CH: A critical review of 2020 research on harms from efforts to change sexual attractions and behaviors: minimal advancement of science, maximal advancement of agendas. J. Hum. Sex. 2020b; 11: 87–108.\n\nRosik CH, Lefevor GT, Beckstead AL: Sexual minorities who reject an LGB identity: who are they and why does it matter?. Issues Law Med. 2021; 36(1): 27–43. PubMed Abstract\n\nRosik CH, Popper P: Clinical approaches to conflicts between religious values and same-sex attractions: contrasting gay-affirmative, sexual identity, and change-oriented models of therapy. Couns. Values. 2014; 59: 222–237. Publisher Full Text\n\nRyan C, Toomey RB, Diaz RM, et al.: Parent-initiated sexual orientation change efforts with LGBT adolescents: Implications for young adult mental health and adjustment. J. Homosex. 2020; 67(2): 159–173. PubMed Abstract | Publisher Full Text\n\nSalway T, Ferlatte O, Gesink D, et al.: Prevalence of exposure to sexual orientation change efforts and associated sociodemographic characteristics and psychosocial health outcomes among Canadian sexual minority men. Can. J. Psychiatry. 2020; 65(7): 502–509. PubMed Abstract | Publisher Full Text\n\nSantero P: Change Effects in U.S. Men with Unwanted Same Sex Attraction after Therapy. [PsyD Dissertation]. Southern California Seminary. 2011.\n\nSchumm WR: What was really learned from Tasker and Golombok’s (1995) study of the children of lesbian and single parent mothers?. Psychol. Rep. 2004; 94: 422–424. PubMed Abstract | Publisher Full Text\n\nSchumm WR: Navigating treacherous waters – one researcher’s 40 years of experience with controversial scientific research. Comprehensive. Psychology. 2015; 4(4): 17.CP.4.24. 1-40. Publisher Full Text\n\nSchumm WR: Same-sex parenting research: A critical assessment. London, UK: Wilberforce; 2018.\n\nSchumm WR: Avenues for future LGBT theory and research. JSM J. Sex. Med. 2020; 4(2): 1–7.\n\nSchumm WR, Dugan M, Nauman W, et al.: Using free websites to perform statistical calculations in basic statistics courses at high school or college levels. Sunkrist Sociology and Research Journal. 2021; 2(1): 1009. 1-7.\n\nSchumm WR, Denton W: Trends in premarital counseling. J. Marital Fam. Ther. 1979; 5(4): 23–32. Publisher Full Text\n\nSprigg PS: Searching for evidence of harm: 79 key studies do not demonstrate that sexual orientations change efforts (SOCE) are more harmful than other counseling. J. Hum. Sex. 2021; 12: 6–40.\n\nSullins DP: Absence of behavioral harm following non-efficacious sexual orientation change efforts: A retrospective study of United States sexual minority adults, 2016-2018. Front. Psychol. 2022; 13(823647): 1–12. Publisher Full Text\n\nSullins DP, Rosik CH, Santero P: Efficacy and risk of sexual orientation change efforts: a retrospective Analysis of 125 exposed men [version 2; peer review: 2 approved]. F1000Res. 2021; 10: 222. PubMed Abstract | Publisher Full Text\n\nSutton PM: Serving persons with (unwanted) same-sex attraction and behavior (SSA) from the Roman Catholic tradition. Journal of Human Sexuality. 2019; 10: 17–52.\n\nVanVoorhis CRW, Morgan BL: Understanding power and rules of thumb for determining sample sizes. Tutor. Quant. Methods Psychol. 2007; 3(2): 43–50. Publisher Full Text\n\nWhitehead N, Whitehead B: My genes made me do it. Lafayette, LA: Huntington House Publishers; 1999.\n\nWilliams AJ, Botanov Y, Kilshaw RE, et al.; Potentially harmful therapies: a meta-scientific review of evidential value. Clin. Psychol. Sci. Pract. 2020; 28(1): 5. 1-16."
}
|
[
{
"id": "139899",
"date": "30 Jun 2022",
"name": "Anna Forsythe",
"expertise": [
"Reviewer Expertise Systematic Literature review",
"Meta-analysis",
"Humanistic and Economic burden of disease",
"Health Economic analyses of interventions."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, this is a 3rd re-analysis of a survey conducted in 2011 among a sample of 125 highly religious adult males. The author did not provide any information on the survey development or validation, putting into question the validity of the results – measuring relevant concepts or accurately detecting change. The reliability of the results of the analyses must be considered in light of the very small samples (mostly <30 patients). The results of the analyses should be interpreted with extreme caution and cannot be used to derive the conclusions that the author has reached. Considering the many methodological flaws of this paper and the outdated timing of data collection, it is not clear how this research can add any value the scientific community. I would not recommend indexing.\nThe study was conducted in a convenience sample of highly religious, predominantly white, largely college educated, and generally economically secure adult men who freely consented to undergo SOCE. Importantly, based on this selection bias if this paper is meant to inform the public discussion on policies regarding SOCE, then it is essential to highlight the multitude of ways in which the study population does not represent those who are the focus of bans and proposed bans on SOCE: minors under the age of 18 from all socioeconomic, ethnic, and racial groups without regard for religious affiliation and who may be coerced by families and faith groups to undergo SOCE. As such, any attempts to broaden the implications of the analyses beyond the specific population initially surveyed are merely opinions of the author and not substantiated by the research in the paper.\n\nThe original study referenced in this article demonstrated that in the majority (55%) of the original sample, no change (complete or partial) in sexual behavior followed SOCE. Most changes were reported with magnitude of change ranging from a quarter to ½ standard deviation of the original values, without any evidence of validation whether such change is meaningful. Neither the original study nor the current re-analysis establish a minimally important difference (MID) for the reported outcomes.\n\nThis study is the third analysis of the original survey conducted in 2011. Despite the availability of multiple, larger, more methodologically robust studies with more diverse and representative populations, the author chose to return to a >10-year-old sample. Also notable is that while still a largely heteronormative dominated culture, significant social change has occurred as evident with the recognition of marriage equality, awareness of gender identity and dysphoria. Considering the rapidly evolving social and cultural landscape regarding LGBTQ issues, and the availability of newer data on SOCE, it is questionable whether another re-analysis of a limited, biased small-sample-size, older study merits publication.\n\nThe selection of recent publications referenced in this study appears to be incomplete, as it does not include several important, recently published papers, most covering much larger and more representative/generalizable populations:\nBlosnich et al. (20201). Turban et al. (20202). UCLA School of Law Williams Institute. Conversion therapy and LGBT youth. Published June 2019. Accessed March 1, 2021. https://williamsinstitute.law.ucla.edu/publications/conversion-therapy-and-lgbt-youth/ The Trevor Project. The Trevor Project National Survey on LGBTQ Youth Mental Health 2020. Published 2020. Accessed March 1, 2021. https://www.thetrevorproject.org/wp-content/uploads/2020/07/The-Trevor-Project-National-Survey-Results-2020.pdf\n\nThe 77-question survey (originally used in the 2011 study and re-analyzed for the second time in this manuscript) was not a methodologically robust survey: it did not follow FDA Patient-Reported Outcomes guidance, select patient-relevant concepts, or validate the questions to evaluate if a meaningful change could be measured. Conducting additional statistical analyses on an exploratory, unvalidated questionnaire does not make the original results any more reliable. The author should add information on the creation and validation of the original questionnaire, including the methodological limitations.\n\nTables 2 through 7, as well as analysis to support question 10, report statistical analyses based on very small sample size (all <30 patients). The study was not prospectively powered to find meaningful results in these small samples, and thus the results can only be considered non-significant trends.\n\nSince the time of the survey, gay marriage has become legal in all 50 states. Thus, the assumptions behind the fourth question (marital status, with marriage being defined as “between a man and a woman”) are no longer valid or generalizable. A key limitation of the research is that individuals now have the opportunity to be in a legally and socially recognized homosexual marriage, which may impact their willingness to undergo—and their experience of—SOCE.\n\nThe author understates the level of concern expressed by the international medical community regarding SOCE. The introduction and discussions sections of this paper should explicitly state that the issue goes beyond one of scholarly controversy: the American Academy of Pediatrics, the American Psychological Association, the American Academy of Child and Adolescent Psychiatry, the American Medical Association, the American Counseling Association, the American Psychiatric Association, and the United Nations Human Rights Office of the High Commissioner, among other medical, mental health, and human rights organizations, formally oppose SOCE.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "200847",
"date": "01 Sep 2023",
"name": "G Tyler Lefevor",
"expertise": [
"Reviewer Expertise LGBTQ+ health",
"religion/spirituality"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI am very concerned about the adequacy of this paper as a scientific endeavor. Below I detail two major concerns and several minor concerns.\nMajor concern #1) I am concerned that the premise of this piece is statistically unsound. The authors write, “Our analyses used parametric statistics, but the assumption of normality was violated for most of our variables.” If assumptions of normality are violated, then nonparametric statistics should have been used. As such, the authors’ findings rest on an entirely unfounded statistical foundation.\nMajor concern #2) The authors routinely generalize past what their data allows them to say. The sample they used differs from the general population in many ways, including being entirely cisgender men, being mostly religious, and being recruited because of its interest in pursuing SOCE. The authors final statement in their abstract, “Therefore, calls to ban SOCE legally appear to be founded upon incomplete or inaccurate data and thus premature, while more higher quality research is yet needed regarding SOCE,” reaches as broad as possible (to all Americans); however, the authors do not have data to support this assertion. This article cannot be indexed with such a politically motivated interpretation of the authors’ findings that goes beyond the data in the abstract.\n\nMethod:\nThe authors should redescribe the sampling procedure so that the reader can understand the population from which the current sample was taken. This population is going to introduce substantial interpretive constraints on this paper.\n\nGenerally, obtaining a Cronbach’s alpha that is lower than .7 is seen as grounds for not using a scale in scientific research. I would encourage the authors to not use the “prior same-sex sexuality” scale for this reason. With an alpha as low as .58 it is unclear what is being measured here.\n\nI am concerned about the helpfulness measure. Because participants were able to select in or out of the measure, it is unclear how to understand the participants who did not respond to one (or more) of the helpfulness questions. As such, it does not make conceptual sense to create a mean “helpfulness” score because participants likely only responded to items that they perceived as helpful. Better analyses might look at the items that participants saw as helpful versus those not responded to.\n\nWhat does a median split look like on a dichotomous variable (sexual identity)? Also, please provide the general descriptive statistics for sexual attraction, behavior, and identity. Does “low attraction” actually mean a substantial degree of same-gender attraction?\n\nResults:\nIt appears that you are measuring same-sex identity on a continuous scale? This seems unlikely, but I am otherwise confused how this variable was assessed with a t-test.\n\nYou did not provide rationale for your median split, which makes it harder to interpret results that use it. I am not confident that these groups are substantially different or how to interpret what low vs. high is.\n\nWhat was the relationship between sexual attraction, behavior, and identity? My guess is that on your third question, you are running into some multicollinearity problems and should perhaps only include one indicator of sexual orientation. This would explain why same-sex identity and behavior had different signs.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-580
|
https://f1000research.com/articles/10-322/v1
|
26 Apr 21
|
{
"type": "Research Article",
"title": "Massive Open Online Course (MOOC) Opportunities in Health Education (HE) in a mandatory social isolation context",
"authors": [
"Gandy Dolores-Maldonado",
"Jorge L. Cañari-Casaño",
"Rosalia Montero-Romainville",
"German Malaga",
"Jorge L. Cañari-Casaño",
"Rosalia Montero-Romainville",
"German Malaga"
],
"abstract": "Background: Routine care for prevention and health promotion has reduced significantly due to the Covid-19 pandemic and mandatory social isolation measures. In this context, it is necessary to identify and describe Massive Open Online Courses (MOOCs) that provide opportunities for health education, promotion, and prevention aimed at the general population. The study is a systematic review of MOOCs on health education, health promotion, and prevention for the general population in a pandemic context. Methods: We developed a search for MOOC courses aimed at the general population on health education, health promotion, and prevention in different available MOOC platforms. We executed a descriptive analysis of the main characteristics of the selected MOOCs. Results: There were 117 MOOCs chosen on health education, promotion, and prevention for the general population. Coursera (40.3%) was the platform that offered the highest quantity of MOOCs; more than half of the MOOCs were in English (52.9%). The median (interquartile range) duration of the selected MOOCs was 11 (6–15) hours. The predominant themes were \"Health promotion\" (43%) and \"Food and nutrition\" (31%), and the origin was mainly from Europe (37.8%). Conclusions: MOOC offerings in health education are diverse, predominantly in English, of European origin, and in health promotion issues. This study opens an opportunity to multiply initiatives in different territories, considering other languages and topics more akin to each territorial reality, allowing it to be a more equitable learning opportunity in times of pandemic and compulsory social isolation.",
"keywords": [
"health education",
"MOOC",
"eHealth",
"digital health literacy",
"eLearning",
"Social isolation"
],
"content": "Introduction\n\nIn December 2019, the COVID-19 pandemic was triggered by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), revealing the fragility of the health systems of developing countries; as of February 1, 2021, the cases amounted were 134,228,450, with 2,229,565 deaths worldwide (COVID-19 Map - Johns Hopkins Coronavirus Resource Center) and the countries with the highest fatality due to COVID-19 are mostly low-middle-income countries (LMICs) with precarious health systems or those that have already collapsed.22\n\nPrimary care service efforts have concentrated on containing the COVID-19 pandemic, for which there is a great concern about what could be neglected (OPS/OMS Perú - OPS/OMS Perú), reduction in access to medical doctors, drugs and growth monitoring during the lockdown period.3 Also, disruptions in drug supply chains are likely associated with defaulters on immunization schedules, which may lead to future outbreaks of preventable diseases such as diphtheria.4 It has been estimated that maternal and child neglect in LMICs could be devastating in a context where maternal deaths could increase up to 60% and infant mortality up to 41%.5 The control of endemic infectious diseases, such as malaria,6 as well as chronic non-communicable diseases (NCDs), such as hypertension and diabetes, have been neglected or suspended,7 and there has been an increase in mental illnesses such as anxiety, depression, and suicide.8 Furthermore, there is a concern of the population to visit health systems for their routine care for fear of contagion.9 Against this, some countries implemented remote healthcare systems (teleconsultation)10 and health communication campaigns. However, these strategies have been insufficient to cover the demand for healthcare effected by the pandemic and mandatory social isolation measures.\n\nThe pandemic context requires changes and identification of strategies that can help meet the indirect effects of neglect of diseases not related to COVID-19 in health systems. In this scenario, Massive Open Online Courses (MOOCs) could be an educational option to disseminate systematized courses on education, health promotion, and prevention aimed at the general population.\n\nMOOCs, in the past, have been an opportunity for health education for developing countries. Among their advantages are global accessibility, flexible hours, multiple teaching tools, and that they are generally free. MOOCs have been an educational response to emerging and re-emerging disease epidemics.11 However, to access these resources, inequities exist for developing countries, such as language barriers and technological access.12\n\n\nMethods\n\nFor this study, we conducted a digital search on MOOC platforms like Coursera, edX, FutureLearn, XuentangX, Udacity, Miríadax, Alison, Canvas Network, and OpenWHO, among others to identify MOOCs with content related to health education (education, promotion, and prevention of health) aimed at the general public. Also, the search involved explored topics related to health, well-being, and medicine. We included terms as nutrition, healthy life, physical activity, medical care, healthy nutrition, mental health, and variants.\n\nThree authors conducted the MOOC search manually and independently on the mentioned virtual platforms. The search development was between the months of June and December 2020. Likewise, we had to consult websites on larger platforms available in the world like Class Central and MOOC List. We started the search of each virtual platform and examined MOOC contents with the terms described above. The eligibility criteria for selecting the MOOCs were that they had content related to health education, and were aimed at the general population; further, we considered availability of registration/access at the time of the search.\n\nSubsequently, through a peer review, the researchers excluded MOOCs that showed highly specialized content or requested a prerequisite. MOOCs aimed at professionals or indicated that they were MOOCs for professional certification were also not considered, neither were those only available as paid content. If a conflict or inconsistency existed about our exclusion criteria, it was solved through deliberation peer review. We organized MOOCs by groups according to similar topics for a better description.\n\nThe data analysis was about the place of origin, principal language, and duration of the course. We used frequency measures to describe the categorical characteristics and dispersion measures to describe the hours. The analysis was using STATA version 16 (RRID:SCR_012763), Statistical analysis may also be performed using RStudio open source software for Windows, version 4.0.0.\n\n\nResults\n\nWith the established search criteria, a total of 217 MOOC courses were found on the different platforms. After excluding MOOC courses because they were specialized, unavailable, aimed at other target audiences, or without relation to health education, we selected 117 of the total MOOCs to be analyzed (Figure 1).\n\nThe 117 MOOCs analyzed were classified into six groups according to their content, with themes such as “health promotion” and “food and nutrition”. These latter two accounted for more than 60% of the total MOOCs included. Regarding the duration of time, the MOOCs had a median (interquartile range) of 116–15 hours and the topics of health promotion and community health and social rights presented higher medians, as well as a minimum of 8.5 hours and a maximum of 16.5 hours (Table 1).\n\nFrequency, median and interquartile range of MOOC duration time.\n\nOf the total number of courses on the topics “Health promotion” and “Psychology and mental health”, 21 (50%) and 12 (52.17%) were offered on the Coursera platform. (Table 2). Likewise, all the courses around COVID19 (5 MOOCs) were classified (4 MOOCS) in “Psychology and mental health” and 1 (4 MOOC) in “Health promotion”.\n\nDistribution of MOOC topics by platform.\n\n* The rows represent 100%.\n\nRegarding the principal language, English was identified in 62 (53%) of the MOOCS the language of preference, followed by Spanish in 18 (15.4%) MOOC courses (data not shown). Likewise, the principal language for all topics was English, with the exception of the climate change and health topics (See Table 3).\n\nDistribution of MOOC topics by language and origin.\n\n* The rows represent 100%.\n\nRegarding the origin of the MOOC courses, we found that 44 (37.6%) of the MOOCs were from institutions in Europe, followed by America 27 (23.1%) and Asia 26 (22.2%) (Data not shown). In the case of America, 25 (21.4%) were from North America and 2 (1.7%) from South America (data not shown). The topics of health promotion, psychology, and mental health and health care came mainly from universities in Europe; and the food and nutrition topic mainly from Asia (See Table 3).\n\n\nDiscussion\n\nWe identified 117 MOOC courses on health promotion. The majority are offered in English and are carried out mainly by institutions in Europe. Most of the courses were on the topics of health promotion and food and nutrition.\n\nFrom the preliminary search, it was evident that a large number of MOOCs were highly specialized, were aimed at professionals,13,14 or offered professional certification,11,15,16,17 and some are not available without payment. Although we have not included these MOOCs in the study, it is essential to notice that it can be an indicator of the limited supply of MOOCs with a profile aimed at the general public or users of primary level care centers, with the content of free health education and aimed at prevention and healthcare. We consider that this is an extremely important point regarding access to health education in a context of compulsory social isolation.\n\nRegarding the predominant themes of health promotion and food and nutrition, certain similarity was found with another study whose main topics were food, nutrition, your health, and introduction to health nursing, courses were aimed at professionals.18 MOOCs on health and medicine allow patients to acquire health education on specialized topics. Patients can gain understanding in disease implications, conditions, techniques, and available interventions around their disease, especially in the early stages. Besides, there are some useful topics which are still taboo, such as contraception, drug addiction, and acquired immunodeficiency syndrome (AIDS); courses focused on these topics help people educate themselves without having to visit an office.\n\nThe MOOCs found around psychology and mental health turn out to be a learning opportunity for stress management in times of compulsory social isolation. The results end up being part of recommendations to review said web-based interventions in mental health literacy promotion.19 Because adolescents and young people present more difficulties20 for decision-making in health often searching for information on the web,21 it is evident that they do not differentiate between reliable and less reliable information and that they do not know how to translate what they read into healthy behaviors.22\n\nAmong other issues, community health and social rights take a position in the context of compulsory social isolation since many decisions about health can be taken collectively in the community environment;23 additionally, many of them can be taken at the family level or by the influence of peers, without considering the repercussions of community leadership in some scenarios.24 Therefore, individual decisions can be even more relevant; for example, vaccination can affect a significant group of the population and have an impact on a higher incidence of some pathologies at the community level,25 especially when there is an increase in those who will not be vaccinated even during the COVID-19 pandemic.26\n\nTherefore, access to information through a MOOC could empower people who would not otherwise know about the options offered.18 This study shows that various institutions and organizations worldwide have seen MOOCs as an educational opportunity due to their relatively low cost27 and whose success depends on the quality of their contents,28 the teacher's strategies, and the focused courses.\n\nSimilar to previous studies was evidence that the Coursera platform was the one that hosted the largest number of MOOCs.18,29 Regarding the origin of the MOOCs, the largest number were from developed countries,30 from institutions in Europe and North America, similar results were described in other studies,11,18,31 being, by default smaller quantity offered by Latin American countries.32 This predominant origin could be because more than half of the MOOCs were offered and developed in English11,18,33 and only 22% in Spanish. Proof of this is that of the 23, 13, and four MOOCs on psychology and mental health, health care, community health and social rights, respectively, only one MOOC for each topic was in Spanish.\n\nBecause the majority of MOOCs are in English, it may be a limitation for access and learning opportunities in times of pandemic for the Latin American population. As well as language, aspects such as the absence of a computer and internet, or educational level34 may also limit access to MOOCs in times of compulsory social isolation.\n\nConsidering the fact that these courses were offered by developed countries, this could limit the topics addressed to being oriented with a different health reality from that of developing countries, where diseases such as anemia, malnutrition, or infectious diseases are the most frequent. This scenario could explain the high level of MOOCs from North America and Europe (Heather Miller and Martin Odersky. Functional Programming Principles in Scala: Impressions and Statistics | Scala Documentation) compared with South America, Africa, and Oceania.36 It is known that courses are built based on a context and socioeconomic condition for a target population, and participation levels were higher when considered these variables.28 MOOCs with an approach based on the reality of LMICs37 could be an opportunity, addressing issues such as chronic malnutrition, anemia, among frequent health problems that this population suffers, even more so in times of pandemic due to the restricted care of primary health centers to provide services on these issues.\n\nAmong the limitations were that the chosen courses are based exclusively on the authors' criteria. The possibility of including studies that did not meet the inclusion criteria was lowered by performing the peer review. Courses classified into topics related to health education considered when compiling MOOCs for the review. However, if a MOOC has an incorrect classification, it would not have been identified for review. In cases for which MOOCs were offered in languages different than English, we used Google Translate for content translation. Finally, the study aimed not to evaluate the quality of the contents in the MOOCs; however, almost all the MOOCs declared their institutional origin, which was predominantly universities.\n\nFinally, the study showed most of the MOOC courses in health education aimed at the general population or users of health systems were framed mainly in the themes of health promotion and food and nutrition, originating from European institutions and North America and with a higher predominance of the English language.\n\nMOOCs are shown as key tools to empower people, so in a pandemic context, the need to invest in alternative methods of dissemination of knowledge for knowledge-based empowerment would arise, covering the capacities of the general public that at present it is affected by not having access to care in health services of the first level of care. In addition to this, a critical shortage of human resources in health and healthcare, comprising a limited number of medical professors and limitations in physical infrastructures are reasons that increase the need to access online courses in health education of the level primary. Although the MOOCs’ origin was mainly from university institutions a future analysis of the quality of the contents must be addressed for greater comprehensiveness.\n\n\nData availability\n\nOpen Science Framework: Underlying data for ‘Massive Open Online Course (MOOC) Opportunities on in Health Education (HE) during of mandatory social isolation context’, https://doi.org/10.17605/OSF.IO/5UJ3V1.38\n\nThis project contains the following underlying data:\n\nA database with information from the MOOCS, institutions, platform and language.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgements\n\nWe express our acknowledgement to Corali Torres Paz de Fetaya for her review of the English version of our manuscript.\n\nJLC is a doctoral student studying an Epidemiological Research Doctorate at Universidad Peruana Cayetano Heredia under FONDECYT/CIENCIACTIVA award EF033-235-2015 and supported by training grant D43 TW007393 awarded by the Fogarty International Center of the US National Institutes of Health.\n\n\nReferences\n\nLlanos Zavalaga LF, Castro Quiroz JA, Ortiz Fernández J, Ramírez Atencio CW: Cuando crear sinergia no siempre es Salud: Análisis y propuesta en la evolución del Sistema de Salud en Perú. Rev Medica Hered 2020 Apr 29 [cited 2020 Oct 25]; 31(1): 56–69. Publisher Full Text\n\nNavarro JC, Arrivillaga-Henríquez J, Salazar-Loor J, Rodriguez-Morales AJ: COVID-19 and dengue, co-epidemics in Ecuador and other countries in Latin America: Pushing strained health care systems over the edge [Internet]. Vol. 37, Travel Medicine and Infectious Disease. Elsevier Inc.; 2020 [cited 2021 Jan 8]. p. 101656. Reference Source\n\nMatsungo TM, Chopera P: Effect of the COVID-19-induced lockdown on nutrition, health and lifestyle patterns among adults in Zimbabwe. BMJ Nutr Prev Heal 2020 Dec 1 [cited 2021 Feb 23]; 3(2): 205–12. Available from: http://www.\n\nNelson R: COVID-19 disrupts vaccine delivery. Lancet Infect Dis 2020 May 1 [cited 2021 Feb 23]; 20(5): 546. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRoberton T, Carter ED, Chou VB, Stegmuller AR, Jackson BD, Tam Y, et al.: Early estimates of the indirect effects of the COVID-19 pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study. Lancet Glob Heal 2020 Jul 1 [cited 2020 Oct 25]; 8(7): e901–8. Reference Source\n\nTorres K, Alava F, Soto-Calle V, Llanos-Cuentas A, Rodriguez H, Llacsahuanga L, et al.: Malaria Situation in the Peruvian Amazon during the COVID-19 Pandemic. Am J Trop Med Hyg 2020 Sep 3 [cited 2020 Oct 25]; tpmd200889. Reference Source\n\nPesantes MA, Lazo-Porras M, Cárdenas MK, Diez-Canseco F, Tanaka-Zafra JH, Carrillo-Larco RM, et al.: Diabetes, COVID-19 y atención primaria. Rev Peru Med Exp Salud Publica 2020 Sep 24 [cited 2020 Oct 25]; 37(3): 541–6. Publisher Full Text\n\nRoy A, Singh AK, Mishra S, Chinnadurai A, Mitra A, Bakshi O: Mental health implications of COVID-19 pandemic and its response in India [Internet]. International Journal of Social Psychiatry SAGE Publications Ltd; 2020 [cited 2021 Jan 8]. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuarcaya-Victoria J: Mental health considerations about the COVID-19 pandemic. Rev Peru Med Exp Salud Publica 2020 [cited 2020 Oct 25]; 37(2): 327–34. Publisher Full Text\n\nBhaskar S, Bradley S, Chattu VK, et al.: Telemedicine Across the Globe-Position Paper From the COVID-19 Pandemic Health System Resilience PROGRAM (REPROGRAM) International Consortium (Part 1). Front Public Heal. 2020 Oct; 556720: 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHernández-Vásquez A, Bendezu-Quispe G, Torres-Roman JS, Salinas-Ochoa B: Utility of massive open online courses (MOOCs) concerning outbreaks of emerging and reemerging diseases. F1000Research. 2017 [cited 2020 Oct 25]; 6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLambert SR: Do MOOCs contribute to student equity and social inclusion? A systematic review 2014–18. Comput Educ. 2020 Feb 1; 145: 103693.\n\nMahajan R, Gupta P, Singh T: Massive Open Online Courses: Concept and Implications [Internet].Vol. 489, INDIAN PEDIATRICS. 2019 [cited 2020 Oct 25]. Reference Source\n\nBendezu-Quispe G, Quijano-Escate R, Hernández-Vásquez A, Inga-Berrospi F, Condor DF: Massive open online courses for continuing education for nursing professionals in Peru. Rev Lat Am Enfermagem 2020 [cited 2020 Oct 25]; 28: 1–7. Reference Source\n\nMaxwell WD, Fabel PH, Diaz V, Walkow JC, Kwiek NC, Kanchanaraksa S, et al.: Massive open online courses in U.S. healthcare education: Practical considerations and lessons learned from implementation. Curr Pharm Teach Learn 2018 Jun 1 [cited 2020 Oct 25]; 10(6): 736–43. Reference Source\n\nUpdated numbers from our platform - FutureLearn [Internet]. [cited 2020 Oct 25]. Available from: Reference Source\n\nChristensen G, Steinmetz A, Alcorn B, Bennett A, Woods D, Emanuel EJ: The MOOC Phenomenon: Who Takes Massive Open Online Courses and Why? SSRN Electron J 2014 Apr 23 [cited 2020 Oct 25]. Reference Source\n\nLiyanagunawardena TR, Williams SA: Massive open online courses on health and medicine: Review. Vol. 16. Journal of Medical Internet Research. 2014: e191.\n\nBrijnath B, Protheroe J, Mahtani KR, Antoniades J: Do web-based mental health literacy interventions improve the mental health literacy of adult consumers? results from a systematic review. J Med Internet Res 2016 Jun 1 [cited 2020 Oct 25]; 18(6). Reference Source\n\nKutcher S, Bagnell A, Wei Y: Mental Health Literacy in Secondary Schools. A Canadian Approach. Child Adolesc Psychiatr Clin N Am 2015 Apr 1 [cited 2020 Oct 25]; 24(2): 233–44. Reference Source\n\nKim SU, Syn SY: Research trends in teens’ health information behaviour: A review of the literature. Health Info Libr J 2014 [cited 2020 Oct 25]; 31(1): 4–19. PubMed Abstract | Publisher Full Text\n\nJain AV, Bickham D: Adolescent health literacy and the Internet: Challenges and opportunities. Curr Opin Pediatr 2014 [cited 2020 Oct 25]; 26(4): 435–9. PubMed Abstract | Publisher Full Text\n\nHarris J, Springett J, Croot L, Booth A, Campbell F, Thompson J, et al.: Can community-based peer support promote health literacy and reduce inequalities? A realist review. Public Heal Res 2015 Feb [cited 2020 Oct 25]; 3(3): 1–192. Reference Source\n\nBatterham RW, Hawkins M, Collins PA, Buchbinder R, Osborne RH: Health literacy: Applying current concepts to improve health services and reduce health inequalities. Public Health 2016 Mar 1 [cited 2020 Oct 25]; 132: 3–12. PubMed Abstract | Publisher Full Text\n\nFrench MG: Relevance of Health Literacy to Precision Medicine [Internet]. Relevance of Health Literacy to Precision Medicine 2016 [cited 2020 Oct 25]. Reference Source\n\nLazarus JV, Ratzan SC, Palayew A, Gostin LO, Larson HJ, Rabin K, et al.: A global survey of potential acceptance of a COVID-19 vaccine. Nat Med 2020 Oct 20 [cited 2021 Jan 30]; 1–4. Publisher Full Text\n\nHoy MB: MOOCs 101: An Introduction to Massive Open Online Courses. Med Ref Serv Q 2014 Jan [cited 2020 Oct 25]; 33(1): 85–91. PubMed Abstract | Publisher Full Text\n\nBarteit S, Sié A, Yé M, Depoux A, Louis VR, Sauerborn R: Lessons learned on teaching a global audience with massive open online courses (MOOCs) on health impacts of climate change: A commentary. Global Health 2019 Aug 22 [cited 2020 Oct 25]; 15(1): 52. Reference Source\n\nThe impact and reach of MOOCs: A developing countries’ perspective. [cited 2020 Oct 25]. Reference Source\n\nPereyra-Elías R, Huaccho-Rojas JJ, Taype-Rondan Á, et al.: Publicación y factores asociados en docentes universitarios de investigación científica de escuelas de medicina del Perú. Rev Peru Med Exp Salud Publica. 2014 Sep 25; 31(3).\n\nSubhi YAKRBS, et al.: Massive open online courses are relevant for postgraduate medical training. Dan Med J. 2014 [cited 2020 Oct 25]; 01–10. Reference Source\n\nCulquichicón C, Helguero-Santin LM, Labán-Seminario LM, Cardona-Ospina JA, Aboshady OA, Correa R: Massive open online courses in health sciences from Latin American institutions: A need for improvement? [Internet]. F1000Research. Faculty of 1000 Ltd 2017 [cited 2020 Oct 25]; 6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQuijano-Escate R, Rebatta-Acuña A, Garayar-Peceros H, Gutierrez-Flores KE, Bendezu-Quispe G: Learning in times of social isolation: Massive open online courses on COVID-19. Rev Peru Med Exp Salud Publica 2020 Sep 24 [cited 2020 Oct 25]; 37(2): 375–7. Publisher Full Text\n\nGoldberg LR, Bell E, King C, O’Mara C, McInerney F, Robinson A, et al.: Relationship between participants’ level of education and engagement in their completion of the Understanding Dementia Massive Open Online Course Approaches to teaching and learning. BMC Med Educ 2015 Mar 26 [cited 2020 Oct 25]; 15(1): 60. Reference Source\n\nView of MOOCs: A systematic study of the published literature 2008-2012 [Internet]. [cited 2020 Oct 25]. Reference Source\n\nKoutropoulos A. GMS. ASC. WI. HRJ. KNO. et al. Emotive Vocabulary in MOOCs: Context & Participant Retention European Journal of Open, Distance and E-Learning, I. Eur J Open, Distance E-Learning [Internet]. 2012 [cited 2020 Oct 25]. Reference Source\n\nNilsson M, Evengård B, Sauerborn R, Byass P: Connecting the Global Climate Change and Public Health Agendas. PLoS Med 2012 Jun 5 [cited 2020 Oct 25]; 9(6): e1001227. Publisher Full Text\n\nMaldonado GKD: (2021, April 2). Massive Open Online Course (MOOC) Opportunities on in Health Education (HE) during of mandatory social isolation context. Publisher Full Text"
}
|
[
{
"id": "85974",
"date": "21 Jun 2021",
"name": "Waleed Al-Rahmi",
"expertise": [
"Reviewer Expertise computer and education"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. The aim of this research not clear. The authors should clarify the aims.\n2. The research problems are not clear. Therefore, the authors should address the research gap first, and I suggest adding new section to explain about the real problems.\n3. I suggest adding research model, and test this model by Structural Equation Modeling (SEM), Why? Because we need to see the validation of theories applied in this research.\n4. I suggest for authors to read and cite the following references:\nA. The use of Massive Open Online Courses (MOOCs) in blended learning courses and the functional value perceived by students B. Integrating innovation diffusion theory with technology acceptance model: Supporting students’ attitude towards using a massive open online courses (MOOCs) systems. C. Massive Open Online Courses: enhancing caregiver education and support about dementia care towards and at end of life. D. Massive Open Online Courses (MOOCs): Data on Higher Education. E. Perceived user satisfaction and intention to use massive open online courses (MOOCs). F. Predicting user perceived satisfaction and reuse intentions toward Massive Open Online Courses (MOOCs) in the Covid-19 pandemic: An application of the UTAUT model and quality factors.\n\n5.\n\nThe research methodology is not clear, the authors should explain more and add some references.\n\n6.\n\nThe results analysis is not enough to show the research contributions. Therefore, the authors should add more analysis.\n7.\n\nThe authors should explain more what is the difference between this research with prior experimental results, and related research.\n8.\n\nThe authors should add new section about the limitations of this research, as well as what is the future research?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8230",
"date": "26 May 2022",
"name": "GANDY KERLIN GANDY KERLIN",
"role": "Author Response",
"response": "Dear Waleed Mugahed Al-Rahmi We are grateful for your comments. Our responses are described below. 1. The aim of this research not clear. The authors should clarify the aims. Thank you for your comments. We had improved the description of the aims in the last paragraph. 2. The research problems are not clear. Therefore, the authors should address the research gap first, and I suggest adding new section to explain about the real problems. We are grateful for your comments, so we have modified the introduction, reworded the justification of the study and included some additional references. 3. I suggest adding research model, and test this model by Structural Equation Modeling (SEM), Why? Because we need to see the validation of theories applied in this research. Your comment is interesting and would certainly enhance research aimed at assessing causality itself. Structural equation modeling (SEM) is a multivariate statistical technique for testing and estimating causal relationships from statistical data and qualitative assumptions about causality. On the other hand, our study is of cross-sectional design and we set out from the beginning to perform descriptive analysis using secondary information. Therefore, the use of structural equation modeling (SEM) is not part of our methodology. 4. I suggest for authors to read and cite the following references: A. The use of Massive Open Online Courses (MOOCs) in blended learning courses and the functional value perceived by students B. Integrating innovation diffusion theory with technology acceptance model: Supporting students’ attitude towards using a massive open online courses (MOOCs) systems. C. Massive Open Online Courses: enhancing caregiver education and support about dementia care towards and at end of life. D. Massive Open Online Courses (MOOCs): Data on Higher Education. E. Perceived user satisfaction and intention to use massive open online courses (MOOCs). F. Predicting user perceived satisfaction and reuse intentions toward Massive Open Online Courses (MOOCs) in the Covid-19 pandemic: An application of the UTAUT model and quality factors. Thank you for sharing these studies with us. We visualize that the studies focus on measures of effect on participants participating in massive open online courses (MOOCs). Therefore, we believe that our study aims to identify and describe MOOCs that provide health education, promotion and prevention opportunities for the general population during a COVID-19 pandemic. In this opportunity, we did not set out to learn about the results in the participants of this study. 5. The research methodology is not clear, the authors should explain more and add some references. Thank you for your comment, we would like to know what part of the methodology is not clear to you. We would be happy to make modifications to make it more understandable for you. 6. The results analysis is not enough to show the research contributions. Therefore, the authors should add more analysis. Thank you very much for your appreciation. We value more complex analyses such as multivariate statistical analyses in research. However, in this opportunity and due to the context of the pandemic, we thought it was convenient to carry out a research that would allow us to demonstrate the offer of courses related to health education focused on prevention in a context where hospitals were not attending patients focused on disease prevention, given that the cases of COVID-19 were increasing. 7. The authors should explain more what is the difference between this research with prior experimental results, and related research. Thank you for your comment. In the second paragraph of the discussion, we note many courses that are specialized and aimed at professionals. These courses were not included in our research as our objective is to describe the supply of courses available on health education (prevention and promotion), not disease treatment. We did not find previous research describing these types of courses on virtual platforms. 8. The authors should add new section about the limitations of this research, as well as what is the future research? In the antepenultimate paragraph of the discussion, we describe our limitations for example the criteria for choosing a course were exclusively the decision of the researcher. Regarding future research, in the last paragraph of the discussion, we stated that future research should aim at assessing the quality of the content of these courses, as our research does not address this."
}
]
},
{
"id": "121485",
"date": "16 Feb 2022",
"name": "Maya Adam",
"expertise": [
"Reviewer Expertise Health communication",
"health promotion"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn general, I think this is a very interesting manuscript and it makes a potentially valuable contribution to the literature on open online public health education.\nSome suggestions for improvement follow:\nIn the background/rationale for the study, I wonder if the authors might also consider adding some brief statistics about the rise in global engagement with online courses that was spurred by the pandemic? Then the narrative would roughly go: 1) Routine care and preventive health visits went down, 2) General education through open online courses went up, 3) Can open online public health courses function as a potential bridge at times like these when face-to-face interactions are limited?\nIn the methods section of the abstract, it would be helpful to briefly (but a bit more clearly) describe the inclusion and exclusion criteria for the courses described in this study.\nI think the conclusion in this study could be more clearly worded, especially in the abstract. Phrases like “in health promotion issues” and “multiply initiatives in distant territories” are somewhat vague and could be stated more clearly. I also think this study speaks to the potential for massive open online public health courses to increase access to important health promotion messages, even outside of “times of pandemic and compulsory social isolation”. This is an interesting direction for future research that could be stated here.\nI have to preface this next comment by applauding the authors for their ability to write an academic manuscript in a language that may not be their first, based on their institutional affiliations. I could not have written an academic manuscript like this in a second language. One comment that I hope will be helpful: In general, the use of strong, active verbs throughout would strengthen the writing stylistically. For example, a sentence like “In December 2019, the COVID-19 pandemic was triggered by severe acute respiratory syndrome coronavirus 2 (SARSCov-2), revealing the fragility of the health systems of developing countries.” Could be rewritten to read: “In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARSCov-2) triggered the COVID-19 pandemic.” Another example “It has been estimated that maternal and child neglect in LMICs could be devastating…” could be more strongly worded as “Researchers suggest that maternal and child health neglect…” (or similar). Secondly, longer “run-on” sentences can become sources of confusion. An example of this is your sentence: “The pandemic context requires changes and identification of strategies that can help meet the indirect effects of neglect of diseases not related to COVID-19 in health systems.” Perhaps this sentence could be revised to be simpler and more direct so that it’s easier to understand on first pass.\nMy final suggestion: it might be interesting to include information about enrollment number for the different courses. These are often available to the public and could give a better sense of the potential for global reach and scaling of these courses.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8229",
"date": "26 May 2022",
"name": "GANDY KERLIN GANDY KERLIN",
"role": "Author Response",
"response": "Dear Maya Adam We are very grateful for your comments and suggestions. Below are the responses to each of the comments: In general, I think this is a fascinating manuscript and it makes a potentially valuable contribution to the literature on open online public health education. Some suggestions for improvement follow: First suggestion: In the background/rationale for the study, I wonder if the authors might also consider adding some brief statistics about the rise in global engagement with online courses that was spurred by the pandemic? Then the narrative would roughly go: 1) Routine care and preventive health visits went down, 2) General education through open online courses went up, 3) Can open online public health courses function as a potential bridge at times like these when face-to-face interactions are limited? Answer: Thank you very much for your comments; it’s very interesting. We have added statistics about online courses during the pandemic according to class central and Shravan Goli, boss of the products to MOOCs Coursera. Also, we have structured the introduction according to your suggestion. Second suggestion: In the methods section of the abstract, it would be helpful to briefly (but a bit more clearly) describe the inclusion and exclusion criteria for the courses described in this study. Answer: We consider this recommendation very precise. We briefly added the inclusion and exclusion criteria. Third suggestion: I think the conclusion in this study could be more clearly worded, especially in the abstract. Phrases like “in health promotion issues” and “multiply initiatives in distant territories” are somewhat vague and could be stated more clearly. I also think this study speaks to the potential for massive open online public health courses to increase access to important health promotion messages, even outside of “times of pandemic and compulsory social isolation”. This is an interesting direction for future research that could be stated here. Answer: Your comment is very pertinent. We have omitted some phrases and modified the conclusion in the abstract. Fourth suggestion I have to preface this next comment by applauding the authors for their ability to write an academic manuscript in a language that may not be their first, based on their institutional affiliations. I could not have written an academic manuscript like this in a second language. One comment that I hope will be helpful: In general, the use of strong, active verbs throughout would strengthen the writing stylistically. For example, a sentence like “In December 2019, the COVID-19 pandemic was triggered by severe acute respiratory syndrome coronavirus 2 (SARSCov-2), revealing the fragility of the health systems of developing countries.” Could be rewritten to read: “In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARSCov-2) triggered the COVID-19 pandemic.” Another example “It has been estimated that maternal and child neglect in LMICs could be devastating…” could be more strongly worded as “Researchers suggest that maternal and child health neglect…” (or similar). Secondly, longer “run-on” sentences can become sources of confusion. An example of this is your sentence: “The pandemic context requires changes and identification of strategies that can help meet the indirect effects of neglect of diseases not related to COVID-19 in health systems.” Perhaps this sentence could be revised to be simpler and more direct so that it’s easier to understand on first pass. Answer: Thank you very much for your accurate comments and examples. We have identified different phrases longer and that can cause confusion. We have modified some sentences for a better understanding. Fifth suggestion: My final suggestion: it might be interesting to include information about enrollment number for the different courses. These are often available to the public and could give a better sense of the potential for global reach and scaling of these courses. Answer: Thank you very much for your comment. We are trying to keep up with the number of people enrolled, however most of these courses are currently closed and indicate future dates to start again. In other cases, they are in a new phase of registration for the course. So, it would be very difficult to know exactly the number of people enrolled in the course."
}
]
}
] | 1
|
https://f1000research.com/articles/10-322
|
https://f1000research.com/articles/11-578/v1
|
26 May 22
|
{
"type": "Research Article",
"title": "Pathogenic Enterobacteriaceae require multiple culture temperatures for detection in Cannabis sativa L.",
"authors": [
"Kevin McKernan",
"Yvonne Helbert",
"Liam T Kane",
"Lei Zhang",
"Nathan Houde",
"Anne Bennett",
"Juliana Silva",
"Heather Ebling",
"Stephen McLaughlin",
"Yvonne Helbert",
"Liam T Kane",
"Lei Zhang",
"Nathan Houde",
"Anne Bennett",
"Juliana Silva",
"Heather Ebling",
"Stephen McLaughlin"
],
"abstract": "Background: Cannabis safety testing requires adequate detection of a broad class of bacteria known as Enterobacteria, from the family of Enterobacteriaceae. These organisms are responsible for many food-borne illnesses including gastroenteritis, and are common targets in the food testing industry. While all these organisms contain 16S DNA, not all of them grow on commercial culture-based platforms at a single culture temperature. Methods: We assessed four Enterobacteria (Aeromonas hydrophila, Pantoea agglomerans, Yersinia enterocolitica, Rahnella aquatilis) that vary in their preferred culture temperature, human pathogenicity and prevalence in cannabis. We cultured them on two different plating media and compared these results to two different qPCR assays. Results: All four bacteria grew on one plating medium at 30°C. 75% of them failed to grow at 36°C. Using a different plating medium, 75% grew at 30°C and zero grew at 36°C. Two different commercialy available quantitative PCR assays detected 100% of the organisms. Conclusions: Several Enterobacteria are highly medium- and temperature-sensitive, and can easily evade culture-based detection. Some of these bacteria are known to infect cannabis and may pose a clinical risk to cannabis trimmers or consumers. Quantitative PCR detected all of these species. Quantitative PCR is often criticized for failing to discern live versus dead DNA, but the definition of “live” is dependent on the culture medium and temperature used.",
"keywords": [
"Cannabis",
"Enterobacteriaceae",
"Microbiome",
"Whole Genome Sequencing",
"qPCR",
"culture"
],
"content": "Introduction\n\nCannabis safety testing requires a complex array of proficiencies, including expertise in the detection and quantification of cannabinoids, pesticide residues, heavy metals, volatile compounds, mycotoxins and microbial burden1. Each one of these fields of expertise is incredibly nuanced and often suffer from a lack of readily available laboratory standards that can easily cross state lines with the current federal interstate commerce laws in the United States2.\n\nThe 2018 Farm bill enabled the transport of hemp (<0.3%THC) across state lines. As a result, the cannabis microbial space has recently introduced AOAC Standard Method Performance Requirements (SMPRs) and microbial Certified Reference Standards (CRMs) that contain relevant hemp matrix3. These tools are welcomed by the industry; however the microbial testing space remains conflicted over the lack of a gold standard4,5. Traditional reference methods used in the food industry have long used cellular culture or petri-dish plating technologies to assess microbial burden. However, not all organisms can be cultured and often the organisms that can require different growth temperatures, media and time to propagate. These conditional modes of detection often fail to identify relevant pathogens.\n\nAdditionally, culturing human pathogens can present additional risks to laboratory personnel or civilians, given the frequently documented cases of laboratory leaks6. Molecular methods using gDNA or RNA can provide more comprehensive surveys. Replication of the organism’s DNA or RNA can reduce and, in some cases, even eliminate the replication of the pathogen. These methods are less reliant on the viability of the organism or its required carbon sources7–11. These techniques are also less susceptible to undercounting viable but not culturable organisms (VBNC) or sublethal injuries that many decontamination or “curing” techniques induce12,13. These “decontaminated” cells are often still metabolically active and require more time to culture as the organism must first repair the 8-oxo-G damage to their DNA prior to replication14–17.\n\nMany of the decontamination protocols used in the cannabis field have limited peer reviewed evidence of the degree of sublethal injury and the shelf life of the decontaminated product. Often, products that pass microbial testing may be found to have excessive mold or bacterial growth at a later date in the supply chain18. This often directs growers to ‘lab shop’ for laboratories utilizing methods that are blind to a particular decontamination technique or culturing platform that can’t detect their most common contaminants.\n\nHere we describe one scenario where such lab shopping would improve pass rates for a given grower but expose patients to pathogenic risks. We also investigated the abundance of these microbes in published cannabis microbiome studies19–21.\n\nFour Enterobacteria (Aeromonas hydrophila, Pantoea agglomerans, Yersinia enterocolitica, Rahnella aquatilis) were acquired from the American Type Culture Collection (ATCC) and plated on various media and temperatures; we then compared the quantity of 16S DNA from these organisms using qPCR.\n\n\nMethods\n\nAeromonas hydrophila, Pantoea agglomerans, Yersinia enterocolitica, Rahnella aquatilis were acquired from ATCC (ATCC#7966, ATCC#43348, ATCC#9610, ATCC#33990). ATCC recommends 30°C, 26°C, 30°C, 30°C for the growth of these respective organisms. Since Enterobacteria testing is usually done at 36°C, we plated organisms at 36°C and 30°C. To improve the visibility of some species, each detected colony was manually marked in blue in with a sharpie. We compared these CFUs to Ct values generated using the Medicinal Genomics Entero qPCR assay (#420108) and Medicinal Genomics TAC qPCR assay (#420106).\n\nOrganisms were resuscitated from lyophilized stocks by inoculation into 30ml of Tryptic Soy Broth (TSB) without selection for overnight static growth, according to the ATCC recommended growth temperatures listed above. Cells/ml were estimated via serial dilution and plating on both 3M EB Petrifilm and 3M RAC Petrifilm. Once a colony forming unit (CFU/ml) of each growth was observed, these counts were used to make four different dilutions targeting the same final CFU concentration in triplicate (12 total Petrifilm per organism per temperature point). This two-stage process was performed to avoid too numerous to count (TNTC) plates. A 1ml extract of each final dilution was plated on each plate.\n\nFor qPCR, a 10-fold serial dilution of each stock growth (into ddH20) was performed starting at 1/10th, 1/100th, 1/1,000th, 1/10,000th and 1/1,000,000th. These were purified according to the manufacturer’s instructions, and subjected to qPCR with two different qPCR assays (Medicinal Genomics TAC assay #420106 and Medicinal Genomics Entero assay #420108).\n\nPCR cycling (according to the manufacturers instructions) was performed with an initial 95°C denaturization for five minutes, 40 cycles of 95°C for 15 seconds and 65°C for 1 minute.\n\nSince many organisms and growth conditions produced no colonies, only the presence or absence of a signal during qPCR was evaluated. These organisms are found in many inclusion and exclusion documentation for culture-based enumeration products currently AOAC approved for use22. Many of these accreditation bodies like AOAC look to see Ct data correlated with CFUs. These correlations will be impossible to draw if many organisms fails to form colonies but consistently amplify with qPCR.\n\nRead analysis was performed using the OneCodex bioinformatics platform (Underlying data). The microbiome platform contains 171 public cannabis microbiome libraries. The data includes previously published 16S amplicon sequences and whole genome sequencing of colonies derived from cannabis flowers19–21. Read totals and species abundance calculations were derived from parsing the results of the CSV download of the Complete Result Table for each of the 171 classification analyses and counting up 'Reads with Children' for each result with the rank of species. Links to these data are supplied in the Extended data23. Libraries containing fungal ITS amplification were omitted from the search.\n\n\nResults\n\nAeromonas hydrophila, and Rahnella aquatilis failed to grow at 36°C on two different plating media (3M RAC and EB Petrifilms) but successfully grew on these media at 30°C. Yersinia enterocolitica also failed to grow at 36°C on EB plates but grew successfully at 30°C on EB plates and grew at both 30°C and 36°C with RAC plates. Pantoea agglomerans only grew on RAC plates at 26°C and 30°C and did not grow on EB plates at any temperature (Figure 1–Figure 4 and Table 1). Quantitative PCR detected all four organisms (Figure 5).\n\nRAC = 3M rapid aerobic count plate. EB = 3M enterobacteria plate. qPCR TAC = qPCR total aerobic count assay. qPCR Entero = qPCR enterobacteria assay.\n\nEach qPCR reaction contained a spike-in cannabis internal control in the HEX (green) channel. The target total aerobic count (TAC) or Entero qPCR assay is labelled with a fluorescein amidite (FAM) dye (Blue). qPCR is performed according to the manufacturer’s instructions.\n\nPreviously published cannabis microbiome studies were searched for sequencing read abundance of the four microbes (Underlying data24). Three of 171 samples contained Aeromonas sequences over 1% read abundance, while Pantoea agglomerans was above 1% in 30/171 samples and even consisted of over 87% of the reads in one sample (Figure 6). Four other Pantoea were also found in the cannabis microbiome data, namely Pantoea ananatis, Pantoea dispersa, Pantoea stewartii and Pantoea cedenensis. These are all available from ATCC and have recommended growth temperatures of 28°C, 26°C, 26°C, and 30°C, suggesting more organisms native to cannabis may be missed by plating at a single temperature.\n\n\nDiscussion\n\nAeromonas hydrophila is responsible for 13% of gastroenteritis cases in the US. It has been detected in 3/171 microbiome sequencing samples (McKernan et al.2016) at very low read levels (Figure 6). This is consistent with many fecal-oral pathogens that are not native to cannabis plants25.\n\nPantoea agglomerans is less pathogenic than Aeromonas hydrophila but is ubiquitously found in multiple independent cannabis microbiome studies with both PCR and culture-based plating19,23,26. It was seen in 30/171 microbiome sequencing samples and is often the most abundant read count even in 16S amplification surveys (Figure 7). Several samples with high Pantoea read abundance are a result of whole genome shotgun surveys of isolated colonies from metagenomic surveys performed on TYM studies utilizing potato dextrose agar (PDA) as a growth medium19.\n\nTop: Pantoea Illumina Read Abundance in 30/171 microbiome samples. Bottom: normalized Illumina read abundance. Whole genome shotgun sequencing of isolated colonies is represented as (*). Other samples are metagenomic sequences from 16S amplification.\n\nPantoea agglomerans is described as a plant growth-promoting rhizobacteria for Cannabis27,28. Cruz et al. documented 53 pediatric cases of Pantoea agglomerans infections, mostly from penetrating trauma from vegetative matter or catheter-related bacteremia29. Seok et al. described a case of Pantoea agglomerans-induced bilateral endophthalmitis30. The skin rashes and infections, described by Okwundu et al. may be relevant for trimmers in constant contact with cannabis plant matter and sharp trimming tools31.\n\nMcKernan et al. reported Pantoea agglomerans growing more frequently on PDA-25°C than PDA with Chloramphenicol (PDA-CAMP-25°C) or Dichloran Rose Bengal with CAMP (DRBC-25°C)19. These culture media are used for TYM detection and they consistently harbor the off-target growth of a common Enterobacteria found on Cannabis. The failure of Enterobacteria plating media to culture one of the most common Enterobacteria (at 36°C) found in cannabis will lead to continual discordance of molecular methods compared to plating systems.\n\nYersinia enterocolitica is listed by the American Center for Disease Control (CDC) as a pathogen of concern. The CDC stated that Yersinia enterocolitica is “responsible for 117,000 illnesses, 640 hospitalizations and 35 deaths every year in the US” and is one of many Yersinia that cause yersiniosis32. This is recognized as a fecal-oral transmitted infection, usually from contaminated water on outdoor farms with livestock33.\n\nRahnella aquatilis is more commonly found in water supplies34. The CDC discovered their first clinical isolate in 1985 from a burn wound, but it has been detected in various bodily fluids from urine, sputum, stool and bronchial lavage35. Most cases involve immunocompromised hosts. Urinary tract infections and sepsis are documented in the clinical literature35,36.\n\n\nConclusions\n\nThere is no universal carbon source or temperature that can capture all pathogenic risks on cannabis. These are inhaled products and should be held to higher standards than orally ingested products.\n\nRegulators may be tempted to default to the pre-existing tools given their long history in the food industry. We described a scenario in the cannabis testing industry where this misplaced trust in traditional methods will harm the patient but improve profits of growers. With the high prevalence of Pantoea agglomerans in multiple cannabis microbiome and plate-based surveys of cannabis matrices, defaulting to a platform with known blind spots will lead to further conflict in the industry.\n\nGiven that Panotoea agglomerans is one of the few published plant-growth promoting organisms in cannabis, and the frequency at which it grows on total yeast and mold medium, as well as its failure to grow at the same temperature as other Enterobacteria, this organism will continue to confuse culture-based microbial detection platforms. It should be noted that the Enterobacteria regulations are often more stringent than total yeast and mold regulations (1,000 CFU/g versus 10,000 CFU/g), and organisms that fail to grow on Enterobacteria plates but do grow on total yeast and mold plates may never trigger a positive test. A range of 1,001 to 9,999 CFU/g of Pantoea agglomerans will fail to be detected on Enterobacteria plating tests (at 36°C) while also passing a TYM test using PDA.\n\nPantoea agglomerans is also CAMP-sensitive which explains its reduced prevalence in TYM testing using CAMP selection19. It is possible for CAMP-based TYM testing, 3MEB Petrifilm testing and 3M RAC Petrifilm testing to fail to detect this organism if multiple growth temperatures are not utilized. Higher-specificity molecular methods offer a more parsimonious solution to this problem.\n\nqPCR is often criticised as an inadequate replacement to petri-based enumeration methods because of its lack of concordance to plating. This becomes a circular argument when the plating methods have known and obvious blind spots. In this study, qPCR detected all of the pathogens and plating failed to culture all of them on 3M EB Petrifilm plates at 36°C, and failed to culture 75% of them on RAC plates at 36°C. This is a scenario where qPCR might be accused of detecting non-viable organism, when the organisms are, in fact, viable except on the chosen medium or temperature.\n\nPCR can amplify non-viable organisms’ DNA. Tools are available to remove free circulating DNA from lysed cells using nucleases that can be chemically inactivated prior to PCR37. The efficacy of nucleases on VBNC organisms whose cell membranes or cell walls are still intact is a nascent field that needs further investigation. PCR can detect VBNC organisms, while plating requires much longer incubation times and potentially unique medium to allow these organisms to resuscitate. This brings the shelf life of products that pass short duration culture testing into sharp focus, as only organisms that can actively replicate with the proper temperature and carbon source can be detected. Molecular methods offer a more universal detection platform, as all organisms have DNA and non-viable or lysed organisms’ DNA are nuclease-sensitive and easy to account for. The sublethal injuries or VBNC states of microbes on partially decontaminated or cured product requires further discussion regarding the goal of microbial testing. For example, dried foods require longer incubation times to properly adjust for microbial resuscitation that can occur on products with long shelf lives. Cannabis flowers are often dried for two weeks and their microbiome may resemble that often seen in dried foods38,39.\n\nThe inability to detect these organisms at temperatures lower than body temperature (30°C versus 36°C) is often justified as being an irrelevant temperature for human health. This is not supported by the clinical literature where these organisms, despite their lower ex vivo culturing temperature, still infect humans. Not all compartments of the human body are at a single temperature or supply a fixed low complexity carbon source. This is highly relevant to viral tropism in the human respiratory pathway and is believed to drive much of the seasonality of influenza and coronaviruses40. We have evidence that these organisms infect humans and that they remain undetected on an inhaled product when using a single medium and temperature for replicative detection. If we continue to demand more modern, more sensitive and more specific technologies like qPCR that perfectly emulate previous culture-based technologies which fail to culture specific microbes, we will not only fail to advance the field of clinical microbiology, but we will fail patients as well.\n\n\nData availability\n\nFigshare: qPCR data for Pathogenic Enterobacteriaceae require multiple culture temperatures for detection in Cannabis sativa L.,\n\nhttps://doi.org/10.6084/m9.figshare.1935075541\n\nThis project contains the following underlying data:\n\n- Y.Enterocolitica A.Hydrophilla_Dilution_TAC_Entero_assays .csv (qPCR results)\n\nFigshare: Pathogenic Enterobacteriaceae require multiple culture temperatures for detection in Cannabis sativa L., https://doi.org/10.6084/m9.figshare.19346411.v242\n\nThis project contains the following underlying data:\n\n- Petrifilm data (culture plate detection images)\n\nFigshare: Pantoea_Aeromonas_OneCodex, https://doi.org/10.6084/m9.figshare.19179140.v124\n\nThis project contains the following underlying data:\n\n- pantoeapantoea_agglomerans_submit021520223.xlsx (sequencing read abundance data for the four assessed Enterobacteria)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nNCBI SRA: Cannabis microbiome sequencing reveals several mycotoxic fungi native to dispensary grade cannabis flowers, Accession number SRX1441690: https://identifiers.org/insdc.sra:SRX1441690\n\nBioProject: Cannabis microbiome evolution in culture, Accession number PRJNA343388: https://identifiers.org/bioproject:PRJNA343388\n\nBioProject: Under Counting of Total Yeast and Mold on Cannabis using DRBC, Accession number PRJNA725256: https://identifiers.org/bioproject:PRJNA725256",
"appendix": "Acknowledgements\n\nWe thank Sherman Hom and Michael Catalano for helpful edits to the manuscript.\n\n\nReferences\n\nValdes-Donoso P, Sumner DA, Goldstein R: Costs of cannabis testing compliance: Assessing mandatory testing in the California cannabis market. PLoS One. 2020; 15(4): e0232041. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAdesina I, Bhowmik A, Sharma H, et al.: A Review on the Current State of Knowledge of Growing Conditions, Agronomic Soil Health Practices and Utilities of Hemp in the United States. Agriculture. 2020; 10(4): 129. Publisher Full Text\n\nCASP A: Cannabis Analytical Science Program. AOAC International, 2021. Reference Source\n\nTanaka T, Kawasaki K, Daimon S, et al.: A hidden pitfall in the preparation of agar media undermines microorganism cultivability. Appl Environ Microbiol. 2014; 80(24): 7659–7666. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStaley JT, Konopka A: Measurement of in situ activities of nonphotosynthetic microorganisms in aquatic and terrestrial habitats. Annu Rev Microbiol. 1985; 39: 321–346. PubMed Abstract | Publisher Full Text\n\nWikipedia: List of laboratory biosecurity incidents. Reference Source\n\nMay FJ, Stafford RJ, Carroll H, et al.: The effects of culture independent diagnostic testing on the diagnosis and reporting of enteric bacterial pathogens in Queensland, 2010 to 2014. Commun Dis Intell Q Rep. 2017; 41(3): E223–E230. PubMed Abstract\n\nImdad A, Retzer F, Thomas LS, et al.: Impact of Culture-Independent Diagnostic Testing on Recovery of Enteric Bacterial Infections. Clin Infect Dis. 2018; 66(12): 1892–1898. PubMed Abstract | Publisher Full Text | Free Full Text\n\nConnor BA, Rogova M, Whyte O: Oral typhoid vaccine and culture independent testing for travelers' diarrhea. J Travel Med. 2017; 24(6). PubMed Abstract | Publisher Full Text\n\nTai AY, Easton M, Encena J, et al.: A review of the public health management of shigellosis in Australia in the era of culture-independent diagnostic testing. Aust N Z J Public Health. 2016; 40(6): 588–591. PubMed Abstract | Publisher Full Text\n\nJanda JM, Abbott SA: Culture-independent diagnostic testing: have we opened Pandora's box for good? Diagn Microbiol Infect Dis. 2014; 80(3): 171–176. PubMed Abstract | Publisher Full Text\n\nBraun RS, Mendis N, Li L, et al.: Quantification of Viable but Non-Culturable Cells of Legionella pneumophila. Methods Mol Biol. 2019; 1921: 45–53. PubMed Abstract | Publisher Full Text\n\nLi L, Mendis N, Trigui H, et al.: The importance of the viable but non-culturable state in human bacterial pathogens. Front Microbiol. 2014; 5: 258. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPitonzo BJ, Amy PS, Rudin M: Resuscitation of microorganisms after gamma irradiation. Radiat Res. 1999; 152(1): 71–75. PubMed Abstract | Publisher Full Text\n\nHieke AC, Pillai SD: Escherichia coli Cells Exposed to Lethal Doses of Electron Beam Irradiation Retain Their Ability to Propagate Bacteriophages and Are Metabolically Active. Front Microbiol. 2018; 9: 2138. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBergen AW, Qi Y, Haque KA, et al.: Effects of electron-beam irradiation on whole genome amplification. Cancer Epidemiol Biomarkers Prev. 2005; 14(4): 1016–1019. PubMed Abstract | Publisher Full Text\n\nCastle PE, Garcia-Closas M, Franklin T, et al.: Effects of electron-beam irradiation on buccal-cell DNA. Am J Hum Genet. 2003; 73(3): 646–651. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZimmerman S: What’s in Illinois’ legal weed? Sometimes contaminants, Sun-Times testing finds. Chicago Sun Times, 2021. Reference Source\n\nMcKernan K, Helbert Y, Kane L, et al.: Whole genome sequencing of colonies derived from cannabis flowers and the impact of media selection on benchmarking total yeast and mold detection tools [version 2; peer review: 2 approved]. F1000Res. 2021; 10: 624. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcKernan K, Spangler J, Helbert Y, et al.: Metagenomic analysis of medicinal Cannabis samples; pathogenic bacteria, toxigenic fungi, and beneficial microbes grow in culture-based yeast and mold tests [version 1; peer review: 3 approved, 1 approved with reservations]. F1000Res. 2016; 5: 2471. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcKernan K, Spangler J, Zhang L, et al.: Cannabis microbiome sequencing reveals several mycotoxic fungi native to dispensary grade Cannabis flowers [version 2; peer review: 2 approved]. F1000Res. 2015; 4: 1422. PubMed Abstract | Publisher Full Text | Free Full Text\n\nExpertise AF: NF VALIDATION, Validation of alternative analytical methods. 2018.\n\nHolmes JE, Lung S, Collyer D, et al.: Variables Affecting Shoot Growth and Plantlet Recovery in Tissue Cultures of Drug-Type Cannabis sativa L. Front Plant Sci. 2021; 12: 732344. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcKernan K: Pantoea_Aeromonas_OneCodex. figshare. Dataset. 2022. http://www.doi.org/10.6084/m9.figshare.19179140.v1\n\nVujanovic V, Korber DR, Vujanovic S, et al.: Scientific Prospects for Cannabis-Microbiome Research to Ensure Quality and Safety of Products. Microorganisms. 2020; 8(2): 290. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaghinasab M, Jabaji S: Cannabis Microbiome and the Role of Endophytes in Modulating the Production of Secondary Metabolites: An Overview. Microorganisms. 2020; 8(3): 355. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLyu D, Backer R, Robinson WG, et al.: Plant Growth-Promoting Rhizobacteria for Cannabis Production: Yield, Cannabinoid Profile and Disease Resistance. Front Microbiol. 2019; 10: 1761. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlpiste FO, Ezquerra GM, Pujol RM: Wound infection by Pantoea agglomerans after penetrating plant injury. Indian J Dermatol Venereol Leprol. 2021; 1–3. PubMed Abstract | Publisher Full Text\n\nCruz AT, Cazacu AC, Allen CH: Pantoea agglomerans, a plant pathogen causing human disease. J Clin Microbiol. 2007; 45(6): 1989–1992. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSeok S, Jang YJ, Lee SW, et al.: A case of bilateral endogenous Pantoea agglomerans endophthalmitis with interstitial lung disease. Korean J Ophthalmol. 2010; 24(4): 249–251. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOkwundu NMercer JPantoea agglomerans cutaneous infection. Molecular Imaging. 2019; 23(1): 41–43. Publisher Full Text\n\nCDC: Yersinia enterocolitica.\n\nSabina Y, Rahman A, Ray RC, et al.: Yersinia enterocolitica: Mode of Transmission, Molecular Insights of Virulence, and Pathogenesis of Infection. J Pathog. 2011; 2011: 429069. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim KY, Jordan D, Krishnan HB: Rahnella aquatilis, a bacterium isolated from soybean rhizosphere, can solubilize hydroxyapatite. FEMS microbiology letters. 1997; 153(2): 273–277. Publisher Full Text\n\nTash K: Rahnella aquatilis bacteremia from a suspected urinary source. J Clin Microbiol. 2005; 43(5): 2526–2528. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKuzdan C, Soysal A, Özdemir H, et al.: Rahnella aquatilis Sepsis in a Premature Newborn. Case Rep Pediatr. 2015; 2015: 860671. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVillarreal JV, Jungfer C, Obst U, et al.: DNase I and Proteinase K eliminate DNA from injured or dead bacteria but not from living bacteria in microbial reference systems and natural drinking water biofilms for subsequent molecular biology analyses. J Microbiol Methods. 2013; 94(3): 161–169. PubMed Abstract | Publisher Full Text\n\nBeuchat LR, Mann DA: Comparison of New and Traditional Culture-Dependent Media for Enumerating Foodborne Yeasts and Molds. J Food Prot. 2016; 79(1): 95–111. PubMed Abstract | Publisher Full Text\n\nMcKernan K, Helbert Y, Ebling H, et al.: Microbiological examination of nonsterile Cannabis products: Molecular Microbial Enumeration Tests and the limitation of Colony Forming Units. OSF. 2018. Publisher Full Text\n\nShaw Stewart PD, Bach JL: Temperature dependent viral tropism: understanding viral seasonality and pathogenicity as applied to the avoidance and treatment of endemic viral respiratory illnesses. Rev Med Virol. 2022; 32(1): e2241. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcKernan K: qPCR data for Pathogenic Enterobacteriaceae require multiple culture temperatures for detection in Cannabis sativa L. figshare. Dataset. 2022. http://www.doi.org/10.6084/m9.figshare.19350755.v1\n\nMcKernan K: Pathogenic Enterobacteriaceae require multiple culture temperatures for detection in Cannabis sativa L. figshare. Figure. 2022. http://www.doi.org/10.6084/m9.figshare.19346411.v2"
}
|
[
{
"id": "147745",
"date": "22 Sep 2022",
"name": "Zamir K. Punja",
"expertise": [
"Reviewer Expertise Fungal pathogens of cannabis",
"molecular detection",
"total yeast and mold analysis",
"disease management"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe research described in this article shows how the temperature used for incubation of samples derived from plating assays of cannabis flower tissues used in commercial laboratories can influence the outcome regarding which species of microbes can grow out. The study focused on 4 bacterial species, all members of the family Enterobacteriaceae. Members of this family are known to cause severe gastrointestinal disorders if ingested. Two plating media were used and Petri dishes were incubated at 26°C, 30°C and 36°C for comparison. Detection using culture plating was compared using quantitative PCR (q-PCR). This method was shown to be able to detect all bacterial species. The authors concluded that q-PCR can provide better detection as it does not rely on growth of the microbes on culture media and is more sensitive, as well as providing a higher level of safety against potential exposure to the microbes.\nComments to authors. 1. Please provide the rationale for selection of the 4 species used in this study, namely Aeromonas hydrophila, Pantoea agglomerans, Yersinia enterocolitica, Rahnella aquatilis.\n2. Is there evidence that the above 4 bacterial species can be found in cannabis samples? There is some mention of two of them in the manuscript but not for all. Please elaborate.\n3. The recommended temperatures for growth of these bacteria is 26-30°C. Why was the testing in this study conducted at 30°C and 36°C?\n4. Is there any evidence that commercial testing labs may be using 36°C as an optimal growing temperature for their extracted samples?\nIn the Introduction, the authors set the stage for why molecular-based methods can provide a more consistent and potentially reliable method to assess presence of a harmful microbe in cannabis samples compared to culture-based methods. They cite the lack of reference microbial testing methods based on culture plating techniques. They correctly point out that not all microbes can be cultured on media in the laboratory. And some can pose a risk to the investigator. These are well justified reasons for conducting the proposed study.\nIn the Methods, the source of the bacterial strains is presented and the growth conditions are specified. The dilution series for plating and qPCR are presented. The analyses of results included a comparison to the currently available microbiome studies based on 16S RNA sequences.\nIn the Results, the temperature requirements for the bacterial species on different media are presented. The results clearly show a discrepancy in growth at different temperatures and on different media. The images of Petri dishes in Figures 1-4 clearly show the differential growth of the 4 species. A comparison of the sequence reads of the four microbes showed that two genera (Aeromonas and Pantoea) were present. The remaining two genera included in the study (Yersinia and Rahella) were not detected in the database. This requires a bit more explanation as to why they were included in this study. Is the lack of detection in previous microbiome and metagenomic studies a consequence of the technical approaches used and do the authors consider these two as important genera or does the current study place Yersinia and Rahella in the inconsequential group of microbes to be assayed ? The wider detection of Pantoea is interesting given its widespread ecological role in plants including cannabis. The authors make a point of note that P. agglomerans growth is affected by growth media and temperature of incubation based on previous work and its presence may remain undetected in culture based methods. The Summary Table 1 is useful.\nIn the Conclusions, the authors reiterate the differences in results between culture based approaches to molecular based approaches for microbial detection, with a particular emphasis on P. agglomerans. They present a valid argument for how plating assays would fail to recognize this species, especially on CAMP-containing media. The authors end with an analysis of why qPCR methods have advantages over culture based methods for assaying microbes of importance in cannabis. They also address concerns on the potential detection of non-viable organisms by q-PCR and ways to circumvent that.\n\nThis reviewer’s perspective is that this study was well conducted and designed to meet the objectives of comparing growth and detection of 4 Enterobacteria in a comparative study using culture based methods with molecular based methods (qPCR). The results and supporting data do show in particular that Pantoea agglomerans would fail to be detected in the former assays compared to the latter. The supporting data are clear in this regard.\nCan this type of study be extended to additional microbes? That would be the type of data that could be used to sway regulatory agencies on the difficulties in using methods adapted from the food industry that are based on culture plating for evaluation of the microbial content of cannabis flowers. For example, can Pseudomonas species similarly be affected by culture-based techniques? I refer specifically to P. aeruginosa that can cause secondary infections on concern in humans and appears to be increasing in prevalence. There is a growing body of evidence that Aspergillus species can similarly be affected by culture-biased methods for detection.\nThis study is worthy of publication based on the above analysis. Additional studies of this type are needed to support the inclusion of more molecular-based methods for microbial detection in cannabis samples destined for human use. Concurrently, there may be studies that show that easy-to-culture fungi and yeasts can be enumerated from cannabis samples using culture-based methods that are standardized and easy to use. Evaluations of this type are best suited when they are backed by scientific evidence comparing one approach vs. another. This study has succeeded in doing that with a particular group of Enterobacteria. Additional studies are warranted on other groups of microbes commonly found in cannabis products.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8894",
"date": "13 Oct 2022",
"name": "Kevin McKernan",
"role": "Author Response",
"response": "Thank you for the thoughtful comments. Comments to authors. 1. Please provide the rationale for selection of the 4 species used in this study, namely Aeromonas hydrophila, Pantoea agglomerans, Yersinia enterocolitica, Rahnella aquatilis. These organisms are listed on AOAC exclusion criteria for E.coli testing in Cannabis. https://www.aoac.org/wp-content/uploads/2021/02/SMPR-2020_012.pdf 17/44 of these organisms have growth temperatures listed by AOAC as below 37C. We have posted this list with their respective genomes on figshare. https://figshare.com/ndownloader/files/37838916 2. Is there evidence that the above 4 bacterial species can be found in cannabis samples? There is some mention of two of them in the manuscript but not for all. Please elaborate. Pantoea was found in 30/171 microbiomes and Aeromonas in 3/171 microbiomes. Yersina and Rahnella were not found in any of the cannabis microbiomes surveyed in this study. These organisms were selected not due to their likelihood of being found on cannabis but simply due to their presence in AOAC exclusion testing. More diverse cannabis microbiome sequencing is required to definitely understand their presence. 3. The recommended temperatures for growth of these bacteria is 26-30°C. Why was the testing in this study conducted at 30°C and 36°C? We followed ATCC growth recommendations for these organisms with the exception of Pantoea agglomerans where we grew it at 26C, 30C and 36C as some strains are listed at 26C and some at 30C. 36C was investigated for all samples as that is the recommended testing temperature from 3M and in our experience most labs are following this recommendation. 4. Is there any evidence that commercial testing labs may be using 36°C as an optimal growing temperature for their extracted samples? Yes. Most labs are following 3M’s recommended growth temperature of 37C +/- 1C as per AOAC official methods. https://multimedia.3m.com/mws/media/695831O/product-instructions-3m-petrifilm-enterobacteriaceae-count-plate.pdf https://multimedia.3m.com/mws/media/1015782O/petrifilm-rapid-aerobic-ifu.pdf Can this type of study be extended to additional microbes? That would be the type of data that could be used to sway regulatory agencies on the difficulties in using methods adapted from the food industry that are based on culture plating for evaluation of the microbial content of cannabis flowers. For example, can Pseudomonas species similarly be affected by culture-based techniques? I refer specifically to P. aeruginosa that can cause secondary infections on concern in humans and appears to be increasing in prevalence. There is a growing body of evidence that Aspergillus species can similarly be affected by culture-biased methods for detection. We are in the process of expanding this as we evaluate more of our methods with AOAC. This is an important point regarding Pseudomonas. In previous work (https://osf.io/vpxe5/), we noticed Pseudomonas aeruginosa triggered false positive TYM tests on the Biomerieux Tempo platform. This platform uses a pH sensitive indicator dye such that any organism that is both resistant to the antibiotics in their growth media and that shifts the pH of the growth media will trigger positive results. Pseudomonas aeruginosa is known to produce acid during growth. Aspergillus is also sensitive to Chloramphenicol and many culture based fungal detection methods rely on antibiotics to enable 3-5 day growth of fungi. Some labs are resorting to MALDI-TOF to help speciate ambiguous Aspergillus colonies however Tam et al. has found this fails to properly speciate closely related Aspergillus species as many peptides are conserved at the amino acid level but diverge at the genotype level. Nonsynonymous variants and intronic variants offer more signature to split closely related species. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993464/"
}
]
}
] | 1
|
https://f1000research.com/articles/11-578
|
https://f1000research.com/articles/11-489/v2
|
26 May 22
|
{
"type": "Research Article",
"title": "Establishment of diagnostic reference level and radiation dose variation in head & neck and pelvis treatment planning in radiation therapy computed tomography",
"authors": [
"Ms. Shreekripa Rao",
"Dr. Rajagopal Kadavigere",
"Dr. Krishna Sharan",
"Suresh Sukumar",
"Mr. Srinidhi GC",
"Mrs. Rechal Nisha Dsouza",
"Mr. Suman S",
"Ms. Shreekripa Rao",
"Dr. Krishna Sharan",
"Suresh Sukumar",
"Mr. Srinidhi GC",
"Mrs. Rechal Nisha Dsouza",
"Mr. Suman S"
],
"abstract": "Background: This observational study aims to establish a discrepancy in the radiation dose distributed for head & neck and pelvis localization in Computed Tomography (CT) imaging in radiation therapy. The objective and need of the current study are to establish Diagnostic Reference Level (DRL) for head & neck and pelvic CT protocols in Radiation Therapy planning and compare them with other regional, national and international DRL. The established DRL will be used to find further optimized DRL for Radiation Therapy Computed Tomography (RTCT). Methods: A total of 120 patients with Head & Neck cancers and 90 patients with pelvic cancers to be treated with radiotherapy prescribed for the RTCT with ages above 18 years old and above were included in the current study. The advanced Philips 16 slice big bore CT acquired all the CT simulation images. Results: Third quartile standards of Dose Length Product and effective dose for Head & Neck, and pelvis were 790.65mGy.cm, 2.45179 mSv, and 999.7 mGy.cm, 15.48mSv respectively. The third quartile CTDIvol value for the same order of procedure is 17.6 mGy. Tube voltage of 120kVp and 300mAs and used for radiotherapy planning. Conclusion: The first regional Radiation therapy Computed tomography simulation Diagnostic reference levels have been projected and deliver a platform for dose evaluation and optimization due to the limited number of papers on radiation therapy, computed tomography, and diagnostic reference levels. Comparison with previously available RT CT diagnostic reference levels indicated some radiation dose variation, so exposure parameters should be revised and improved.",
"keywords": [
"Radiotherapy",
"Diagnostic reference levels",
"Head & Neck",
"Pelvis",
"DLP",
"and CTDIvol"
],
"content": "Introduction\n\nComputed tomography (CT) plays a significant part in the radiotherapy treatment process. CT enables personalized radiation treatment delivery with the help of cross-sectional imaging. CT is the only modality used to calculate 3D-dose in radiotherapy.1 Additionally, it facilitates inaccurate delivery of radiotherapy by obtaining digitally reconstructed radiographs for setup verification of the patient on the teletherapy machine before starting treatment.\n\nDespite these advantages, CT carries a significant disadvantage of utilizing ionizing radiation for imaging, with the inevitable risk of stochastic effects. As mentioned in the ALARA principle, these imaging doses, which patient organs will receive during the treatment, should be as low as possible. The “International Commission on Radiological Protection” (ICRP) implemented the “Diagnostic Reference Level” (DRL) used in radiological procedures. A Diagnostic reference level is not a regulatory limit. It is a benchmark that, when exceeded, triggers a review. ICRP recommends that the DRL represent the local practice within a particular geographical area. DRL will not distinguish between good or bad medical practices. The motive of establishing a DRL is to reduce the dose of ionizing radiation that does not contribute to giving any additional clinical information to a medical practitioner. DRL is estimated to improve the radiation dose and image quality.2\n\nDRLs are not applicable in radiotherapy practice, but it is necessary to apply DRL for different imaging techniques used in radiotherapy treatment, imaging for patient position verification, and treatment planning. DRL is the 75th percentile of effective dose distribution, calculated with patient or phantom data. Regional, national and international levels DRLs may be estimated and compared.2 We need to periodically estimate DRLs as there may be a change in the work practice.\n\nDiagnostic reference level for CT procedure is already available, and studies will still establish diagnostic reference levels regionally and nationally. For radiotherapy planning CT, the scanning parameters and the scan length for each region are different. It is essential to establish a DRL for the same. Some studies on establishing DRL for radiotherapy planning CT have already been published.1–3 The objective and need of this study are to establish diagnostic reference levels for head & neck and pelvic CT protocols in RT treatment planning and compare them with other regional, national and international DRL. The established DRL will be used to find further optimized DRL for RT CT.\n\nAn image of acceptable quality can be obtained using a minimum radiation dose. The present study was conducted using a phantom to assess the radiographic technical parameters that could lead to the lowest radiation dose and acceptable image quality. The outcomes of this study can be used to improve Head & neck, and pelvis radiographic examinations.\n\n\n2. Methods\n\nThis study was conducted after obtaining approval from the ethical committee of Kasturba (IEC number 925/2018) Hospital. The expected outcome of the current study is “standardization of Radiotherapy Planning CT Head and Neck and Pelvic protocol and optimization of dose can be achieved by using reference DRLs.” By using a convenient sampling technique and Kappa co-efficient, a total of 120 patients with head and neck cancer and 90 patients with pelvic cancer to be treated with radiotherapy (Mean age 53.33 ±8.5, Male 54.16 ± 15 Female 52.5±12.17) were prescribed for RTCT with the age of 18 years and above were taken for the study after obtaining a voluntary written informed consent form from February 2019-August 2019 All the CT simulation images were acquired in the advanced Philips 16 slice big-bore RT CT machine, with a tube voltage of 120 kVp and 300 mAs and used for radiotherapy1 planning. During the prospective study, information such as the patient’s gender, region of interest, Field-Of-View (FOV), type of cancer, DLP, and CTDIvol were noted. The examination protocol and the exposure parameters used to take the scan were also collected. The data collected for this study was anonymized entirely.\n\nIn this study, we have included and analysed CT procedures of the Head & Neck, and Pelvis. The CT image acquisition parameters are given in Table 1.\n\nScanning length per examination varied from one scan to another scan. The considered length for head & neck investigation was from the vertex of the Head to the carina, and for the pelvis, the procedure is from the D10-D12 area to the mid femur. The “American Association of Physicists in Medicine suggests that the scanned volume should extend at least 5 cm superiorly and inferiorly beyond the target area”.4\n\nAll RTCT scan images were verified and approved by the oncologist after confirming them to be suitable for volume delineation. The effective dose was arrived at using the Normalized effective dose (k) coefficients and K’s value according to the updated AAPM report 96.\n\nPatient weight 40 – 80 kg mean weight 60 kg ± 5 kg\n\nThe obtained CT image of a different patient was analyzed for dose and quantitate image quality. The “signal-to-noise” and “contrast-to-noise” ratios for other density regions were analyzed by sketching circular regions of interest (ROIs) of 20-22 mm2 and were manually positioned in the different areas and background to encompass the homogeneity of measured tissues.3\n\nThe location of ROIs for quantitative image quality assessment of the pelvis and Head and neck is shown in Figure 1A and Figure 1B, respectively.\n\nAnalysis of the SNR, CNR, and FOM ratios for the phantom and the participant population were arrived at by the following equation5:\n\nThe statistics were analyzed using IBM SPSS STATISTICS 26.0 software. The descriptive statistical analysis included the average, standard deviation, median, and the third quartile for CTDI vol and total dose length product (DLP), calculated for each procedure.\n\nThe maximum crucial part of dose optimization is completed earlier than the patient rests on the Computed tomography table, in the phrases of ensuring the “justification of the clinical indication for CT.” Numerous investigators have discovered different techniques for reducing radiation doses.6–10\n\nOnce it is determined that a CT scan is required, the work of reducing radiation dose should confirm that pictures with interpretable indicative data can be achieved with the most reduced feasible radiation dose. A low dose CT scan without the required diagnostic information helps but could lead to further imaging or damage of significant time for producing management choices. “In contrast, a high-dose CT with image quality superior to it needed to get diagnostic information could increase considerations over radiation dose risks.”\n\nTo observe a harmony between “image quality and imaging dose, a CatPhan 500 phantom,” which has a 20 cm width, was filtered. “Scans were procured with a rotation time of 0.5 s, slice thickness of 3 mm, the pitch of 0.6, and the greatest accessible, effective tube current”. With the use of reconstruction algorithms, the raw data were reconstructed from the phantom data. “The reconstructed images of the CATPHAN from all diverse tube voltage and effective tube current-time product settings were reviewed by five experienced medical physicists.” “To calculate the contrast-to-noise ratio, circular regions of interest were drawn with the signal ROI inside the 20 mm diameter target in the different density material and the background ROI outside but next to the target. To determine the appropriate tube voltage, the CNR, the increased dose, and penetration were considered”.11 Some of these parameters can optimize the dose and image quality.\n\nBecause of the rectilinear relationship between radiation dose & applied tube current, tube current (measured in milliamperes) change is the utmost commonly used scan limit to modify dose.12 Tube current (milliamperes) can be modified manually by selecting fixed or constant milliamperes with a user-required image quality measured to alter tube current based on body shape and body regions. While unnecessarily vigorous tube current reduction causes increased image noise in the mediastinum and chest wall, previous research has shown that tube current can be decreased to 15 to 50 mAs without compromising the diagnosis of lung or mediastinal anomalies.13\n\nAnother scan parameter typically tailored for radiation exposure adaptation is tube potential (measured in kilovolts). The variation in radiation dose corresponds to tube current and is generally relative to the square of the adjustment of applied pinnacle kV. (kVp), for example, bringing down the tube potential from 140 to 120 kVp brings about a 35% reduction.\n\nThe total radiation dose associated with CT examination is the dose length product (DLP; measured in milli-gray multiplied by centimetres). For helical CT acquisitions, it is calculated as the product of volume CT dose index (CTDIvol, in milli-gray) and scan length (in centimeters). Therefore, a reduction in scan length results in a direct and linear decrease in the DLP. Scan length should always be curtailed to the area of interest.13\n\nThis experimental study was conducted in the same setup. The image acquisition was accomplished using a CATPHAN 502 phantom. These scans were used to relatively compare the quality of the obtained images using the technical parameters. Image acquisitions were obtained for the different mAs and kV settings to reduce radiation dose. As with tube current, lowering tube potential also improves image noise, improving image contrast. In some studies, it is mentioned that in common, chest CT can be performed at 80 kV in subjects smaller than 50 to 60 kg and 100 kV for subjects weighing up to 75 to 80 kg.13\n\nThe improved image noise with decreased kilovolts does not influence general image quality considerably. Earlier investigations described weight-based streamlining of kilovolts and milliamperes for paediatric chest CT with a considerable decrease in dose.13\n\nA total of 100 images were acquired using the different technical parameters mentioned in Table 2. The acquired images were assessed for objective and subjective image quality acceptability by determining the SNR, CNR, and FOM.\n\nScanning parameters of the phantom study with different kVp and mAs are shown in Figures 2A, 2B, 2C, 2D, 3A, 3B, 3C, and 3D.\n\nImaging parameters used in the phantom study are given in Table 2.\n\n\n3. Results\n\nIn this study, we have used a total of 70 males and 50 female head and neck and 90 female patients that are diagnosed with cancer. The mean, median, effective dose, and third quartile values for DLP, which is the present protocol DRL for the Head and neck and pelvic scans, are summarised in Table 3. All the subjects underwent the scan, and all the participants were eligible for potential reasons. All the 120 participants underwent scans without no missing data.\n\nThe mean and standard deviation for image quality (SNR and CNR) and Figure of merit (FOM) for the Head & Neck, and Pelvic scans are summarized in Table 4 and Table 5.\n\nDetermination of optimal protocol on phantom data\n\nThe summary of the technical parameters selected from the experimental study to be used in the optimization process is presented in Table 6.\n\nThe CNR, SNR, and FOM are calculated for ROI created in the phantom scan. The CNR and SNR are compared with the CNR, and SNR is calculated in the patient scans taken in 120 kVp and 300 mAs, selected some combinations of kVp and mAs which was nearer to the patient scan.\n\n\n4. Discussion\n\nIn the imaging techniques that use ionizing radiation, involving radiotherapy planning computed tomography scans, to minimize patients’ risk corresponding to the linear no-threshold model, radiation dose needs to be optimized. Diagnostic reference levels are indicators of the typical practice in a country or a region. Because equipment and procedure protocols can vary between different facilities in countries or areas, it is good to establish national or regional diagnostic reference levels.14 The use of DRL is recognized as a dose optimization tool by many professional and regulatory organizations, including ICRP, ACR, IAEA, and AAPM.\n\nThe focus of the current research was to establish a diagnostic reference level for present RTCT. This study is the first of its kind RTCT simulation DRLs in India. The Radiotherapy CT scanner and the CT scanner used in radiology have some differences. The CT scanner used for the Radiotherapy scan preferably needs to have a big bore size compared to the radiology CT bore. The reason is to allow some specific fixtures used in radiotherapy CT simulation, which is required to maintain the same position of the patient throughout the radiotherapy treatment and avoid some normal structures from the path of radiation. The literature reports a 10 – 20 mGy more dose delivered with big bore CT than with small-bore size CT scanner because of the variations in mAs settings.15 Comparing Radiotherapy CT DRL with Radiology CT scan procedure DRL is not appropriate because of several differences between the two, including different scanning lengths, protocols, and the requirement of different quality of images.4,16\n\nClerkin et al.17 projected a “National Irish DRL of 882 mGy cm and CTDIvol of 21 mGy for the Head and neck RT localization CT. Our study’s results comply with this study’s recommendations, with the DLP of 790.65 mGy cm and CTDIvol of 17.76 mGy”.\n\nNika Zalokar et al.1 projected DRL of 708.2 mGy cm, 663.1 mGy cm, and CTDIvol of 17.7 mGy, 18.3 mGy for pelvic RT localization CT with Philips and Siemens CT, respectively. The output measurement for the pelvis scan was from the “L3-L4” portion to 2 cm under the ischiatic bone. Study results with the Dose length product of 999.7 mGy cm and CTDIvol of 17.76 mGy, and the scan length is D10-D12 region to the mid femur.\n\nToro et al.18 studied patient exposure concentrations in Computed tomography models by comparing only CTDIvol standards. All CTDIvol values in our study were lower compared to that study. However, wide variations in CTDIvol have been found among various CT units.\n\nThe current study has a few limitations. This study calculates SNR, CNR, and FOM. However, the correlation between the dose and quality of the image was not addressed based on BMI and chest circumference. The radiation doses that cancer patients obtain throughout imaging have not been significant because of the treatment doses. The RT CT dose optimization is required because cancer patients might require undergoing many CT scans. In the current study, the variation in CTDIvol, DLP, and scanning protocol in Head and Neck and Pelvis cancer Radiation therapy localization CT imaging in the departments authorize the establishment of DRLs. It may be necessary to consider BMI-specific modified RT CT protocols, and this area warrants further investigation.\n\n\n5. Conclusion\n\nThe first regional radiation therapy Computed tomography simulation DRLs have been projected and deliver a platform for dose assessment and optimization. Due to the limited number of literature papers on radiation therapy, Computed tomography DRLs. These provide a basis for dose optimization among RT centres and may facilitate the reduction in cumulative radiation exposure. Comparison with previously established RT CT DRLs showed some radiation dose variation, so exposure parameters should be reviewed and optimized.\n\n\nData availability\n\nHarvard Dataverse, V1. Establishment of Diagnostic reference level and Radiation dose variation in Head & Neck and Pelvis treatment planning in RT CT, https://doi.org/10.7910/DVN/GIGDBG.19\n\nThis project contains the following underlying data: Slice number of the exact location where we had to draw a Region of Interest (ROI) for obtaining the Hounsfield unit and Standard deviation of the area where the ROI is plotted. The collected values from the region of interest will give the Contrast to Noise Ratio (CNR), Signal to Noise Ratio (SNR), and Figure of Merit (FOM). While calculating the radiation dose levels for an individual part, critical parameters like Dose Length Product (DLP), CTDIvol, and scan length are considered. All the above data has been liked with the link below.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nZalokar N, Žager Marciuš V, Mekiš N: Establishment of national diagnostic reference levels for radiotherapy computed tomography simulation procedures in Slovenia. Eur. J. Radiol. 2020 Jun 1; 127.\n\nMcCollough CH, Clinic M: Diagnostic Reference Levels.2010.\n\nBhosale P, Wagner-Bartak N, Wei W, et al.: Comparing CNR, SNR, and Image Quality of CT Images Reconstructed with Soft Kernel, Standard Kernel, and Standard Kernel plus ASIR 30% Techniques. Int. J. Radiol. 2015; 2(2): 60–65. Publisher Full Text Reference Source\n\nMutic S, Palta JR, Butker EK, et al.: Quality assurance for computed-tomography simulators and the computed-tomography-simulation process: Report of the AAPM Radiation Therapy Committee Task Group No. 66. Vol. 30, Medical Physics. John Wiley and Sons Ltd;2003; 2762–2792.\n\nChang KP, Hsu TK, Lin WT, et al.: Optimization of dose and image quality in adult and pediatric computed tomography scans. Radiat. Phys. Chem. 2017 Nov 1; 140: 260–265. Publisher Full Text\n\nPulmonary Nodules Experimental and Clinical Studies at LowDose CT.\n\nItoh S, Ikeda M, Isomura T, et al.: Screening helical CT for mass screening of lung cancer: application of low-dose and single-breath-hold scanning. Radiat. Med. 1998 Mar-Apr; 16(2): 75–83. PubMed Abstract\n\nRadiology E, Gartenschläger M, Schweden F, et al.: Chest radiology Pulmonary nodules: detection with low-dose vs conventional-dose spiral CT. vol. 8. Springer-Verlag;1998.\n\nBjörkdahl P, Nyman U: Using 100- instead of 120-kVp computed tomography to diagnose pulmonary embolism almost halves the radiation dose with preserved diagnostic quality. Acta Radiol. 2010; 51(3): 260–270. PubMed Abstract | Publisher Full Text\n\nHeyer CM, Mohr PS, Lemburg SP, et al.: Image quality and radiation exposure at pulmonary CT angiography with 100- or 120-kVp protocol: Prospective randomized study. Radiology. 2007 Nov; 245(2): 577–583. Publisher Full Text\n\nChen GP, Noid G, Tai A, et al.: Improving CT quality with optimized image parameters for radiation treatment planning and delivery guidance. Phys. Imaging Radiat. Oncol. 2017 Oct 1; 4: 6–11. Publisher Full Text\n\nSingh S, Kalra MK, Moore MA, et al.: Dose reduction and compliance with pediatric CT protocols adapted to patient size, clinical indication, and the number of prior studies. Radiology. 2009 Jul; 252(1): 200–208. PubMed Abstract | Publisher Full Text\n\nSingh S, Kalra MK, Ali Khawaja RD, et al.: Radiation Dose Optimization and Thoracic Computed Tomography. Radiol. Clin. N. Am. 2014; 52: 1–15. Publisher Full Text\n\nVassileva J, Rehani M: Diagnostic reference levels. AJR Am. J. Roentgenol. 2015 Jan 1; 204(1): W1–W3. Publisher Full Text\n\nGarcia-Ramirez JL, Dempsey JF, Low DA, et al.: Performance evaluation of an 85-cm-bore x-ray computed tomography scanner designed for radiation oncology and comparison with current diagnostic CT scanners. Int. J. Radiat. Oncol. Biol. Phys. 2002; 52: 1123–1131. PubMed Abstract | Publisher Full Text\n\nMc Ardle O, Mullaney L: Title: Establishment of national diagnostic reference levels for breast cancer CT protocols in radiation therapy. Running Title: Establishment of DRLs for breast cancer CT protocols in RT.2016.\n\nClerkin C, Brennan S, Mullaney LM: Establishment of national diagnostic reference levels (DRLs) for radiotherapy localization computer tomography of the Head and neck. Rep. Pract. Oncol. Radiother. 2018 Sep 1; 23(5): 407–412. PubMed Abstract | Publisher Full Text\n\nToroi P, Kaijaluoto S, Bly R: Patient exposure levels in radiotherapy CT simulations in Finland. Radiat. Prot. Dosim. 2015 Dec 1; 167(4): 602–607. PubMed Abstract | Publisher Full Text\n\nSuresh S: Establishment of Diagnostic reference level and Radiation dose variation in Head & Neck and Pelvis treatment planning in RTCT. Harvard Dataverse, V1. 2022. Publisher Full Text"
}
|
[
{
"id": "167569",
"date": "09 Feb 2024",
"name": "Rekha Reddy Buchapudi",
"expertise": [
"Reviewer Expertise Radiation Oncology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this research study authors intends to establish Diagnostic Reference Levels (DRLs) for head and neck and pelvic Radiotherapy planning Computed Tomography (RTCT) which is relevant and important to optimize the dose and objective image quality assessment done to check on image quality due to radiation dose optimization.\nThe authors have discussed about the need and relevance of dose optimization in RTCT planning by finding out the Diagnostic Reference Levels (DRLs) which is recognized as tool for dose optimization by international organizations.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 2
|
https://f1000research.com/articles/11-489
|
https://f1000research.com/articles/10-367/v1
|
10 May 21
|
{
"type": "Research Article",
"title": "Factors contributing to under-reporting of patient safety incidents in Indonesia: leaders’ perspectives",
"authors": [
"Inge Dhamanti",
"Sandra Leggat",
"Simon Barraclough",
"Taufik Rachman",
"Sandra Leggat",
"Simon Barraclough",
"Taufik Rachman"
],
"abstract": "Background: Understanding the causes of patient safety incidents is essential for improving patient safety; therefore, reporting and analysis of these incidents is a key imperative. Despite its implemention more than 15 years ago, the institutionalization of incident reporting in Indonesian hospitals is far from satisfactory. The aim of this study was to analyze the factors responsible for under-reporting of patient safety incidents in Indonesian public hospitals from the perspectives of leaders of hospitals, government departments, and independent institutions. Methods: A qualitative research methodology was adopted for this study using semi-structured interviews of key informants. 25 participants working at nine organizations (government departments, independent institutions, and public hospitals) were interviewed. The interview transcripts were analyzed using a deductive analytic approach. Nvivo 10 was used to for data processing prior to thematic analysis. Results: The key factors contributing to the under-reporting of patient safety incidents were categorized as hospital related and nonhospital related (government or independent agency). The hospital-related factors were: lack of understanding, knowledge, and responsibility for reporting; lack of leadership and institutional culture of reporting incidents; perception of reporting as an additional burden. The nonhospital-related factors were: lack of feedback and training; lack of confidentiality mechanisms in the system; absence of policy safeguards to prevent any punitive measures against the reporting hospital; lack of leadership. Conclusion: Our study identified factors contributing to the under-reporting of patient safety incidents in Indonesia. The lack of government support and absence of political will to improve patient safety incident reporting appear to be the root causes of under-reporting. Our findings call for concerted efforts involving government, independent agencies, hospitals, and other stakeholders for instituting reforms in the patient safety incident reporting system.",
"keywords": [
"under-reporting",
"patient safety",
"government organization",
"independent agencies",
"hospital",
"leader"
],
"content": "Introduction\n\nPatient safety is a top priority in healthcare services. Moreover, it is also a critical policy issue as about 10% of hospitalized patients experience adverse events.1 In low- and middle-income countries, an estimated 134 million adverse incidents occur among hospitalized patients every year; these incidents account for an estimated 2.6 million deaths each year. Understanding the causes of incidents provides a foundation for patient safety improvement; therefore, reporting and analysis of patient safety incidents is a key imperative. Lessons learned from the reported safety incidents can help inform interventions to prevent recurrence of similar incidents. However, this can happen only if the hospitals take responsibility for instituting safety measures and share their data at the national level.2\n\nPatient safety incident reporting systems have adopted various formats; a majority of these systems require reporting of incidents by health workers. The types of incidents that need to be reported vary in each country; these range from potential events to sentinel events. The World Health Organization (WHO) has developed a framework for reporting adverse events.3 Subsequently, WHO developed a minimal information model for incident reporting systems4 suitable for adoption by low-income, middle-income, and developed countries. However, the reporting rates show wide variability among countries, with some countries still struggling to implement the system.\n\nThe United Kingdom is one of the countries that have successfully implemented incident reporting. English NHS organisations reported 2,246,622 incidents or 10.3% increase on the incidents reported from April 2019 to March 2020 compared to from April 2018 to March 2019.\n\nAnother example is the Taiwan Patient Safety Reporting System which by 2019, the number of participating institutions has reached 12,491, and the cumulative number of notified cases reported from 2005 has reached 714,896.\n\nIn contrast, the number of incidents reported to the Malaysian Incident Reporting and Learning system over the past 18 years of its operation has been quite low; the number of incidents reported in the year 2016 was 2,769. However, after the implementation of national online reporting system in 2017, the number of reports showed a 105.5% increase from the preceding year.\n\nIndonesia is the fourth most populous country in the world with an estimated population of 270 million. Only half of the country’s 2,925 hospitals are accredited by the Commission for Hospital Accreditation (CHA). The national patient safety incident reporting system was launched in 2005. There are two levels of reporting: hospital level (internal reporting) and national level (external reporting). Internal reporting comprises of written reports pertaining to any incidents occurring in the hospital, ranging from near misses to sentinel events; these incidents are required to be reported within 48 hours. External reporting refers to incident reports that have been analyzed, investigated, and reported eletronically to the National Committee.\n\nIncident reporting is a mandatory requirement for hospital accreditation; however, the performance of the reporting system is far from satisfactory. The national level data is not publically accessible. Moreover, our previous study revealed very low rates of reporting. The total number of incidents reported in 2019 was 7,465; these incidents were reported from 334 out of the 2,877 hospitals (12%) in Indonesia.5\n\nEvaluation of the sytem also revealed some weaknesses such as the existence of punitive system, lack of confidentiality, poor timeliness of reporting, and lack of responsiveness.6 The existing policies, guidelines, and regulations in Indonesia, to a large extent, do not satisfy the WHO-recommended requirements for incident reporting systems. Furthermore, there is a lack of awareness and understanding of the reporting system among officials at almost all levels. Several studies have identified the barriers that contribute to low incident reporting rates in Indonesian hospitals.7–9\n\nThe high prevalence of under-reporting severely undermines the capacity of incident reporting systems to promote learning and improve patient safety. We used previous framework in identifying the factors that lead to patient safety incident reporting that consisted of organizational factors, work environment, process and system of reporting, factors related to patient safety team at hospital level, knowledge and skills of reporting personnel, individual characteristics of health care professionals, professional ethics, fear of adverse consequences, and incident characteristics. In-depth characterization of factors that contribute to under-reporting is a key imperative to improve patient safety incident reporting systems. However, despite its importance, this form of study has never been conducted in Indonesia. Therefore, we aimed to analyze the factors that contribute to under-reporting of patient safety incidents in Indonesian public hospitals based on the perspectives of leaders of hospitals, government departments, and independent institutions.\n\n\nMethods\n\nA qualitative research methodology was adopted for this study using semi-structured interviews of key informants. The approach to phenomenology was applied, as it was intended to thoroughly explore the point of view of the leaders. A purposive sample of organizations including government departments, independent institutions, and public hospitals in the East Java Province and the capital city of Indonesia; were selected for this study. The key informants included staff members working in leadership positions at organizations involved in patient safety implementation. A total of 26 participants were approached all but one agreed to be interviewed, with a total of 25 participants from nine organizations were enrolled. The details of the participants are presented in Table 1.\n\nThe hospitals chosen were district referral public hospitals which are required to have a functional incident reporting system (internal and external reporting) managed by the hospital patient safety team for accreditation purposes; however, none of the sampled hospitals had ever reported any incident to the national level.\n\nLetters were sent to the participating organizations to solicit the names of respective key persons. Participants were the key persons that were knowledgeable about the reporting of patient safety incidents in Indonesian hospitals. Following that, we arranged an interview with their respective offices, with no other people present. The focus of the interview was to determine the potential causes of under-reporting of patient safety incidents. The questions were sent to participants prior to the interview. The first author conducted the interviews in Indonesian. The interviews were lasted from 20 minutes to one hour. All interviews were audio-recorded, transcribed, coded and managed using Nvivo 10 (NVivo, RRID:SCR_014802). The majority of those interviewed did not know the researchers personally. To ensure confidentiality, the participant’s identity was noted using initials; however, the identity of the organization was not concealed. In regard the reflexivity, the researchers, in particular the first researcher, are interested in patient safety and have performed a number of research studies on the related topic. She has spent her time at the university in Indonesia and has the necessary expertise to examine the cultural and Indonesian context relevant to the research.\n\nThe transcripts were not returned to the participants, nor was feedback provided to them. The transcripts were entered into NVivo 10 and analyzed using a deductive analytic method focused on pre-defined themes derived from the research questions. The deductive approach used an organizing framework that entails coding that was conducted by two coders. The data were coded based on themes, with the initial goal of identifying certain core aspects of the data that specifically relate to the research questions.10 The first step was data reduction which entailed selection of the section or text from the transcript and their coding based on the themes. The second step entailed displaying the data in tabular format followed by drawing of conclusions. Subsequently, thematic analysis was performed for the synthesis and cross-referencing of emerging topics.11 We looked at the phenomenon using the principle of triangulation by looking at the phenomenon from various viewpoints, through different lenses, with different questions.\n\nEthical approval for this study was obtained from the Committee on Ethics for Human Research at the Faculty of Health Sciences, La Trobe University, Australia with the ethics application number FHEC13/197. Institutional approval was also obtained from each of the participating entities. Written informed consent was obtained from respondents prior to their enrolment.\n\n\nResults\n\nWe categorized the responses according to the emerging themes. A summary of responses is presented in Table 2.\n\n\n\n- Most hospitals do not understand the benefits and the importance of reporting\n\n- Hospitals perceive no benefit of reporting\n\n\n\n- No direct feedback provided to hospitals\n\n- There is no guarantee that the National Committee would take corrective action based on the report\n\n\n\n- Not all hospitals have received training\n\n- Lack of concern from the government regarding conducting socialization\n\n\n\n- Lack of knowledge about the reporting procedure and the content of reporting\n\n- Lack of awareness among hospital staff about the need for reporting the incident\n\n- Feeling uncomfortable about reporting an incident\n\n\n\n- Many hospitals doubt the confidentiality of reporting\n\n\n\n- Concerns about legal issues\n\n- There is no policy to ensure that it is safe for hospitals to report incidents\n\n\n\n- Culture of reporting has not yet been established in hospitals\n\n- There are barriers to building a patient safety culture and reporting culture in hospitals\n\n- The blaming culture within hospitals is still dominant\n\n\n\n- Reporting and analysis of the incident takes time and effort, especially for doctors and nurses\n\n- The hospital patient safety team’s performance is not optimal as the responsibility for carrying out the tasks or programs is assigned to a single person\n\n\n\n- Need to change the reporting system\n\n- Lack of rewards and sanctions in the system\n\n\n\n- Lack of leadership at the hospital level\n\n- Weak role of the IMOH in handling the reporting of incidents\n\nBased on the data presented in the table, we identified some potential causes of under-reporting of patient safety incidents that were confirmed by the three types of organizations.\n\nParticipants from government departments and independent agencies agreed that the lack of appreciation of the value and significance of reporting incidents may lead to under-reporting.\n\n\n\n“… the view from the hospital that the benefits for hospitals that report are limited, because there is no feedback.” (National Committee, A2)\n\n\n\n“Maybe they do not understand that the goal is learning because they always ask, what's in it for us if we report?” (Indonesian Hospital Association (IHA) provincial level, A7)\n\nParticipants reflected on the lack of feedback provided to the reporting hospitals. This was because of the lack of annual reporting and sharing of data at the national level. As recorded by one interviewee:\n\n\n\n“If the hospital sees that sending reports is beneficial, maybe the number of reports could increase. So that is a factor of the hospital, so in addition to internal difficulties in the hospital, the hospital also needs to be provided some kind of feedback [after reporting]” (IHA provincial level, A7)\n\nAnother reported cause of under-reporting was training, as not all hospitals received training or have been socialized by the government. Some participants reported:\n\n\n\n“Maybe because the government, such as the Ministry of Health or the Provincial health department lacks the intensity to socialize to as much detail as possible. Maybe the other reasons are afraid of being found out that the hospital is [having] bad [reputation] if they have many [reported] cases.” (C Hospital, H7)\n\n\n\n“The cause was solely due to the government's lack of interest in socializing incident reporting.” (A Hospital, H2)\n\nLack of knowledge was identified as one of the reasons of low reporting rates; this included the lack of knowledge about the reporting process, lack of understanding of the requirement for reporting an incident, and lack of knowledge about the anonymity of reporting. As mentioned by some participants:\n\n\n\n“The concern from the hospital [to report the incident] was lacking” (Hospital B, H5)\n\n\n\n“[To] Raise awareness of all health workers in this hospital to be more aware that it [the reporting] is something that needs attention.” (Hospital B, H4)\n\n\n\n“The first cause was that health workers do not understand the importance of the reporting system. Secondly, they do not understand which incidents should be reported. (Hospital C, H8)\n\n\n\n“But also maybe because they feel uncomfortable [in reporting] even though the report does not mention the name of the hospital, it is anonymous, but there might be inconvenience.” (IHA national level, A5)\n\nMany participants from independent agencies emphasized concerns pertaining to the confidentiality of reporting. As some participants have remarked:\n\n\n\n“It is their belief, [the reporting is] not confidential and so on. Convincing them is also not easy, sometimes they have made it [the internal reporting], but it is not reported to the external agency. That [...] well, that might have caused low reporting. \"(National Committee, A1)\n\nSome participants reported that the fear of repercussions of incident reporting, both personal and institutional, is a common cause of low reporting. According to an ICHA participant, fear of litigation by the patient often prevents the reporting of incidents attributable to acts of omission or commission by a health worker. This is due to lack of policy safeguards for the reporting hospital. As one participant reported:\n\n\n\n“There must be some kind of law that guarantees that this report problem is safe for the hospital.” (IHA provincial level, A7)\n\nHospitals are yet to institutionalize a culture of patient safety and incident reporting owing to the prevalence of a blaming culture in hospitals. Some participants reported:\n\n\n\n“I think there are many factors that become obstacles at the hospital level, ranging from difficulties in building a culture of safety to difficulties in building a culture of reporting. (IHA provincial level, A7)\n\n\n\n“This hospital should also not cover up what happened […] sometimes it covers up what happens.” (Hospital B, H4)\n\nThe participants working at hospitals claimed that incident reporting is a cause of additional stress for health workers, especially doctors and nurses. Moreover, the workload is not fairly distributed within the hospital patient safety team as only one person is usually assigned the task of incident-monitoring, reviewing, and taking further actions.\n\n\n\n“The patient safety team itself cannot distribute the tasks, so the task is assigned to one person.” (Hospital C, H8)\n\nThe perspectives from the independent agencies highlighted the need to change the reporting system from voluntary to mandatory. One participant reported:\n\n\n\n“So this reporting should not only be encouraged but must be made mandatory […] if not reported there must be feedback from [...] the related agencies about the lack of reporting, that is.\" (IHA provincial level, H2)\n\nThe participants also emphasized the need for direct feedback from the related organization, both for reporting and non-reporting hospitals. Furthermore, there is no formal system of rewards and punishment, which could help improve the reporting.\n\nThe participants from the independent agencies and hospitals mentioned about the lack of leadership at the government and hospital level. Strict monitoring and oversight is required for reporting of accidents, according to hospital-based participants. Moreover, hospital leaders also fail to understand the blame-free principle of incident reporting. Lastly, lack of participation by the regional health office was also one of the triggers for under-reporting.\n\n\n\n“So indeed there must be a strict control, so frankly from the management there must be strict control, [...] that means yes [...] including supervision attached to the reported.” (Hospital B, H4)\n\n\n\n“One of the causes for not reporting is punishment, so people do not want to report. Actually, the leader must have understood that concept of non-punitive safeguards against incident reporting?” (IHA national level, H1)\n\n\n\n“Although the government has included [patient safety] in the accreditation standard, it needs to emphasize the involvement of regional health offices in this patient safety incident reporting system, so that several organizations that carry out monitoring can check and re-check each other” (IHA provincial level, H2)\n\nWe then classified the factors as hospital-related and nonhospital-related (government or independent agency) factors, as seen in Table 3.\n\n\nDiscussion\n\nReporting of patient safety incidents in Indonesia continues to face many challenges. Most of the causes of under-reporting identified in this study have been reported in previous studies conducted in Indonesia7,12–14 and globally,15,16 either as barriers to reporting of incidents or as factors that affect patient safety incident reporting. After almost two decades, the implementation of the reporting system has not reached its potential and some classical problems have continued to persist.11\n\nThis study found a divergence between government departments and independent organizations on the one hand and hospitals on the other hand about the perceived causes of under-reporting. Respondents from government departments and independent organizations reported about the lack of feedback for the hospital and lack of awareness of the benefits of reporting as the causes of under-reporting; hospitals, on other hand, did not refer to the same problem. Conversely, respondents from hospitals referred to the burden of reporting which was not reported by other organizations. This discrepancy could be attributed to the fact that the sampled hospitals had never reported the incidents to the National Committee; therefore, they were not aware about the issue of lack of feedback or did not perceive the benefits of incident reporting.\n\nReporting of incidents is an essential first step to learn from the experience. However, in Indonesia, very little work has been done to document the lessons learned from the national patient safety incident reporting and how it can improve the processes of care or patient outcomes. There has been a lack of institutional feedback mechanism ever since the inception of the reporting system. As of April 2021, no annual reports, comprehensive information, or sharing of lessons learned from the reported incidents have been published on the website of the National Committee. This is unfortunate because lessons learned from the incidents can help save lives. Thus, many lives may have been lost just because the national system failed to learn from the incidents.\n\nThe root causes of under-reporting, either the hospital- or government-related, may reflect the lack of government support and the political will to improve patient safety incident reporting. Political will refers to the willingness of political leaders to take action to achieve a set of goals and to sustain the costs of these actions over time with some components include public commitment and resource allocation, enforcement of credible sanctions, continuity of effort, and institutionalization of learning and adaptation. For example, lack of funding for incident reporting in Indonesia was found to constrain the usefulness of reporting.11 Additionally, the role of government in upgrading knowledge and skills of health workers, either through socialization or training in incident reporting, was found to be inadequate; this contributed to the lack of knowledge about the reporting procedure among health workers, lack of understanding of the benefits of reporting, and the absence of institutional reporting culture. The clear message about the importance of reporting in the national policy has not been translated into daily practice at the hospital level. As a consequence, there is a lack of reporting culture.\n\nAdditionally, there is weak enforcement of the credible sanctions regarding the implementation of internal and external reporting system by hospitals as mentioned in Standard 9 of Patient Safety and Quality Improvement.17 The consequences for hospitals that fail to report or meet the quality standards and accreditation requirements have not been clearly stated; consequently, only 12% of Indonesian hospitals reported incidents in 2019.5 To improve reporting, policymakers must set specific and achievable goals for the incident reporting system; for example, application of credible sanctions for hospitals that do not report their incidents, although it is one of the mandatory requirements for accreditation.\n\nThere is poor continuity of efforts for assessing, monitoring, and evaluating the incident reporting system. The hospital incident reporting systems are fragmented and isolated; in addition, establishment of best practices for implementation requires data analysis and sharing at the national level. This also reflects the failure of government to learn and adapt to the emerging circumstances through the fifteen years of the incident reporting implementation.\n\nReforms in patient safety incident reporting are required to help overcome the government or independent agency-related causes of under-reporting in Indonesia. These reforms should include development of a national patient safety strategic plan, setting of priorities, creating a time line, implementing the plan, monitoring and evaluation of the implementation of the policy, and revision and updation of the policy.18 A good example has been shown by the Malaysian Ministry of Health. In Malaysia, patient safety incident reporting is included as one of the patient safety goals; the incident reports are compiled regularly and analyzed every three months by the healthcare facilities and submitted to the National system by by 31st January of the subsequent year. A clear, unambiguous and firm policy is required to develop a successful system. To address the confidentiality issue, Indonesia should adopt the NHS policy where in the identity of the reporter, patient, health worker, and other individuals involved in the incident is not reported. The system is programmed to remove any personal identifiers in the report. This inculcates a sense of safety among the reporting health workers and hospitals and helps increase the number of reports. Further, the reporting also needs to be categorized into mandatory reporting for adverse events and sentinel events and voluntary reporting for any other incidents. The primary focus of reporting should be to draw lessons. Reporting needs to be made compulsory and no incident should be reported as zero incident, so that there is no excuse for not reporting the incident. Lastly, good patient safety leadership at the national, local, and hospital level is crucial to foster institutional changes and improve patient safety.\n\nA key limitation of this study is the potential lack of representativeness of the study sample. Moreover, the opinions of individuals may not be a true reflection of the organization. Thus, due diligence should be exercised while interpreting our results. However, this study addresses several critical issues related to the reporting of patient safety incidents and identifies several areas for improvement.\n\n\nConclusion\n\nOur study identified several causes of under-reporting of patient safety incidents in Indonesia from the perspectives of government departments, independent agencies, and hospitals. Our findings call for concerted efforts by government agencies, independent agencies, hospitals, and other stakeholders to institute comprehensive reforms in the patient safety incident reporting.",
"appendix": "Author contributions\n\nID: conceptualization, data curation, analysis, methodology, project administration, resources, writing original draft and preparation\n\nSL and SB: conceptualization, supervision, validation, review and editing\n\nTR: data analysis, validation, review and editing\n\n\nAcknowledgements\n\nNone declared\n\n\nReferences\n\nSlawomirski L, Auraaen A, Klazinga N: The economics of patient safety–strengthening a value-based approach to reducing patient harm at national level. Organisation for Economic Cooperation and Development–OECD; 2017.\n\nHowell AM, Burns EM, Hull L, et al.: International recommendations for national patient safety incident reporting systems: an expert Delphi consensus-building process. BMJ Qual Saf. 2017; 26: 150–163. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: World alliance for patient safety: WHO draft guidelines for adverse event reporting and learning systems: from information to action. World Health Organization; 2005.Reference Source.Accessed August 22, 2020.\n\nWorld Health Organization: Minimal information model for patient safety incident reporting and learning systems: user guide. World Health Organization; 2016.Reference SourceAccessed August 20, 2020.\n\nDaud A: National Patient Safety Incident Reporting and Learning. . Jakarta: National Patient Safety Committee presentation at the National Health Work Meetings; 2020.\n\nDhamanti I, Leggat S, Barraclough S, et al.: Patient safety incident reporting in Indonesia: an analysis using World Health Organization characteristics for successful reporting. Risk Manag Healthc Policy. 2019; 12: 331. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTristantia AD: Evaluation of Hospital Patient Safety Incident Reporting Systems. Indonesian Health Adminis J. 2018; 6: 83–94.\n\nIskandar H, Maksum H, Nafisah N: Factors causing reduction in reporting on hospital patient safety incidents. Brawijaya Med J. 2014; 28: 72–77.\n\nDhamanti I, Leggat S, Barraclough S: Practical and cultural barriers to reporting incidents among health workers in indonesian public hospitals. J Multidiscip Healthc. 2020; 13: 351. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArcher S, Hull L, Soukup T, et al.: Development of a theoretical framework of factors affecting patient safety incident reporting: a theoretical review of the literature. BMJ Open. 2017; 7: e017155. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAzungah T: Qualitative research: deductive and inductive approaches to data analysis. Qual Res J. 2018; 8: 383–400. Publisher Full Text\n\nMiles MB, Huberman AM: Qualitative data analysis: An expanded sourcebook. Sage; 1994.\n\nMitchell I, Schuster A, Smith K, et al.: Patient safety incident reporting: a qualitative study of thoughts and perceptions of experts 15 years after ‘To Err is Human’. BMJ Qual Saf. 2016; 25: 92–99. PubMed Abstract | Publisher Full Text\n\nMandriani E, Hardisman H, Yetti H: Analysis of dimensions of patient safety culture by health officers at RSUD dr Rasidin Padang in 2018. Jurnal Kesehatan Andalas. 2019; 8: 131–137. Publisher Full Text\n\nDhamanti I, Leggat S, Barraclough S, et al.: Comparison of Patient Safety Incident Reporting Systems in Taiwan, Malaysia, and Indonesia. J Patient Saf. 2020; PubMed Abstract | Publisher Full Text\n\nHarsul W, Irwan AM, Sjattar EL: The relationship between nurse self-efficacy and the culture of patient safety incident reporting in a district general hospital, Indonesia. Clin Epidemiol Glob Health. 2020; 8: 477–481. Publisher Full Text\n\nEngeda EH: Incident reporting behaviours and associated factors among nurses working in Gondar University Comprehensive Specialized Hospital, Northwest Ethiopia. Scientifica. 2016; PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrihartono IP, Wibowo A: Assessment of Medication Administration Error Reporting Among Hospital Nurses in Indonesia. J Patient Saf Qual Improve. 2020; 8: 13–23. Publisher Full Text\n\nHospital Accreditation Commission: National Standard for Hospital Accreditation. Jakarta: Department of Health; 2018.\n\nWHO African Region: Guide for developing national patient safety policy and strategic plan. 2014.Reference Source.Accessed August 20, 2020.\n\nDhamanti I, Leggat S, Barraclough S, et al.: Underlying data for ‘Factors contributing to under-reporting of patient safety incidents in Indonesia: leaders’s perspectives’.Publisher Full Text"
}
|
[
{
"id": "92864",
"date": "09 Sep 2021",
"name": "Katie MacLure",
"expertise": [
"Reviewer Expertise Digital Health",
"Health Inequalities",
"Qualitative Research"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFactors contributing to under-reporting of patient safety incidents in Indonesia: leaders’ perspectives Thank you for the opportunity to review your article. It is well-written and poses important questions for the Indonesian health service and therefore patients and their families. I believe your article can be strengthened by following my constructive comments as follows. I wish you well with your manuscript.\nAbstract\nCheck grammar in the final sentence of the Methods.\n\nCheck consistency of hyphenating hospital related.\n\nThe sentence starting 25 participants should be moved to Results section. There should instead be a description of the interview questions in the Methods section.\n\nThe Methods section should contain a statement on ethical review and how participants were recruited.\nIntroduction\nSentinel events needs further explanation.\n\nLast sentence in paragraph 2 needs at least one reference as does many of the following paragraphs in the Introduction.\n\nParagraph 4, has should be had to maintain past tense.\n\nIt is unusual to have single sentence paragraphs so consider merging 3 and 4.\n\nTypo – 'sytem' instead of 'system'.\n\nThe final paragraph of the Introduction is entirely unreferenced. This is a serious issue impacting the quality of this article.\n\nThere is needs to be a description of tools previously used to explore lack of reporting.\nMethods\n\nNeed to explain why using phenomenology and what it means in this context and provide references. Which type of phenomenology? Can you make this claim when you spoke to some for as little as 20 minutes with no follow up?\n\nInconsistency in calling participants key informants / leaders.\n\nThe numbers participating should be reported in the Results not Methods section.\n\nNo mention of informed consent nor ethical issues (found later at end of Methods section). If you report a participant’s initials and hospital name then they are in effect identifiable – did they consent to such exposure? As they were nominated by someone more senior within the hospital then their identity is known and could have repercussions. Were they provided with an information sheet?\n\nNeed to justify the decision to share the questions in advance. Fine to do so, but you must explain and reference.\n\nGrammar – ‘the interviews were lasted’.\n\nDelete the last sentence in the Data Collection paragraph. It is irrelevant and should have been declared in third person.\n\nData analysis first sentence is repetition from Data collection section.\n\nTwo coder but did they work independently then meet to agree or worked together from the outset?\n\nTable 1 should be in the Results section.\n\nI don’t have access to the question set so cannot relate this to the themes. What was the basis for the questions? There are many validated tools which could have been adopted to allow comparison with other studies – why did you/did you not use such a tool?\n\nLast sentence in Data analysis needs more explanation – which lenses? How can you apply different questions from those in the interview? You are adopting an unusual approach to triangulation so must justify and reference.\nResults\nAre the ‘participants’ responses’ in Table 2 verbatim quotes? These are short, do they capture the context for reporting?\n\nDid you do a subgroup analysis of different hospital types and described earlier?\n\nWhat is the value of Table 2 being placed before the longer participant quotes? If not including verbatim quotes then it may make more sense to move to after the extended quotes.\n\nTables should appear close after the statement which references the table.\nDiscussion\n‘Updation’ is not an English word – maybe it should be!\n\nThe Discussion section needs a lot more referencing to the related literature throughout. At points it comes across as a personal mission with relating the results to the literature.\nConclusion\nThis is very brief. I suggest going back to your original aim and reflecting that in this section. Also indicating any further research which would support development of an improved reporting culture.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8247",
"date": "25 May 2022",
"name": "Inge Dhamanti",
"role": "Author Response",
"response": "Abstract Check grammar in the final sentence of the Methods. Response: Thanks for your feedback. It has been revised into: The interview transcripts were analyzed using a deductive analytic approach. Nvivo 10 was used for data processing prior to thematic analysis. Check consistency of hyphenating hospital related. Response: Changes have been made The sentence starting 25 participants should be moved to Results section. There should instead be a description of the interview questions in the Methods section. Response: The sentence has been relocated to the Result Section. The Methods section should contain a statement on ethical review and how participants were recruited. Response: how the participants were recruited were added. Introduction Sentinel events needs further explanation. Response: Further explanation was added. Last sentence in paragraph 2 needs at least one reference as does many of the following paragraphs in the Introduction. Response: Reference has been added. Paragraph 4, has should be had to maintain past tense. Response: Changed into: Indonesia is the world's fourth most populated country, with an estimated 270 million people. The Commission for Hospital Accreditation (CHA) accredited only half of the country's 2,925 hospitals. In 2005, the national patient safety incident reporting system was established. There were two reporting levels: hospital-level (internal reporting) and national-level (external reporting). Internal reporting required written reports of all incidents that occurred within the hospital, from near misses to sentinel events; these incidences were to be reported within 48 hours. External reporting referred to incident reports that have been reviewed, investigated, and forwarded to the National Committee via electronic means. It is unusual to have single sentence paragraphs so consider merging 3 and 4. Response: the paragraphs were merged Typo – 'sytem' instead of 'system'. Response: revised The final paragraph of the Introduction is entirely unreferenced. This is a serious issue impacting the quality of this article. Response: Reference was added to the paragraph. There is needs to be a description of tools previously used to explore lack of reporting. Response: The tool is explained in the paragraph. We used London protocol framework in identifying the factors that lead to patient safety incident reporting that consisted of patient factors, task and technology factors, individual factor, team factor and work environment. Methods Need to explain why using phenomenology and what it means in this context and provide references. Which type of phenomenology? Can you make this claim when you spoke to some for as little as 20 minutes with no follow up? Response: Thanks for your feedback. We revised the methodology and chose qualitative descriptive analysis rather than phenomenology as the basis for our findings. Due to the fact that it is more appropriate than phenomenology. This was a descriptive qualitative study using semi-structured interviews of key informants that was intended to thoroughly explore the point of view of the participant. Inconsistency in calling participants key informants / leaders. Response: Changed from key informants/leaders into participant. The numbers participating should be reported in the Results not Methods section. Response: Table 1 has been moved into Result section No mention of informed consent nor ethical issues (found later at end of Methods section). If you report a participant’s initials and hospital name then they are in effect identifiable – did they consent to such exposure? As they were nominated by someone more senior within the hospital then their identity is known and could have repercussions. Were they provided with an information sheet? Response: We sent the information sheet, informed consent form, and question list a few days before the interview. We discussed informed consent prior to beginning the interview, and once everything was clear, we began the interview. Need to justify the decision to share the questions in advance. Fine to do so, but you must explain and reference. Response: We decided to share the question ahead of time so that the interviewee would feel at ease and familiar with the subject of the interview. And I've inserted the reference. Grammar – ‘the interviews were lasted’. Response: revised into “the interviews lasted …..” Delete the last sentence in the Data Collection paragraph. It is irrelevant and should have been declared in third person. Response: Thanks. The sentence is removed. Data analysis first sentence is repetition from Data collection section. Response: The sentence is removed. Two coder but did they work independently then meet to agree or worked together from the outset? Response: Yes. The sentence has been revised. Table 1 should be in the Results section. Response: Table 1 has been moved to Results section I don’t have access to the question set so cannot relate this to the themes. What was the basis for the questions? There are many validated tools which could have been adopted to allow comparison with other studies – why did you/did you not use such a tool? Response: Thanks for the question. I agree that there has been a lot of research done on similar topics. However, in order to make the interview questions more relevant to the Indonesian context, we decided to develop them in accordance with the National Guidelines for Patient Safety Incident Reporting. The introduction now includes a reference to the guidelines. Last sentence in Data analysis needs more explanation – which lenses? How can you apply different questions from those in the interview? You are adopting an unusual approach to triangulation so must justify and reference. Response: Thanks for the comment. What I mean by different questions is that the interview was semi-structured, and the probe to the next question could be different because hospitals, government departments, and independent institutions all have different roles when it comes to incident reporting. However, I revised the sentence to make it clearer. Results Are the ‘participants’ responses’ in Table 2 verbatim quotes? These are short, do they capture the context for reporting? Response: Table 2 did not contain the quotes but rather summary of the quotes instead. Some quotes are presented in the next paragraphs. Did you do a subgroup analysis of different hospital types and described earlier? Response: As shown in table 2, all hospitals are of the same type: public hospitals. As a result, we did not conduct a subgroup analysis of different hospital types. What is the value of Table 2 being placed before the longer participant quotes? If not including verbatim quotes then it may make more sense to move to after the extended quotes. Response: Thanks for your suggestion. Table 2 is removed after the extended quotes. Tables should appear close after the statement which references the table. Response: Revised. Discussion ‘Updation’ is not an English word – maybe it should be! Response: Sorry for the typo. It should be updating. Revised into: These reforms should include developing a national patient safety strategic plan, establishing priorities, developing a timetable, implementing the plan, monitoring and evaluating policy implementation, and revising and updating the policy. The Discussion section needs a lot more referencing to the related literature throughout. At points it comes across as a personal mission with relating the results to the literature. Response: Some references have been added Conclusion This is very brief. I suggest going back to your original aim and reflecting that in this section. Also indicating any further research which would support development of an improved reporting culture. Response: Thank you for your suggestion. We have revised the conclusion."
}
]
},
{
"id": "127959",
"date": "04 Apr 2022",
"name": "Yohanes Kambaru Windi",
"expertise": [
"Reviewer Expertise I have a background in public health",
"especially health promotion and behavior",
"health system",
"health insurance",
"and qualitative research"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbstract:\nDelete the sentence, “from the perspectives of leaders of hospitals, government departments, and independent institutions.”, as it is already stated in the Method subsection.\n\nA brief statement on how 25 participants were recruited is important to state in the method subsection.\nIntroduction:\nThere are no supporting sources of reference in paragraphs 3 to 6.\n\nIt is stated that “Several studies have identified the barriers that contribute to low incident reporting rates in Indonesian hospitals.” What are they? Give an example of the reports.\nMethods:\nStudy design and sample: Explain why the participants come from the leaders, not others. If the leader then in what level? Why aren't the staff responsible for the reporting task?\n\nI am afraid this sentence, “In regard the reflexivity, the researchers, in particular the first researcher, are interested in patient safety and have performed a number of research studies on the related topic. She has spent her time at the university in Indonesia and has the necessary expertise to examine the cultural and Indonesian context relevant to the research” goes to the introduction section as the background of this study.\n\nTable 2 perhaps add one column to explain who are the participants (what level of management).\n\nProvide the date of Ethical clearance issued.\nResults:\nMore extended quotes will be beneficial to provide a comprehensive picture of the problem of reporting system\n\nConfidentiality of reporting: Provide more quotes from the participants as It is stated “some participants have remarked”\n\nIf possible, place the statement of the three types of informants (organization) for each theme.\nDiscussion:\nSupporting references to the claim of this research should be expanded.\n\nDetail of discussion each theme generated from the analysis will make the manuscript completer and more interesting.\nConclusion:\nA little expansion of the conclusion is needed.\n\nRefers back to the theme drawn in your results. The conclusion needs to state these issues as the contributing factors of under-reporting of a patient safety incident.\n\nAs a factual contribution to this study, would you provide an example of reformation on patient safety incident reporting?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8248",
"date": "25 May 2022",
"name": "Inge Dhamanti",
"role": "Author Response",
"response": "Abstract: Delete the sentence, “from the perspectives of leaders of hospitals, government departments, and independent institutions.”, as it is already stated in the Method subsection. Response: Deleted as suggested A brief statement on how 25 participants were recruited is important to state in the method subsection. Response: More information has been added to the Methods section. Introduction: There are no supporting sources of reference in paragraphs 3 to 6. Response: There are some references in paragraphs 3 to 6 in the form of link as instructed by the Guidelines for Author below: Web links, URLs, and links to the authors’ own websites should be included as hyperlinks within the main body of the article, and not as references. It is stated that “Several studies have identified the barriers that contribute to low incident reporting rates in Indonesian hospitals.” What are they? Give an example of the reports. Response: More information has been provided. Methods: Study design and sample: Explain why the participants come from the leaders, not others. If the leader then in what level? Why aren't the staff responsible for the reporting task? Response: Leaders play critical roles in the development of an effective and efficient reporting system. We felt it was critical to understand the leader's perspective as well. We included the health workers/staff responsible for incident reporting in a separate study. More information is added about the level of leadership. Staff members in leadership positions, such as executives from independent institutions, heads of government organizations such as DHO/PHO, and hospital directors or heads of units, were among the key informants. I am afraid this sentence, “In regard the reflexivity, the researchers, in particular the first researcher, are interested in patient safety and have performed a number of research studies on the related topic. She has spent her time at the university in Indonesia and has the necessary expertise to examine the cultural and Indonesian context relevant to the research” goes to the introduction section as the background of this study. Response: Thanks for your feedback. The sentences has been removed. Table 2 perhaps add one column to explain who are the participants (what level of management). Response: As the name of the organization was revealed, the position of the participants in the table provided clues as to who the participants are. The information has instead been added to the method section. Provide the date of Ethical clearance issued. Response: As this study was part of a larger study, the ethical clearance was dated 10 October 2013, with data collection taking place from 2013 to 2015. Results: More extended quotes will be beneficial to provide a comprehensive picture of the problem of reporting system Response: Thanks for your feedback. We've included some examples of extended quotes in the results section. Table 2, on the other hand, only highlighted the themes and summaries of the quotes. Confidentiality of reporting: Provide more quotes from the participants as It is stated “some participants have remarked” Response: Thanks for your feedback. More quotes have been added in the Result section. If possible, place the statement of the three types of informants (organization) for each theme. Response: In the result section, we have already described each theme and provided extended quotes accompanied by the type of organization. The majority of the benefits of reporting theme, for example, came from government departments and independent agencies that stated that hospitals see no benefit from reporting incidents. Discussion: Supporting references to the claim of this research should be expanded. Response: Thanks for your feedback. Some new references have been added in the Introduction and Discussion sections. Detail of discussion each theme generated from the analysis will make the manuscript completer and more interesting. Response: Thank you for your feedback. We believe there are many other literatures that focus on each theme or the factors contributing to under-reporting; however, in this paper, we want to highlight the differences in leaders' perspectives on the factors. As a result, rather than going into detail about each theme, we classified the factors into two groups and discussed the root cause and potential recommendations. Conclusion: A little expansion of the conclusion is needed. Response: The conclusion has been revised. Refers back to the theme drawn in your results. The conclusion needs to state these issues as the contributing factors of under-reporting of a patient safety incident. Response: Thanks for your suggestion. We revised the conclusion to include more information about the contributing factors. As a factual contribution to this study, would you provide an example of reformation on patient safety incident reporting? Response: In the Discussion section, we provided examples of WHO-recommended reforms that could be implemented in Indonesia. A Malaysian example and the National Health System were also included."
}
]
}
] | 1
|
https://f1000research.com/articles/10-367
|
https://f1000research.com/articles/11-574/v1
|
25 May 22
|
{
"type": "Research Article",
"title": "Mental health care for young people using video games: a pilot RCT on the development of a new intervention method toward Hikikomori and Futōkō",
"authors": [
"Francesco Panto",
"Tamaki Saito",
"Nobuaki Morita",
"Yasukazu Ogai",
"Tamaki Saito",
"Nobuaki Morita",
"Yasukazu Ogai"
],
"abstract": "Background: Young people in their teens and twenties don’t seek treatment immediately for mental health issues. This is due to the perceived stigma linked to mental health, pragmatic inconveniences to reach clinical settings, and the tediousness to seek help or engage with adults in traditional ways. Alternative approaches aside from drugs administration are needed. Method: We conducted an internet-delivered pilot randomized controlled trial directed to Hikikomori and Futōkō experienced subjects. This study aimed to understand the difference in efficacy for an intervention using a fictional story vs factual scientific information (self-aid texts), as well as the feasibility of an internet delivered program .. Evaluation of emotional transportation and mental health related measures were administered at base line before the program and at one week after the completion of the program.\nResults: 40 participants were enrolled. A post-intervention (T2) Independent T-student showed that Emotional Transportation was significantly lower for the intervention group than for the control group at T2. Relaxation was significantly higher for the intervention group than for the control group at T2. For the other outcome variables, the difference was not statistically significant. An ANCOVA showed that there was a significant effect of groups on emotional transportation (lower in the intervention group). There was a significant effect of groups on empathy (lower in the intervention group); for the other variables the effects of groups were not detected. Conclusions: The results showed a significant diminishment in emotional transportation and empathy for the interventional group contradicting the hypothesis that an enhancement of emotional transportation mediates the positive mental health effects. A marginal improvement in relaxation in the intervention group (T-test) was found. In the posthoc analysis, the positive effects on the relaxation of pre-intervention (habitual) high emotional status of participants were confirmed. This trial is registered with UMIN, ID UMIN000044204.",
"keywords": [
"Hikikomori",
"Futōkō",
"gamification",
"fictional narratives",
"play therapy",
"internet delivered mental health treatment"
],
"content": "Introduction\n\nIn our daily lives, we consume entertainment in various forms (movies, drama, anime, manga, concerts). These activities can provide a narrative consumption experience (Andrade & Cohen, 2007; Deighton, 1992; Escalas & Stern, 2003). Data shows how a significant part of the income of an average person is dedicated to entertainment-related activities (Americans spent 5.8% on average) (U.S. Bureau of Labor Statistics, 2020). Entertainment can include emotional melodramas. This refers to a subtype of dramatic entertainment with a focus on emotional depiction, human struggles, and poignant stories (Britannica). The protagonist usually is depicted along with their sufferings and challenges. The protagonist tries to overcome their problems through sacrifice and bravery. This depiction could foster deep emotional reactions in the spectator. This form of entertainment is ubiquitous and very profitable. From a scientific point of view, it is still unclear why consumers enjoy this kind of entertainment so much. Emotional transportation and empathy toward the characters and the story of emotional melodramas could be the key to understanding these psychological effects (Deighton, Romer, & McQueen, 1989). Some research advanced the hypothesis that a difference in individuals’ empathy (high and low empathizers) interacts with the stimulus characteristic (fictional narratives) level of fictionality in determining the extent of transportation developed toward characters of a story. This could influence the overall effects of the fictional narrative in terms of enjoyment (Argo et al., 2008). An important factor in fictional narrative effects could be the extent to which a spectator is absorbed (Green & Brock, 2000; Wang & Calder, 2006) into the narrative world. A lot of research traditionally focused on the effects of marketing and advertising (Aaker & Williams, 1998; Bagozzi & Moore, 1994). Evaluating the effects of emotional melodramas could be useful in identifying moderating factors, like the role of the level of fictionality (Argo et al., 2008). A broader term for emotional melodrama is “Fictional narratives”. This term refers to a creative production that does not include factual information. Watching films or anime, playing video games, and reading novels are all forms of fictional narratives (Busselle & Bilandzic, 2008). Fictional narrative consumption behavior could enhance personal insight, fostering opportunities for self-discovery (Green & Brock, 2002; Oatley, 1999, 2002; Pelowski & Akiba, 2011). The mechanisms with which narrative works influence the spectator are based on theories like the Green & Brock transportation-imagery model or the emotional transportation theory (Green & Brock, 2002), which are considered a possible explanation for these psychological effects. When the consumer becomes emotionally entangled with the fictional characters of stories, emotional transportation occurs. The spectator of fiction, when specific environmental and personal factors are aligned, would reach a state of emotional detachment from reality, and will be transported into a narrative fictitious world. This process is determined by the empathy the spectator feels toward fictional characters and the vivid imagination of the story which is visualized in the mind of the viewer (Van Laer et al., 2014; Coplan, 2004). Spectators who enjoy a large number of fictional narratives could become more empathetic toward people around them (Mar et al., 2006). Fictional stories could function as a simulation of real social interactions, for this reason, fiction consumption behavior could represent an indirect learning experience (Argo et al., 2008). Emotional effects are considered only a part of the narrative consumption experience, a long-lasting cognitive persuasion may also occur from the experience of enjoying fictional narratives (Coplan, 2004). Narratives could also reduce counter-arguing, leading to change in the belief system of the spectator. In other words, a cognitive transformation experience is possible by simply becoming engaged in the fictional narrative’s world (Green & Brock, 2000; Phillips & Mcquarrie, 2010). An important difference must be drawn between analytical persuasion and narrative persuasion, which stems from the fiction consumption behavior (Petty & Cacioppo, 1986). In fact, analytical persuasion based on true facts (factual stories) involves scrutiny and for this reason, is not considered long-lasting; on the other hand, narrative persuasion is not substantially critical, a characteristic that allows narrative persuasion to be more effective (Appel & Richter, 2007; Locke, 1987; Slater, 2002).\n\nA story can be deemed as fiction or nonfiction based on to what extent the pieces of information underlying the story are true or based on true facts. A story can be entirely fictional or mostly fictional with some non-fictional elements in it. Surely the realism of a story seems linked to the responsiveness of the viewer. If a story seems real people are more likely to make self-inferences (Dalager, 1998). The more realistic the story seems to the viewer, a more intense emotional response could occur (Johnson, 2012). The transportation can mediate the psychological effects of a fictional narrative. Green and Brock (2000) defined transportation as a process in which “all mental systems and capacities become focused on events occurring in the narrative” and the subject becomes “lost in a story.” Empathy of the person and the believable degree of the story (Aldoory 2001) could mediate the transportation and absorption into the world of the story. Why is empathy considered a central part of the effects of fictional narratives? Empathy is described broadly as the ability to understand other people’s emotional or psychological situations (Zahn-Waxler & Radke-Yarrow, 1990). Empathy could predict social behavior, so is considered a pro-social emotion (Batson et al., 1995). Empathy has shown to be interesting not only for its social effects but also for its benefits in the realm of marketing. Eliciting empathy in customers during public service advertisements could influence them to react actively to the message. To influence consumer behavior, some researchers have argued that fictional narratives could be useful in eliciting positive reactions and successfully persuading the viewer of an advertising message (Wells & Gavanski, 1989). Empathy felt toward the characters can create a higher level of positive evaluation of the product or message presented in the advert (Shiv, Edell Britton, & Payne, 2004). Factual information presented as a drama can induce more empathy and can lead to more favorable evaluations of the message compared to a presentation of mere facts without a story format.\n\nSome researchers tried to determine whether emotional reactions to fiction like sadness and anxiety are distinguishable or stronger from emotional reactions to fact (Goldstein, 2009). Goldstein explored whether emotional responses to stories presented as fiction versus fact are different. The study also compared emotional responses to stories in film versus sadness experienced in real life. The results showed similarities between emotional responses to tragic events in fiction versus tragic events in real life of the participants. Notably, the level of sadness reported when recalling the events (true or fiction) were identical. This was confirmed even when the life events were particularly tragic, such as a death of a relative or a serious health problem. An important difference was that the emotional experience of a real-life tragic event was characterized by sadness plus an increased level of anxiety. Sadness reported after watching a film or a drama was not accompanied by anxiety. Coplan (2004) suggested a possible explanation for this difference. The sadness of a real-life event tends to linger after the event is finished; in contrast, when a film ends, we know that we can distance ourselves from that world. This can explain why we enjoy watching films that elicit negative emotions. Usually, anxiety is only related to true life events. Goldstein stated that precisely because the fiction-elicited sadness is unadulterated by anxiety, we pay money to watch sad movies. Because we can use the sadness experienced within the movies to understand our emotions and be prepared to deal with it in our real lives, we precisely enjoy fiction. In this light, the negative emotions of a fictional narrative could be cathartic. Regarding the notion that emotional reactions to fiction may be stronger than that to factual information, there are contradicting data. Researchers in this field have no doubt that fictional works can manipulate our emotions. Contrary to factual works, fictional works are organized to stimulate the sympathy of the audience (Mar et al., 2009). A possible explanation for why stronger emotions are elicited by fiction was proposed by Harris (2000) who stated that while watching fiction our appraisal system is quieted. In other words, when we watch fiction, we don’t judge in terms of the realism of the story, so we enter a safe space in which we can express and feel our emotions (Harris, 2000). Keen (2006) stated that nonfiction readers are skeptical and investigative, whereas fiction readers become immersed in the story and tend to believe what they are reading. Fiction has been described as a “safe arena” for experiencing emotions. In fiction we get rid of self-protection and allow ourselves to feel, and being in a controlled environment we can also explore emotions that usually we don’t get in touch with in real life. In fiction, we don’t have to experience the consequences of our emotions in real life (Zunshine, 2006). Fiction can function as a cognitive and emotional simulation of a real-life event but in a safer space. Coplan (2004, 2006) also argued that we tend to emotionally engage with fictional characters because “we feel no obligation toward them”. For example, if we feel sympathetic toward victims of an incident aired in the news, we might feel the pressure to do something to help them. However, with fictional characters, we have no obligation to them once the story is over. Other scientists argue that the emotional reaction to fiction is similar to the non-fiction one because when we consume fiction, we tend to suspend disbelief, and consequently we react to fiction as if it were real. What other effects can we expect from enjoying fictional narratives? Dumbar et al. (2016) explored neurobiological pathways linked to watching emotional dramas. Our enjoyment of comedy might be linked to laughter, as laughter activates the endorphin system (Manninen et al., 2017). This could be linked to a sense of reward and pleasure. Endorphins acting as analgesics increase tolerance to pain. This could explain why we like comedy. We already discussed the tendency to enjoy tragic plots in narratives as well. Emotional arousal triggered by sad stories could also activate the endorphin system. Because the same areas of the brain which respond to physical pain are also involved in psychological pain (Meerwijk et al., 2012). Social rejection or viewing emotionally valanced pictures or music seems to be linked to an elevation in pain threshold, and consequently this can attenuate responses to negative emotional experiences (Kross et al., 2011). Watching a dramatic film could increases pain threshold as well (Weaver and Zillman, 1994). The endorphin system seems fundamental also for its link to social bonding. Endorphins though the C-tactile neural system enhance the sense of belonging we feel when we are part of a group. This system seems to be activated by a plethora of social activities like laughter, singing, and dancing. Dunbar (2016) tested the hypothesis that emotionally arousing dramas increase the sense of belonging to a group. Johnson (2012) demonstrated in two experimental studies, the effects of reading fiction on empathy and prosocial behavior. Reading fiction was traditionally related to educational and moral development (Alexander, Miller, & Hengst, 2001). Mar et al.’s (2006) research focused on the process of empathetic growth that a viewer or reader of a fictional narrative goes through. They discuss how fiction allows the person to learn by acting as a simulation of social experience, especially when the individual emotions are congruent with the story’s character. When this happens, the viewer starts to draw inferences and make predictions about the plot development and the relationships within the story. This indirect experience of the social interactions of fictional characters, according to Mar et al. (2006) could lead to empathic growth. Empathy is considered a multifaceted skill with affective and cognitive components (De Vingemont & Singer, 2006). Specifically, perspective-taking is considered a basic understanding of another person’s thoughts and emotions. Affective empathy and cognitive perspective-taking are considered important components of emotions we feel toward characters. While consuming fiction may foster empathy, from a psychological point of view determining whether these feelings translate into real-world behaviors is worth considering if we want to build a mental health intervention using fiction. The author of this research focused on the construction of a program that implements visual culture for the sake of the mental health of young Hikikomori and Futōkō sufferers. The term visual culture refers to the use of visual stimuli in the communication of a message. Photography, animation, painting, and video represent a few examples of visual culture we encounter in our daily life. Visual culture is not a result of technological development (even if it surely contributed to its spreading). Humans from the Paleolithic Age used images to depict and frame events and emotions. With the technological developments, “visual culture is everywhere” as stated by Mirzoeff (2009). Between television, computers, and tablets, we spend a major portion of our daily life staring at a screen. Albert Bandura’s studies on observational learning can be applied to visual culture (Bandura, 1977). If we consider visual culture as an environmental factor, we can certainly predict that an exposition to visual culture productions can lead to behavioral changes. When people observe famous characters or actors in cinema, series, cartoons, fashion, social media, etc., they exhibit similar behaviors or a tendency to emulate their behavior. This is deemed possible by the emulation of a role model. Individuals’ appearances on television and social media could induce respect and appreciation. The behavior of these famous people or characters can be imitated as model behavior by the spectator. A notorious example was the 2015 ice bucket challenge, following world-famous names, many famous and non-famous people imitated the same behavior to attract attention to amyotrophic lateral sclerosis (Yılmaz & Yılmaz, 2019). Exaggerating a behavior through visuals may cause the behavior to be perceived as model behavior (Berger, 1977). If the behavior is exaggerated and a little unrealistic to the spectator may become more appealing (glamorized). The more a behavior is idealized the more the advertising could become appealing (Åslund et al., 2010). According to social learning theory (Bandura, 1977) reciprocal determinism, when a behavior is imitated, personal factors and environmental factors interact with each other. Imitating a behavior means also changing our life stories.\n\nVisual culture and fictional narratives can also include video games. In recent years video games have become incredibly widespread and represent one of the most popular entertainment media (Entertainment Software Association, 2015). For the mental health effects of video games, inducing motivation seems the most promising benefit. A substantial amount of research confirms this hypothesis (Garris, Ahlers, & Driskell, 2002; Gee, 2003; Hense & Mandl, 2012; Przybylski, Rigby, & Ryan, 2010). The concept of gamification implies the use of video games not only for entertainment purposes but to reach these beneficial effects. The classic definition of gamification is the “use of game design elements within non-game contexts” (Deterding et al., 2011). Gamification can be applied in a variety of contexts, using in-game content to motivate specific behaviors which can be used in real-life situations (Werbach & Hunter, 2012; Zichermann & Cunningham, 2011). Work, education, health, and marketing are some areas in which gamification is successfully used (Arai et al. 2014; Landers, 2014; Jones, Madden, & Wengreen, 2014). Even if there is a lack of theoretical foundation to explain how games affect motivation, empirically there are a plethora of studies demonstrating these effects (Hamari, Koivisto & Sarsa, 2014). We can assume that the use of gamification at least can foster goal-directed behaviors (Schunk, Meece and Pintrich, 2013), by transferring game design elements to non-game environments (Deterding et al., 2011). A few attempts to use video games for mental health include computerized cognitive behavior therapy (CCBT). CCBT has been demonstrated to be effective in treating depression in young people (Pennant et al., 2015). The online approaches using computerized administration can reduce obstacles to reaching the therapy setting (if locations are difficult to reach), represent a low-cost solution, and reduce the stigma linked to help-seeking behavior for mental health problems (Christensen, Reynolds, & Griffiths, 2011). 25% of young people experience depression by the end of adolescence (Kessler et al., 2001). Even if cognitive behavioral therapy (CBT) is considered a first-line treatment, because antidepressant therapy for young people could be risky (Wise, 2019), most adolescents do not seek help despite great impairments in daily life (Mariu et al., 2011). For the difficulties in accessibility and the stigma related to help-seeking behavior in mental health, many young people prefer to access support from relatives or use self-help or internet-based information (Farranda et al., 2006). An example of a successful intervention using a game was made by SPARX. SPARX was made by a team of researchers and clinicians from The University of Auckland. The project was financed by the country in New Zealand. SPARX is an interactive fantasy game that delivers cognitive behavioral therapy to treat depression in young adults. The young player chooses an avatar and travels in a fantasy world dominated by GNATs (Gloomy Negative Automatic Thoughts). A few intervention studies were conducted to verify the effectiveness of this program in reducing depressive symptoms in help-seeking adolescents compared to treatment as usual. In a randomized controlled trial with 187 adolescents with depression, SPARX was found to be non-inferior to standard treatment, so SPARX is a potential alternative to usual treatment for adolescents with depressive symptoms (Merry et al., 2012). SPARX includes seven levels, which teach young people skills like relaxation, problem-solving, and recognizing and challenging negative automatic thoughts with instructions in a play-based learning fantasy environment. SPARX is structured like a game; when the player starts, a “guide” character (a virtual therapist), states the purpose to help young people “who feel down”. In SPARX-R, a modified version for young people, the guide states: “This version of SPARX was made to help young people who are having hassles and feeling down, stressed, or angry a lot of the time. Even if you are doing fine, SPARX can help strengthen your skills for dealing with problems when they do come along” (Fleming et al., 2020). Another game worth mentioning is Pokémon GO. Kato et al. (2017) analyzed the social phenomenon of Pokémon GO and the possible implications for Hikikomori sufferers, hinting at the future of the gamification approach for mental health. Kato et al. found that the game was able to enhance the motivation of Hikikomori(s) to go outdoor and participate in social activities. The researchers stated that they were amazed to see patients who couldn’t go out venture outdoor for the first time and spend their time in parks filled with other gamers.\n\nHikikomori is a socio-medical condition born in Japan and consequently reported in other economically developed countries. Hikikomori features a withdrawal to various extents from social life. Hikikomori people spend the day confined indoors or they go out avoiding social interactions. According to the Japanese Ministry of Health, Labor, and Welfare (Saito, 2010), Hikikomori is defined as “a phenomenological concept referring to a state of avoidance of social participation (e.g., schooling, employment, socializing outside the house) as a result of various factors. In principle indicates a person generally at home for more than six months, however, this concept recently includes subjects who go out in a way that does not comprise socialization with others”. The lifetime prevalence of Hikikomori in Japan is estimated at around 1.2% (Koyama et al., 2010). A Japanese cabinet report (2019) has estimated the actual amount of Hikikomori in Japan as around 1,150,000 subjects (around 1.2% of the Japanese population). Staying continuously indoors is not a necessary feature of Hikikomori. In fact, according to Saito (1998), it is not necessary to be physically restrained indoors to be considered Hikikomori. The Hikikomori phenomenon is profoundly embedded with school refusal or in Japanese, Futōkō. This is true, particularly for young Japanese students. The author’s research aims to arrange an intervention that could be helpful to school refusal as well. An investigation conducted by the Ministry of Education, Culture, Sports, Science, and Technology (MECSST) has shown that amongst 3,315,453 students registered at high schools in Japan, 48,579 (1.5%) did not attend school regularly. These students are called Futōkō students (Aruga, Suzuki, & Tagaya, 2011). Within school refusal students, dropouts were 12,777 (26.3%). “School refusal” is defined as absence from school for more than 30 days in a year. The reasons for the absence exclude illness and financial problems. The Futōkō student generally is reluctant to attend school for psychological or physical reasons, or social traditions. The students not willing to attend school usually have conflicting emotions between the obligation to attend and the suffering in doing so (Saito, 2006). Even though only a small number of students end up not attending school, a study demonstrated that more than 70% of high school students suffer from school evasion feelings (Yamashita, 1998). Students with feelings of school avoidance (FSA) are more prone to exhibit physical symptoms (abdominal pain, low vitality, feelings of irritation, and body fatigue) (Nakamura et al., 2010). The school refusal experience may be the cause of other mental health problems. Factors related to school refusal have been summarized by Aruga (2020). School grade, gender, family composition, and other various physical and psychological factors could be hidden in the background. According to Aruga (2020), significant predictors of the FSA included isolating tendency, perceptions of maladjustment in learning settings, the experience of mental health problems, unsupportive parenting attitudes, having a mobile phone at a younger age, being male, low self-esteem, poorer understanding in the school learning and experience of being bullied. Aruga (2020) stated that it is important to help students to acquire skills to adjust to different relationships and foster self-esteem, especially early when students are in 10th grade. Identifying the students who are being bullied and providing adequate mental health support is deemed fundamental. Listening to students’ and parents’ anxiety and perceptions of maladjustment could bring opportunities for consultation. A lot of effort has been made in developing interventions for school refusal behavior. One big problem is that a significant proportion of school refusers do not meet any diagnostic criteria (Egger, Costello, & Angold, 2003). Similarly Hikikomori youths who totally refuse to go to school are underrepresented in the scientific littérature. There is little empirical evidence showing the effects of interventions. Consequently, intervention studies with this segment of school refusers also are critical. An underrepresented group of school refusers is those who refuse to attend school but engage in activities outside school (staying home to watch television, going to the mall, going to work). These youth often are labeled as “truants” and are considered deserving of punishment (Lyon & Cotler, 2007). Hikikomori and internet addiction is a complex relationship. Some data point out to the internet as an aggravating factor for social withdrawal (Taylor, 2006). Internet addiction and Hikikomori or Futōkō could become comorbidities of each other. From a different perspective using the internet is indeed the only way for socially withdrawn individuals to communicate with real society, and consequently the usage of the internet could be beneficial for their daily life (Lee et al., 2013; Chan & Lo, 2014). It could be a potential way to interact with medical professionals or even represent a means to attend school. In Japan, fictional narrative (mostly in the form of anime and manga) consumption behavior is often associated with the concept of Otaku. Otaku is a “person with specific interests in a genre or a particular type of object. Otaku(s) are generally extraordinarily knowledgeable about their field of interest and heavily passionate, but usually lack in social common sense” (Kam, 2013). In Japan, specifically, Otaku(s) show high consumption of anime or manga productions and related goods. The relationship between socially withdrawn behavior and Otaku is complicated and not yet elucidated. Saito T. (2019) suggested that Hikikomori individuals often appear reluctant to be labeled as Otaku. There is indeed a social stigma linked to this concept within Japanese society (Saito, 2009). In fact, young Otaku(s) in their school years tend to be bullied due to the “school caste system” in Japanese schools that condemn Otaku(s) as inferior and not able to communicate with others. For this reason, younger Otaku(s) may tend to become Hikikomori later in life, developing an inferiority complex toward the mainstream society. From these factors, we can assume that part of the Hikikomori community consumes fictional narratives habitually. The authors (Panto et al., 2021) previously tried to understand if Hikikomori individuals with habitual consumption of fictional narratives do or do not exhibit psychological benefits. We found a possible correlation with empathy and relaxation (Panto et al., 2021). With this pilot interventional study, we want to explore a beneficial relationship with a form of remote narrative therapy using an original game to help these subjects.\n\nInterventions for Hikikomori are considered very complex and are based on a multi-disciplinary approach. The family intervention considered most effective is the four-grade step by step approach (Saito, 2020). Family members of a Hikikomori have difficulties in approaching the patients primarily for the lack of knowledge about the mental health topics of Hikikomori and the stigma toward this phenomenon (Kato et al., 2017). Is considered important for relatives and family members of Hikikomori to understand this phenomenon and to learn the appropriate skills and knowledge to help Hikikomori patients. For instance, Kubo et al. (2020) developed a 5-day Hikikomori Intervention Program for a family of Hikikomori Patients. The program was inspired by Mental Health First Aid (MHFA), an educational program developed in Australia in 2000 by Langlands et al. (2008). The aim of the program is to increase mental health literacy and to provide coping skills to people who deal with mental health problems. Another educational program dedicated to family members of Hikikomori is the CRAFT Program (Community Reinforcement and Family Training). This program was originally conceived for substance use disorder families (Smith & Meyers, 2004). Sakai later modified the program to adapt to Hikikomoris’ needs. These kinds of educational programs help to target problematic behaviors within the family dynamics. Parental criticism and aggressive behavior from the Hikikomori person are considered the core behavioral problems. With the right interventions problematic behaviors can be targeted and corrected to foster more appropriate interactions within the family (Hanley, Iwata, & McCord,2003). Kubo et al. (2020) arranged a combination of MHFA and CRAFT to support family members of Hikikomori sufferers, and they successfully demonstrated the effectiveness of the program with a single-arm open trial. Matsuguma and Niemiec (2020) proposed an interventional program for Hikikomori using strengths-based theory. Matsuguma presented the results of this attempt in a case study. Psychological strength was defined as “a pre-existing capacity for a particular way of behaving, thinking, or feeling that is authentic and energizing to the user, and enables optimal functioning, development, and performance” (Proctor, Maltby, & Linley, 2010). This skill can be fostered by helping the individual to manage feelings, thinking, and behavior, avoiding overuse or underuse of strengths. For example, overuse of kindness can turn into emotional promiscuity; underuse of kindness can turn into indifference (Freidlin, Littman-Ovadia, & Niemiec, 2017). Psychological strength is considered good for improving self-esteem (Proctor, Maltby, & Linley, 2010) as well as decreasing sadness and hopelessness in patients with suicidality (Huffman et al., 2014). The authors describe a case of a 17-year-old male who became Hikikomori at age 9, firstly refusing to go to school. He felt oppressed by a conformity-valuing school culture and strict school rules. Since he started to shut in, he used to play online video games for seven hours a day and he usually slept during the day. Using positive and strength psychology a team of psychologists started to listen to his stories about his accomplishments during the online video game experience. According to the criteria for strengths-spotting (Kondo et al., 2013), the psychologist identified his strengths and helped him to recognize his positive experiences in the video game. For example, he played 50 vs. 50 match-type games via a network when he was 13. This game required team play, and he was very good with other people in the video-game world. The patient gradually realized his own strengths for the first time. In this case study Matsuguma et al. (2019) used a strength-based approach, where the psychologists tried to shift the focus from the patient’s strengths in the online video game to the real-world. Starting to acknowledge his successful experiences in video games, the client starts to reconstruct his identity from a positive viewpoint. His self-esteem increased and his depressive symptoms decreased. For school refusal the main treatment usually includes psychosocial interventions. Most of the interventions implement behavioral and cognitive strategies to reduce psychological symptoms associated with school refusal and increase attendance. Behavioral strategies include positive reinforcement with gradual exposure to the school environment (Gosschalk, 2004; Moffitt, Chorpita, & Fernández, 2003). Social skills training to cope with negative school situations has also shown promising results (Gosschalk, 2004; Moffitt, Chorpita, & Fernández, 2003). A combination of psychosocial interventions or “package” seems the more feasible approach in most cases. Hospitalization, psychotherapy, and the use of tranquilizers are also an option when necessary (Blagg & Yule, 1984). Behavioral strategies include in-vivo progressive exposure to school, relaxation training, and contingent reinforcement for school attendance; cognitive strategies include recognizing distorted cognitions and structuring coping plans. With these kind of strategies improvements in anxiety, depression, externalizing problems, and self-efficacy for handling school situations are expected. Individual cognitive-behavioral therapy (ICBT) has been demonstrated to be more efficacious than “placebo” (Seligman & Ollendick, 2011). A series of promising interventions are internet-based approaches. Particularly for the nature of Hikikomori and school refusal sufferers who often shut-in and are difficult to be reached with traditional clinical approaches. For example, C-BED (Community-Based Enterprise Development), an internet-based educational tool produced conjointly by the Japanese Ministry of Health Labor and Welfare (MHLW) and International Labor Organization Bangkok (ILO), pioneers an innovative community development methodology. Yokoyama et al. (2019) demonstrated that C-BED allows a peer-to-peer learning experience, enabling young people with a similar social status to share common feelings. They can create an online community and interact in a comfortable environment without the need for any medical authority. This can also make the hierarchical relationship that typically exists between the patient and physician more equal. Overcoming the psychological barriers of external intervention can be fundamental for Hikikomori sufferers. The C-BED program for Hikikomori consists of several modules. The users can interact with each other through text dialogue with online-group chat, which is a very popular way of interacting with young people. Using text dialogue in an online interaction is useful to manage social anxiety and interpersonal fears typical of Hikikomori. The modules also use Dialogical Behavioral Therapy (DBT) approach (Toyota, 2016). Specific online workshops target habitual behaviors of Hikikomori, and the 24-hour accessibility encourages the users to exchange their ideas. The online workshops do not require physical commuting and so are ideal to break the ice of social interactions of socially impaired individuals. The modality of online workshops is surely positive for the above points compared to face-to-face sessions, but cognitive-based tasks when human-to-human interaction is important could show some limitations. Also, the final goal of these kinds of therapies is the reintegration of the person into society, so online support should not be the final goal of psychotherapy for Hikikomori. We already discussed the complicated relationship between Hikikomori, school refusal, and internet usage. A reiterated preconception is the risks of internet addiction for socially recluse people and its detrimental mental consequences. Tateno et al. (2019) noted that there was a trend of male users with internet addiction and gaming, while females with internet addiction preferred the usage of social networking sites (SNS). Subjects at risk for Hikikomori had longer internet usage time and higher scores on internet addiction scales. Males often isolate themselves from the social environment to engage in online gaming while females use the internet so as to not be excluded from their online communities. Internet addictions and Hikikomori is often considered as an interchangeable pair. The reality is that internet usage often represents the only social window for socially withdrawn subjects. Through the online community, they can maintain peer social relationships, participate in work and school activities, as well as take psychotherapy sessions. For example, a major success in using the internet for mental care is the use of internet-delivered CBT for major depression (iCBT), which is increasingly becoming an option (Andersson et al., 2019). iCBT can be delivered with or without therapeutic support, and we can distinguish between guided and unguided iCBT. Unguided CBT is performed entirely without health provider interaction, representing a more affordable therapy (Fairburn & Patel, 2018). Some studies showed better outcomes than the guided one (Cuijpers, Reijnders, & Huibers, 2019). However, a systematic review conducted by Karyotaki et al. (2021) showed that even if guided iCBT was associated with more effectiveness than unguided iCBT for individuals with severe and moderate depression, unguided iCBT was associated with similar effectiveness of guided iCBT in individuals with mild/sub-threshold depression. The correct choice between personalized treatment selection is necessary to ensure the best allocation of guided and unguided CBT, and must rely on the severity of the symptoms. For the definitions, unguided iCBT is defined as CBT delivered via the internet where the only support available is automated and related to technical issues. No support related to the therapeutic content is available. Guided iCBT is defined as CBT delivered via the internet that allows therapeutic support, delivered by a professional or a paraprofessional staff (non-specialists in mental health care but trained to deliver iCBT). Findings in a systematic review and meta-analysis (Karyotaki et al., 2021) of 39 studies comprising 9751 participants showed that individuals with mild/sub-threshold depression were associated with little or no benefit from therapeutic guidance, while guided iCBT was associated with more effectiveness in individuals with moderate and severe depression. Both iCBT modalities outperformed the rreatment-as-usual (TAU) regardless of depression severity. Even if guided iCBT was associated with greater results compared with unguided iCBT. The benefits from the iCBT without therapeutic guidance on mild depression and the consistent low costs could considerably expand treatment coverage of depression worldwide. The authors are planning to build an innovative form of psychological intervention using fictional narratives; in this case, an original game was produced according to the style of Japanese animation productions. Some worth mentioning similar programs which showed efficacy in the form of an entertainment tool are play therapy (sense of well-being and psychological capital) (Chan, 2019), and SPARX (a new computerized cognitive behavioral therapy intervention) which showed efficacy in reducing depressive symptoms in adolescents (Merry et al., 2012).\n\n\nMethods\n\nThe current study was approved by the Bio-Ethical Committee of Tsukuba University on 29th June 2021(ethical approval number 1612).\n\nWritten informed consent for publication of the participants details was obtained from the participants via the participation form.\n\nSince little research has examined the effectiveness of an original narrative program in a form of a game with young socially impaired individuals, the following study was performed to provide a preliminary assessment of the effectiveness of such intervention and an exploration of the feasibility and compliance amongst youngsters with this kind of mental health intervention. This study aimed to investigate: (i) the ability of an original narrative program in the form of a game to enhance participants’ empathy skills and consequently psychological well-being; (ii) whether the participants could finish the program without dropping out, as the novelty of this program was to entertain participants while providing empowerment of their psychological well-being; (iii) explore if a program using fictional narratives in a way to enhance emotional response (emotional transportation) could be as meaningful as the attempts to enhance cognitive pathways, for example in the internet-delivered CBT program, SPARX. The trial was registered at UMIN-CTR with the following ID UMIN000044204. No changes were made in the protocol after the registration of the study.\n\nAs a universal pilot study, strict inclusion/exclusion criteria were not used. 40 individuals with social withdrawal experience (Hikikomori or school refusal) who met the criteria of (i) being Japanese residents; (ii) speaking Japanese; and (iii) self-reporting a social withdrawal experience in the past were enrolled in this pilot study. Participants were required to fill out a participation form online to request participation in the study. After the authors confirmed the participant’s mail address and age (people under 20 were not suitable for this study being considered minors in Japan), participants were randomly assigned to the intervention or control groups. In this study, the goal of the new intervention method was not to make the socially withdrawn individual participate in society in a traditional sense, rather, it was to help the participants to enhance their emotional coping mechanisms to deal with their daily life challenges and to maintain a positive sense of well-being. The selection criteria were: i) having experienced social withdrawal or school refusal in the past or currently (based on self-reporting); ii) having an internet connection and a computer with the specs to download and play the game; iii) being 20 years of age or older; iv) understand the main purpose of this study and can give informed consent to participate in this study. The exclusion criteria were: i) the inability to self-identify as having experienced social withdrawal or school refusal; ii) being under 20 years old.\n\nAn original visual novel game Believe Your Light (Figures 1, 2) was produced using a visual novel games software (Visual Novel Maker by Degica, 2017/11/16) and was used in this pilot study to explore the psychiatric efficacy of this program in improving mental health (empathy, general psychological health, self-esteem, mood). The game was expected to take around 8 hours to finish, the participants could access the game and save their progress at any time, for this reason, they could finish the game in several sessions. The technique utilized to set the characters and the story was a novel technique invented by the first author (Francesco Panto), called Anime Ryōhō © (アニメ療法), based on the structure of a fictional story with fictional characters who overcome mental health struggles and become empowered by their experience. We compared the effects of this novel program to a program using self-education tools consisting of self-aid written brief manuals published by the Japanese Ministry of Health and Welfare. A visual novel game is a form of game entertainment that allows the player to engage with the story presented in the form of 2D illustrations while reading the text like a novel (in this work, the character’s next line changes depending on the choices, but the ending of the story does not). The game used in this study is a game with original characters and a storyline that unfolds while the player clicks in the dialogue window. For the two original characters, we used two original illustrations appositely commissioned and copyright-free music, sound effects, and background images. During any playing time, the screen displayed a background image, a standing picture of the original character changing expression based on the story development, and a message box containing the character’s dialogue. Visual novel games are mainly based on reading a text like a novel, and players can engage with the story through their choices in in-game dialogues while enjoying music and the characters’ story. The story of each of the two characters in this work consisted of 10 chapters and was structured like a “growth story” or “coming-of-age story”. Each of the two-character main protagonists had difficulties in daily life based on a psychological problem. In the first three chapters, the characters talk about their problems through daily life and show their struggles through unfortunate events. In the fourth and fifth chapters, the negative emotions reach their peak, and the characters lose the power to move forward and the desire to do their best. In chapters six to seven, through some sort of catalyst (self-enlightenment, help, and support of the relationships around them, etc.), the characters regain confidence in themselves and become more positive. Chapters nine and ten introduce the new lives of the characters who have been transformed in both mind and body.\n\n(Character concept credits to Panto Francesco, Character illustration credits to Akage Illustration).\n\nThe material used in this study was public documents prepared by the Ministry of Health, Labor, and Welfare consisting of self-aid texts for mental health. We used a total of five documents: Resource 1. Cognitive Therapy and Cognitive Behavioral Therapy for Depression (Resources for Patients); Resource 2: Mental Health Awareness Tips; Resource 3. Stress Reduction Know-How; Document 4. Health Education IV: Ministry of Health, Labor, and Welfare Excerpts (136-146); Document 5. Health Guidance Leading to Behavior Change - Behavioral Therapy for Lifestyle Improvement Resources 1-4 and Document 5 are available on the Ministry’s website (Ministry of Health, Labour and Welfare, Japan).\n\nGeneral Health Questionnaire – 28 (GHQ-28). The General Health Questionnaire – 28 (GHQ-28) Japanese version (Maruyama, Sato, & Morimoto, 1991) is a self-report questionnaire used to screen psychological wellbeing, as well as to detect possible psychological disorders. The GHQ-28 identifies: (1) the inability to carry out normal functions; and (2) the appearance of new and distressing phenomena (Goldberg & Hillier, 1979). Factor analysis of the GHQ-28 identified four 7-item subscales: somatic symptoms (items 1-7), anxiety/insomnia (items 8-14), social dysfunction (items 15-21) and severe depression (items 22-28). A high correlation exists between the anxiety subscale and the total score. Researchers stated that this could show that anxiety is very common in many psychiatric disorders (Goldberg & Hillier, 1979). Subscales are not independent of each other, so the scale is used as a total score to identify the existence of psychiatric symptoms compared to the state of a healthy individual (Salter et al., 2013). For scoring, the individual is asked to rate how he/she feels according to the following criteria: better than usual, same as usual, worse than usual, or much worse than usual. One of the most common scoring methods adopts a Likert scale of 0 to 3, resulting in the score range varying from 0 to 84 (higher scores are indicative of worse mental conditions). For this study we scored from 1 to 4, with 1; “nothing at all” and 4 “frequently”. This Likert scoring system was implemented in the original 60-item GHQ (Goldberg & Hillier, 1979). A score ≥5 has been suggested to hint at a possible psychiatric disorder (Anderson et al., 1996).\n\nRosenberg Self-esteem scale. Rosenberg Self-esteem scale, (Rosenberg, 1965) is a 10-item scale that measures global self-worth assessing both positive and negative feelings about the person’s perception. In this study, we used the Japanese version of the scale (Umegaki, 2017). The scale is uni-dimensional, and all items are scored using a 4-point Likert scale format ranging from strongly disagree (1) to strongly agree (4) (strongly agree, agree, disagree, strongly disagree). Items 2, 5, 6, 8, and 9 are reverse scored, where “strongly disagree” gives 1 point, “disagree” 2 points, “agree” 3 points, and “strongly agree” 4 points. Higher scores indicate higher self-esteem. Factor analysis identified a single factor. All the 10 items of the Rosenberg Self-Esteem Scale are not equally discriminating and are considered to be differentially related to a different aspect of self-esteem. People with high self-esteem are considered to be more likable and attractive and tend to build better human relationships compared to people with low self-esteem. At the same time, some other measures seem to contradict these assumptions. Narcissists are very charming at first but tend to alienate others and disrupt relationships in the long run. Self-esteem has not been confirmed to predict the quality or duration of relationships. Leadership could have an indirect relation to self-esteem. Self-esteem has shown strong a relation to happiness regardless of stress and other circumstances, and high self-esteem can lead to greater happiness. Low self-esteem is more likely to lead to sadness and other negative emotions (Baumeister et al., 2003).\n\nShort-form self-report measure to assess relaxation effect (S-MARE), (Sakakibara et al., 2014). S-MARE is a self-report scale used to assess relaxation. The scale is based on the Relaxation Inventory (Crist et al., 1989). In the item, we can find three subscales (a) physiological tension, (b) psychological relaxation, and (c) anxiety. For each sub-scale, the Cronbach’s coefficient was .93, .94, and .85, indicating a sufficient reliability in measuring relaxation. S-MARE scores were significantly correlated with the Emotional Relaxation Scale (Tokuda, 2011) (r=.446) and with State Anxiety (r= -.531) (N=172). S-MARE has shown reliability regarding the correlation with the cardiac parasympathetic tone (physiological reaction to relaxation stimuli). S-MARE is indeed a valid measure to assess relaxation effects. Normally the assessment of the relaxation effect is carried out after the exposure to a relaxation stimulus evoked by a relaxation technique. For this study, we ask the participants to recall the relaxation state they experienced at the moment of the questionnaire filling. The instrument is a 5-point Linkert scale with scoring ranging from strongly disagree (1) to strongly agree (5).\n\nMultidimensional Empathy Scale (Suzuki & Kino, 2008). The Multidimensional Empathy Scale (MES) is a Japanese 24-item self-report scale to assess the 5 dimensions of empathy. The instrument is a 5-point Linkert scale with responses ranging from “not fitting at all” (1) to “fitting a lot” (5). The scale can assess self/other-orientation of either cognitive or emotional components of empathy. The five dimensions are 1) other-oriented emotional reactivity, 2) self-oriented emotional reactivity, 3) emotional susceptibility, 4) perspective taking, and 5) fantasy. The internal consistency indexes for every sub-scale were.71.60.78.69.70. The Japanese version was validated by several studies and each of the five sub-scales demonstrated a solid relationship with commonly used scales like Interpersonal Reactivity Index (IRI) or Questionnaire Measure of Emotional Empathy QMEE (Mehrabian & Epstein, 1972).\n\nJapanese Edition of Profile of Mood States (POMS) (Akabayashi et al., 1990). POMS questionnaire is a standard test used to measure mood. The first POMS questionnaire was developed in 1971 by Douglas et al. (Spielberg, 1972). The questionnaires consist of a series of descriptive words/statements that describe people’s common feelings. The most commonly used version is the POMS 2, which is suitable for adults aged 18 years and older (POMS 2–A) and another for adolescents 13 to 17 years of age (POMS 2–Y). Both POMS 2 instruments are available as full-length (65 items) and short versions (35 items). In this study, we use the short version (35 items). The subjects are asked to answer based on how they feel in that moment. The score uses a 5-point Likert scale, ranging from “not at all” (0) to “extremely” (4). The only exception is two esteem-related affect subscales which are reverse-scored. A total mood disturbance (TMD) score is calculated by summing the totals for the negative subscales (tension, depression, fatigue, confusion, anger) and then subtracting the totals for the positive subscales (vigor and esteem-related affect). The Japanese edition of POMS was translated from the original version (65items) by McNair et al. (1971). In the Japanese version, six mood scales were measured: depression-dejection, vigor, anger-hostility, fatigue, tension-anxiety, and confusion. The POMS scores correlated with the SADS scores (schizophrenia).\n\nNarrative Transportation Scale (NTS- J). The Japanese version of the scale (Osanai & Kusumi, 2016) was used in this research. NTS-J consists of 12 items in a seven-point scale from “not fitting at all” (1) to “fitting perfectly” (7). Transportation into a fictional narrative’s world is considered a psychological mechanism that can affect beliefs. The transportation experience includes elements such as imagery, affect, and attentional focus. The NTS-J was developed by Green and Brock (2000). A shorter version of the same scale was developed by Appel et al. (2015). Green and Brock argued that transportation is associated with story-consistent beliefs. In this light, highly transported participants have beliefs more consistent with the story consumed and showed a more positive evaluation of the fictional characters. The persuasion effects of narratives have been strongly suggested. A highly transported individual is persuaded to change their real-world beliefs in response to the fictional world experience (Osanai & Kusumi, 2016). Additional studies of the Japanese version of the scale showed the reliability of the scale and the correlation in measuring imaginative involvement and literary response (Bal et al., 2011). Osanai & Kusumi’s scale required the narrative task “Kin no Wa” and “Chiyogami no Haru” to the respondents. For this study, we instructed the participants to answer accordingly to their habitual emotional response to fictional narratives.\n\nWe conducted a randomized controlled study from August 2021 to November 2021. To test the research hypothesis, we chose a group of patients with a past of social withdrawal problems (like Hikikomori and Futōkō sufferers), because of the probable affinity of these subjects towards the use of fictional narratives in their daily life (Panto et al., 2021). Panto F. was responsible for the recruitment and randomization. The study was designed as a single blinded one in which only the participants weren’t aware of the difference between groups. The flyer sponsored the opportunity to play the game regardless of the groups affiliation (control group participants were granted to play the game after the completion of the questionnaire at T2). To encourage the participation of these subjects in the research program and considering that the authors want in the future to make this type of intervention available as a game application to be downloaded from the internet, the recruitment process took place both on- and offline and the study took place online. The authors produced a flyer with an explanation about the research and a QR code of the participation internet site embedded. The flyer was distributed in several psychiatric clinics in Kanto, as well as non-profit help groups for Hikikomori and school refusal sufferers. In addition, the PDF of the flyer was uploaded online to sites dedicated to Hikikomori and school refusal subjects for a limited time, with the help of the managers of these sites. Once we ascertained the consent of the subjects to participate via the participation form, we proceeded with randomization, randomly assigning each subject to the intervention or control group. Each subject participates via email, a nickname, age, and sex. Any other personal information was not recorded. After randomization using a software (program randMS, software Filemaker Pro Advanced®), each subject was assigned a password to access the part of the site dedicated either to the intervention program or to the control program. Subjects assigned to the intervention program did not have access to the part of the site devoted to the control program and vice versa. Subjects were instructed to complete the evaluation questionnaire immediately before the program (T1) and one week after they finished participating (T2). After data collection, we provided a participation incentive (a 2500 JPY prepaid card accessible via mail) to all participants who completed the program and the questionnaires. The trial protocol is shown in Figure 3.\n\n\nData analysis\n\nTo test the hypothesis that participants with past and current Hikikomori and school withdrawal experience who received the fictional narratives intervention would improve their mental health condition after 1 week (T2) through an enhancement of emotional transportation more than the control group, an independent samples t-test and ANCOVA analysis were performed. Afterward, to investigate the role of high emotional transportation of the participants (before intervention) on mental health (all other variables except emotional transportation) we conducted a post hoc analysis using ANCOVA, inputting groups, and the score of emotional transportation at T1 as median split as fixed factors. The level of statistical significance was set at p<.05. All data analysis was performed using SPSS v. 25 (IBM SPSS Statistics, RRID: SCR_019096).\n\n\nResults\n\nThe study began in August 2021 and ended in November 2021. 40 participants (18 female, 22 male, mean age 33 years; SD 10.1) completed the study (maximum 60 years, minimum 20 years). 16 of the 40 participants were in the intervention group and 24 in the control group. Participants were both Hikikomori and Futōkō based on self-reports. Surveys were administered at Time 1 (immediately prior to program participation) and Time 2 (one week after program participation). A total of 61 participants were enrolled in the study (24 in the control group and 37 in the intervention group). 21 participants were excluded from the analysis due to dropping out (only the T1 survey was completed). The remaining 40 participants (16 in the intervention group and 24 in the control group) completed the program and the follow-up survey at T2 (one week after the completion of the program), consequently, they were suitable for the analysis. With regard to the multi-dimension empathy scale (MES) used in the study to assess empathy, due to a technical problem in the online questionnaires only data for three of a total of five sub-scales were collected (precisely self-oriented emotional reactivity, perspective taking, and fantasy). Other-oriented emotional reactivity and emotional susceptibility were excluded from analysis. The participants’ descriptive statistics are shown in Table 1. The means of the scores of each variable at T1 and T2 for intervention and control group are shown in Table 2. To investigate if the pilot study of fictional narratives intervention would improve the mental health condition of Hikikomori and Futōkō experienced participants, after 1 week (T2), through an enhancement of emotional transportation, we conducted an independent T-student and an ANCOVA analysis of variance. As shown in Table 3, a pre-intervention (T1) independent T-student test indicated that there wasn’t any significant difference between the two groups, confirming that randomization process occurred correctly. Consequently, a post-intervention (T2) independent T-student was conducted to explore the effects of intervention on participants (Table 4). The results shown that emotional transportation was significantly lower for the intervention group (Mdn=39.56) than for the control group (Mdn=47.37) at T2, t (38) = 2.42, p = 0.02 (2 tail). Relaxation was significantly higher for intervention group (Mdn=48.5) than for the control group (Mdn=42.16) at T2 t (38) =-1.539, p=0.03 (1 tail). For the other outcome variables, the differences were not statistically significant. An ANCOVA analysis was conducted to confirm further the effects on outcome variables (Table 5). The score of emotional transportation at T2 of the control group was significantly higher (n=24, mean=47.37) than in the treatment group (n=16, mean=39.56). Additionally, within the treatment group, the score of narrative engagement was higher at T1 (n=16, mean=46.87) than T2 (n=16, mean=39.56), indicating a lowering of narrative engagement in the intervention group. There was a significant effect of groups on emotional transportation F (1,37)=6.37p=0.016. The score of empathy in T2 of the control group was higher (n=24, mean=51.37) than in the treatment group (n=16, mean=47.62), indicating a lowering of empathy in the intervention group. There was a significant effect of groups on empathy F (1,37)=7.43 p=0.010. For the other variables, the estimated marginal means of general health at T2 of the control group was higher (n=24, mean=76.75) than in the treatment group (n=16, mean=75.43). The estimated marginal means of relaxation was higher at T2 for the intervention group (n=16, mean=48.5) than for the control group (n=24, mean=42.16). The estimated marginal means of self-esteem was lower at T2 for the intervention group (n=16, mean=24.06) than at T2(n=16, mean=24.16). The estimated marginal means of mood states was lower at T2 for the intervention group (n=16, mean=79.43) than T2(n=16, mean=79.95). However, the difference between groups was not significant for any variable and the effects of groups was not confirmed. A post-hoc analysis, to examine the effect on outcomes of high emotional transportation of participants pre-intervention on the outcome’s variables, was conducted. T1 scores of emotional transportation were classified into high and low groups by median split, and the relationship with each outcome score T2 was explored. The results in Table 4 showed that the main effect of emotional transportation T1 was significant in relaxation in T2 F (1,35) = 4.68p=0.037. This indicates that higher pre-intervention emotional transportation was associated with higher post-intervention (Table 6).\n\n\nDiscussion\n\nThis pilot study wanted to explore the possibility of positive mental health outcomes for people with a history of social impairment by an original visual novel game. The technique implemented in the game comprises the depiction of a story in which the protagonist goes through difficulties and eventually finds a way to cope with their inner struggles. We expect that using a story with fantastic characters in the form of a game with visuals and musical effects to convey emotional reactions would be more effective than a self-aid educational lecture about mental health. In other words, we explored the effects of emotional transportation versus cognitive persuasion. At the same time with this pilot study, we tried to find a way to structure a story of an original fictional narrative that can be not only entertaining but also constructive for the spectator or player’s emotional sphere. The results showed a significant diminishment in emotional transportation and empathy (although the empathy scale lacked two sub-scales) for the interventional group versus the control group, contradicting the hypothesis that an enhancement of emotional transportation mediates the positive mental health effects for the original game used in the pilot study. At the same time, the mean values of outcomes related to mental health (general health, relaxation mood states, except for self-esteem) showed a slight tendency to improve for the interventional group. This was true especially for relaxation even if the effect is marginal and only detected in the T-test. In the posthoc analysis the positive effects on relaxation of pre-intervention (habitual) high emotional status of participants were confirmed. This result was previously suggested by Panto et al. (2021). Green and Brock (2002) have previously discussed how difficult it is to manipulate emotional transportation in an enhancement direction. According to the same authors, creating a diminishment in emotional transportation is relatively easy to achieve; this phenomenon was called “disrupting narratives”. Further studies with a better participation design are needed to better clarify the meaning of this pilot study. In the first place, the rationale beyond this study was to explore the difference in persuasion effectiveness depending on the emotional or the cognitive pathway. The influence of an argument differs between narrative stories and non-narrative texts or simple lists of points (Gebbers et al., 2017). The influence of stories has been attributed to subjects’ deep immersion in the story word (flow experience) (Gerrig, 1993; Green & Donahue, 2009). This experience has been defined as Transportation by Green (2004) or Narrative Engagement by Busselle and Bilandzic (2008). Transportation is considered a psychological state depending on several factors, some situational, such as watching a movie alone and paying attention (Tal-Or, 2016), having previous information about the story obtained prior to engaging (Dixon, Bortolussi, & Sopčák, 2015), as well as individual propensity to get transported into the story world. For example, Appel and Richter (2010) argued that individuals more in need of affection are more transported than individuals low in need of affection. Some researchers suggested that we can define a “Transportability” trait, referring to a latent predisposition to be emotionally transported to a story (Mazzocco et al., 2010). The effects of stories on the attitudes of subjects have been examined in a variety of fields, such as attitudes toward minorities (Green, Brock, and Kaufman, 2004; Johnson, 2012), attitudes toward consumer brands (Kim, Ratneshwar, & Thorson, 2017), and climate changes attitudes (Jones, 2013). In the fields of health and health-related behavior, the effects of stories have been analyzed as well. This has included sun protection (Dunlop, Wakefield, & Kashima, 2009), organ donation (Reinhart et al., 2007), and binge drinking (Van Leeuwen et al., 2016). On the other hand, we have social cognition models of behavior that emphasize social cognition and cognitive functions in the persuasion process (Conner & Norman, 2015). We used the control group nonfictional text to focus on evaluation and cognition in the attitude change of subjects instead of transportation. Besides positive or negative mental health effects, we expect an enhancement of emotional transportation or empathy for the subjects of the intervention groups who engage in a story with high content of fiction. Instead, we measured a diminishment in emotional transportation. As stated by Green, Brock, and Kaufman (2004), this process could be ascribed to “disrupting narratives”. It is in fact extremely difficult to manipulate transportation as suggested in previous studies. Engagement and emotional involvement in the narrative proved difficult to manipulate. Attempts to increase transportation have been unsuccessful many times (Green, Brock, & Kaufman, 2004; Green & Brock, 2000). However, in one of Green and Brock’s (2000) experiments, they succeeded in reducing transportation by having the participants perform distracting tasks while reading a narrative work. Thus, it may be easier to reduce engagement than to increase it. It seems easier to use distracting factors to decrease the focus on the story and consequently transportation. With the design of this study (completely internet-delivered, based on self-report about the timing of follow up) we were unable to observe the participants, determine whether the instructions were followed, or provide an environment that would facilitate the focus of the participants on the appreciation of the narrative work. So, a lot of distractors could have played a role in this diminishing effect. Banerjee and Greene (2012) analyzed the differences between first and third-person narratives in terms of emotional transportation and found that there wasn’t any difference whether the story was narrated in the first or a third person. This study explored anti-drug persuasion obtained through emotional transportation. According to the authors, greater transportation was associated with stronger anti-cocaine expectancies. Another interesting result of this research was that the effects of transportation toward anti-cocaine expectancies (health education), were mediated by greater sadness and lower contentment. A high level of transportation was associated with a higher level of sadness, but a higher level of sadness was associated with a lower level of anti-cocaine expectancies. Traditionally researchers indicated a positive association between sadness and positive persuasive outcomes (Dillard & Peck, 2000). Sadness is defined as a withdrawal emotion, the action tendency of sadness is inaction or withdrawal (Dillard & Shen, 2005). If a fictional story elicits too much sadness, the behavioral change could be hindered, being that too much sadness led to inaction. Instead, according to Banerjee and Greene (2012), lower levels of sadness were associated with stronger persuasive outcomes. In this light the story used in this pilot study could elicit a lower level of sadness and maybe more contentment, being associated with lower emotional transportation but better health outcomes (relaxation, etc.).\n\nIt has been suggested that the effects of narrative persuasion (thus emotional and behavioral change) may mediate the so-called sleeper effect (Eagly & Chaiken, 1993). In this case, it is possible that the changes caused by the intervention program will not be highlighted unless the participants are followed up a few months after the program. The sleeper effect is one of the psychological phenomena related to persuasion. In general, the effect of persuasive communication gradually increases over time, beginning immediately after the viewing of the persuasive message. The sleeper effect is thought to occur when a persuasive message is accompanied by a contradictory cue (discounting cue) like an unreliable source or strong expectancies toward the persuasion. Normally when a subject is exposed to a persuasive message (e.g., an attractive and persuasive television advert) in the normal course of events, supportive attitudes toward the message increase immediately after receiving the message. Over time, however, the newly formed attitude gradually returns to the attitude held before receiving the message. This process of normal decay of persuasive messages appears to be the most frequently observed longitudinal pattern in the study of persuasion (Eagly & Chaiken, 1993). On the other hand, when messages include clues of inconsistency (e.g., message disclaimers, unreliable sources, etc.), recipients begin to doubt the legitimacy of the message, suppressing the attitudinal change caused by persuasive messages. However, as time goes on, the source of the message and the associated distrust fades, the unconvinced part of the message is forgotten, and the message situation is assumed to be legitimate. In this case, the message tends to become more persuasive over time. This is called the sleeper effect (Hovland & Weiss, 1951; Cook & Flay, 1978). The sleeper effect was originally discovered when the effects of propaganda films were examined. Soldiers’ behavior after viewing the film was measured five days and nine weeks later. The results from the propaganda showed no significant change after five days, but a greater effect (supportive attitudes) after nine weeks. In other words, is believed that the soldiers forgot about the strong propaganda pressure after nine weeks, and the credibility of the message increased. Other factors which could explain the results of the pilot study in relation to the marginal effects on outcomes and the diminishing in emotional transportation of the intervention group are the generation of defense mechanisms against negative emotions. The contents of the original game in the intervention program touched on human vulnerability, mental suffering, and life troubles. In other words, the contents are extremely emotional, rather than the educational contents of the control group. It it’s possible that the participants invoked defensive mechanisms like blocking in response to negative emotions elicited by the program (Cramer, 2014). Another possible factor implicated is reactance. Reactance occurs when a subject experiences psychological pressure to accept a certain view; in this case, the subject tends to adopt the view contrary to the intention of the persuasive process (Steindl et al., 2015). This effect is often used in reverse psychology. For the above reasons, in a longer follow up more positive effects could have been detected. The material used to produce the original game was very basic due to the low budget. A visual story capable of eliciting high emotional transportation maybe needs to be richer in characters’ expressions, music, and visual effects similar to popular commercial products. Another possibility is that the contents of the stories (emotional struggles) didn’t match the participants’ perceived condition.\n\nThe internet-delivered mental health intervention field is a novel one but is surely promising, especially in a digitalized society. Some of the most data-backed interventions are represented by CBT in the form of an application or a game. CBT elicits the cognitive pathway of persuasion directed to behavioral changes; instead, the game of this pilot study aimed to use emotional transportation rather than the cognitive pathway as a means to induce attitude and behavioral change and this is almost unprecedented in a serious game. Regarding CBT in the form of a game, we can refer to the attempt performed by Mantani et al. (2018) with Kokoro App and SPARX by Kuosmanen et al. (2017). The Kokoro app is an application that includes sessions of self-monitoring, behavioral activation, and cognitive restructuring presented by anime-like characters. The participants in the study were 164 patients with antidepressant-refractory depression recruited from 20 psychiatric clinics and hospitals in Japan. The primary outcome was depression severity assessed at week nine. The study demonstrated the effectiveness of the Kokoro app. Aside from the results on the primary outcome, considering the accessibility and affordability the authors believe that this kind of internet-delivered treatment should be considered in the future as a valid alternative to TAU. This pilot study proposing a mental health support tool intended primarily for young people with emotional disturbance could be an accessible and affordable support tool for people reluctant to get in touch with medical facilities. SPARX wants to promote well-being and prevent low mood, stress, and anger in youths. SPARX is a serious game that teaches the player positive coping mechanisms, problem-solving and help-seeking techniques, and the novelty of SPARX is that in doing these tasks the game uses elements of games like challenges and interactions with program characters. These gaming elements are suggested to improve engagement and facilitate learning (Wouters et al., 2013). The original game in this pilot study follows similar logic (more prone to transportation than cognitive processing) and aims to teach emotional regulation through the examples of the character’s vicissitudes. Evidence for the effectiveness of serious games (“computerized interventions which utilize gaming for serious purposes”, Fleming et al., 2014) for enhancing mental health is limited but exists (Lau et al., 2017; Johnson et al., 2017). Gaming interventions have shown promising results in the area of depression prevention and treatment (Fleming et al., 2020; Li, Theng, & Foo, 2014). With regard to the rationale of using a gaming remote approach with socially withdrawn subjects, Chan (2019) explored the effectiveness of an alternative intervention approach for Hong Kong hidden youth using a gaming platform to provide play therapy. Results showed the efficacy of play therapy on empowerment effect, sense of well-being, and coping abilities (psychological capital). Chan (2019) used role-playing games like “Capture territories”, board games like “Monopoly”, and simulation games like “The Sims Online”. Chan (2016) argued that the mainstream society approach toward treating socially withdrawn individuals is for them to become productive and contribute to society, and enhance social skills and careers to reconnect them with society; however, the risk is to overlook their interests and natural tendencies. According to Chan and Lo (2014) socially withdrawn people “(i) habitually stay on the online gaming platform for a prolonged period of time; and (ii) are able to develop close online friendships”. So, they are able to build social human relationships via the internet. Based on the concept of ‘starting where the client is’ (Goldstein, 1983, p. 267), Chan (2019) wanted to use online games as therapeutic play for socially withdrawn individuals. For the same reasons, the authors conceived an approach that wants to facilitate emotional regulations rather than a drastic reconnection to mainstream society. As Chan (2019) pointed out, the traditional approach could rather lead to a disempowerment of these subjects because they faced their inability to meet mainstream society’s expectations. On the contrary, empowerment is based on helping them within their interests and comfort zone, at least in the first phase. The pilot study carried out by the authors retains some aspects of already existing approaches using CBT providing games or play therapy but at the same time conveys some novelty to the literature emphasizing the use of original fictional stories in which characters go through emotional struggles to overcome them. We can suppose that the relaxation effect hereby measured was linked to the physiological and psychological relaxation experienced while participating in the program. According to previous research, the relaxation effect is correlated with emotional relaxation, physiological tension, and state anxiety. Participants in the interventional group tended to be more relaxed while participating in the program. Even if the results were marginal, this result could have a meaningful interpretation. Aiming to achieve emotional regulation via the appreciation of a story rather than a boring lecture could act as a protective factor against physiological and emotional tension. The effect of fictional narratives on anxiety symptoms and emotional tension could be very useful. Cognitive elaboration often arouses from a rhetorical message (public advertisements, texts, or visual material high in information contents) whether transportation is more easily aroused from narrative and fictional stories. With a rhetorical message, the viewer tends to be heavily influenced by the credibility of the message source. For example, if a person were told that an advertiser is not trustworthy, they will be unlikely to be persuaded by a product from that non-trustworthy advertiser (even if the product is particularly good). On the contrary, people are more motivated to accept a fictional world, often temporarily, at least for enjoyment purposes (Rubin, 1994). From jury decision-making (Pennington & Hastie, 1988) to likelihood estimates (Gregory, Cialdini, & Carpenter, 1982), the influence of narrative has been demonstrated. Another important difference between rhetorical messages (non-fiction) and fiction is represented by characters; “Character is the driving force in fiction” (Surmelian, 1969, p. 139; Radway, 1997, p. 282). In the narrative world, characters are an internal source of information and beliefs, so the attachment to protagonists may have a role in belief changes. On the contrary, in non-fictional messages, the source of credibility is external or “given”. In this light, the credibility source of the narrative may be more stable. Gilbert (Gilbert, 1992; Gilbert, Tafarodi, & Malone, 1993) suggests that changing beliefs is a very plausible effect of fictional narratives consumption, when a person becomes transported, he will be less able to disbelieve any concept. A person transported is also reluctant to critically analyze the contents. Gerrig and Prentice (1991) showed that transported subjects seem to incorporate even false assertions such as “mental illness is contagious,” into their real-world belief structures after being influenced by a narrative. Fiction-based belief change has been proved by several researchers (Prentice, Gerrig, & Bailis, 1997; Strange & Leung, 1999; Wheeler, Green, & Brock, 1999). The results of our study after a 1 week of follow-up showed a significant diminishment in emotional transportation and empathy but a slight improvement in relaxation (significant only for T-test) and other mental health measures (non-significant). Fictional narratives showed promising effects on anxiety symptoms and emotional tension. In 2014, Dumtrache tested the effects of cinema therapy on diminishing anxiety in young people. Participants who took cinema therapy sessions scored lower on the Hamilton anxiety rating scale compared to participants in the control group (Dumtrache, 2014). Mojdeh et al. (2013) examined the effects of watching a movie on a family member’s anxiety level during their relative’s surgery. The anxiety level was assessed with STAI. Even if the person was anxious about an oncoming relative’s surgery, watching a movie significantly reduced anxiety (Mojdeh et al., 2013). These results hint at a possible protective role of fictional narratives regarding anxiety and emotional tension (Fatahi et al., 2021). In the posthoc analysis the positive effects on relaxation of pre- intervention (habitual) high emotional status of participants were confirmed. This positive result was already suggested by Panto et al. (2021). The results about diminishing emotional transportation could reflect the contents of the original game being low in sadness and high in contentment or, on the contrary, could reflect a lack of emotional transportation toward the story by the participants (depiction of negative emotions, lack of similarity, and relation with the story). Regarding mental health effects, the estimated marginal means for all the measures except for self-esteem (Rosenberg) were slightly more positive for the intervention group at 1-week follow-up. The effects for relaxation were significant (only for the t-student test) but still marginal.\n\nThis study was a pilot with numerous limits from the design point of view. More studies with high-quality fictional narratives (market quality games or animation) and a longer follow-up are needed to better understand with kind of possibilities this approach could bring. The overuse of the internet was considered by some researchers a predictor of severity for socially impaired individuals; however, very little evidence exists regarding the psychological effects of fictional narrative consumption behavior. The authors are willing to explore more the efficacy of an internet-based program in the form of a game with a fantastical story to understand further the possible positive and supportive role of remote interventions for emotionally struggling youths. Targeting emotional and psychological disturbance with a computerized interactive program could be useful as a tool of emotional support for mental health struggling youths.\n\n\nLimitations and future prospects of this study\n\nThis research aimed to structure a new form of intervention for young people with mental health issues. In performing this task, the authors are trying to overcome a lot of barriers and stereotypes about the use of media and entertainment in the mental health field. It is clear how media and entertainment don’t represent per se a toxic factor for our mental health, but rather the frequency of use and the entertainment content we consume shape the positive and negative effects on our minds. In the context of mental health for young people, it is nonsensical not to use a resource so powerful and so ubiquitous as technological entertainment. So, the next step would be to find a means to implement this resource in a meaningful way. This research wanted to make the first attempt to understand with kind of positive psychological effects we can expect from the consumption of entertainment and in particular fictional narratives. Traditionally the use of games or the consumption of media has been related to violence and anti-social behavior (Przybylski & Weinstein, 2019), however as shown in the discussion the use of materials that are pro-social in nature seems to, on the contrary, boost pro-social behavior and emotions, constituting a protective factor for consumers. This research represents one of the first attempts to understand which dimensions of mental health could possibly be improved using narrative fiction materials with socially impaired individuals (Hikikomori and school refusal sufferers) and to structure a way to reach them remotely. This is especially meaningful for socially impaired individuals. For Hikikomori and school refusals sufferers, it is incredibly difficult to connect to mental health aid resources. Recently experts in the field agree that the final goal in helping these people is not to make them participate in the social context in a traditional manner but instead to support them emotionally in the way they prefer without any coercion. From this point of view, the final goal shouldn’t be to “take them out” but instead to support their mental health during the “shut-in” period. In this study, we assumed that the emotional transportation aroused by the consumption of fictional narratives could lead to an improvement in psychological well-being. In persuasion research, this topic has been explored with researchers trying to understand the role of emotional and cognitive pathways involved in emotional and behavioral changes in the recipients of a message. We tried to explore a few dimensions like empathy, self-esteem, relaxation, mood state, etc. The lack of research on this topic toward Japanese socially impaired individuals represents the first limitation. We didn’t genuinely understand which dimension of mental health could be particularly influenced by the consumption of fictional narratives. Another limitation is that the population we choose for this research isn’t representative of the ideal population we want to dedicate this program to in the future. In fact, to make easier the interpretation of results and for the affinity of fictional narrative consumption and social impairment, we chose to recruit Hikikomori and people with experience of school withdrawal, and for the limitations in the numbers we had to recruit older participants. Even if in the future we want to utilize this program totally delivered by the internet, assessing the effects in a particular psychological dimension in a pilot study is fundamental to controlling environmental conditions and minimizing any confounding factors that could influence the results. This should be made by precisely controlling the study participation environment and checking that the instructions are observed. In this study when we ask the participants about their fictional narratives consumption habits in the questionnaire survey and when we ask them to answer the questionnaire after the participation in the intervention and control program, we couldn’t monitor the participants’ behavior. We don’t know if the instructions about the timing of answering the survey were followed (for example we made a 1-week follow-up questionnaire survey, but this was always available to participants, consequently we don’t know if the instructions were respected). Another big limitation of the present study was surely the materials used in the intervention group. The model theory predicted that an enhancement in emotional transportation could benefit indirectly the emotional and behavioral dimensions of the consumer. To achieve this task a material consisting of a fictional narrative story will have to be produced with this scope in mind. The story must not only be able to enhance emotional transportation but must also resonate with a variety of issues which can make a lot of consumers engage at the same time. Also, as the very famous movies, games, and anime productions teach us, the quality (visual musical, and technology-wise) must be very high. This monumental task is not easy to achieve with few resources. If we look at the budget of great blockbuster movies or worldwide famous Japanese productions, it is easy to understand how many people and how much money are involved in the production of these monumental artworks. The novelty of the program we want to propose with this study is that while being a tool for mental health it would be entertaining and funny to engage with, in particular to young people. This pilot study’s attempts, however, didn’t have any reference on to what extent negative emotion depiction serves as the scope of enhancing mental health, or on the contrary, constitutes a hindrance. In the future, more attempts are needed to understand the relative role of positive emotions and negative emotions’ depiction role on emotional persuasion.\n\n\nConclusion\n\nEven if the results were marginal for mental health predictors and we couldn’t detect an improvement in emotional transportation after a week, the results of this pilot study are encouraging for further exploration in this field. Firstly, we confirmed a wish to engage in fictional narratives consumption by socially impaired individuals aside from pure pleasure. Secondly, we confirmed an effect on emotional transportation and empathy of fictional narratives, as well as an improvement in relaxation. However, the rationale and the right process to structure an original fictional narrative remains an ongoing task, being that we demonstrated that it is difficult to manipulate emotional transportation. In the future, the authors are planning to explore more the efficacy of an internet-based program in the form of a game or an anime production with a fantastical story to understand further the possible positive and supportive role of remote interventions for emotionally struggling youths. The internet-delivered mental health intervention field is a novel one but is surely promising, especially in a digitalized society.\n\n\nData availability\n\nHarvard Dataverse: Mental health care for young people using videogames; a pilot study on the development of a new intervention method toward Hikikomori and Futōkō, Panto et al. https://doi.org/10.7910/DVN/YBCEGO.\n\nThis project contains the following underlying data:\n\n- data Mental health care for young people using videogames a pilot study on the development of a new intervention method toward Hikikomori and Futoko Panto et al sav.tab\n\nHarvard Dataverse: Mental health care for young people using videogames; a pilot study on the development of a new intervention method toward Hikikomori and Futōkō, Panto et al. https://doi.org/10.7910/DVN/YBCEGO.\n\nThis project contains the following extended data:\n\n- Study protocol presentation.pdf\n\n- English translation of S-MARE and MES scales.docx\n\n- Intervention original game for windows in Japanese.zip\n\n- Original game copyright disclaimer CC license.pdf\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Please see the license PDF file for specific license details on the game.\n\n\nReporting guidelines\n\nCONSORT checklist and flowchart for ‘Mental health care for young people using video games: a pilot RCT on the development of a new intervention method toward Hikikomori and Futōkō. https://doi.org/10.7910/DVN/YBCEGO.",
"appendix": "References\n\nAaker J, Williams P: Empathy versus pride: The influence of emotional appeals across cultures. J. Consum. Res. 1998; 25(3): 241–261. Publisher Full Text\n\nAkabayashi A, Yokoyama K, Araki S, et al.: Clinical states (POMS). Japanese J Psychosom Med. 1991; 31: 577–582.\n\nAldoory L: Making health communications meaningful for women: Factors that influence involvement. J. Public Relat. Res. 2001; 13(2): 163–185. Publisher Full Text\n\nAlexander KJ, Miller PJ, Hengst JA: Young children’s emotional attachments to stories. Soc. Dev. 2001; 10(3): 374–398. Publisher Full Text\n\nAnderson C, Laubscher S, Burns R: Validation of the Short Form 36 (SF-36) health survey questionnaire among stroke patients. Stroke. 1996; 27: 1812–1816. PubMed Abstract | Publisher Full Text\n\nAndersson G, Titov N, Dear BF, et al.: Internet-delivered psychological treatments: From innovation to implementation. World Psychiatry. 2019; 18(1): 20–28. PubMed Abstract | Publisher Full Text\n\nAndrade EB, Cohen JB: On the consumption of negative feelings. J. Consum. Res. 2007; 34(3): 283–300. Publisher Full Text\n\nAppel M, Richter T: Persuasive effects of fictional narratives increase over time. Media Psychol. 2007; 10(1): 113–134.\n\nAppel M, Richter T: Transportation and need for affect in narrative persuasion: A mediated moderation model. Media Psychol. 2010; 13(2): 101–135. Publisher Full Text\n\nAppel H, Crusius J, Gerlach AL: Social comparison, envy, and depression on Facebook: A study looking at the effects of high comparison standards on depressed individuals. J. Soc. Clin. Psychol. 2015; 34(4): 277–289. Publisher Full Text\n\nArai S, Sakamoto K, Washizaki H, et al.: A Gamified tool for motivating developers to remove warnings of bug pattern tools. 2014 6th International Workshop on Empirical Software Engineering in Practice. 2014. Publisher Full Text\n\nArgo JJ, Zhu R, Dahl DW: Fact or fiction: An investigation of empathy differences in response to emotional melodramatic entertainment. J. Consum. Res. 2008; 34(5): 614–623. Publisher Full Text\n\nAruga M, Suzuki E, Tagaya A: Factors involved in the feelings related to school avoidance among high school students in Nagano prefecture, Japan. Jpn. J. Nurs. Sci. 2011; 9(1): 38–55. PubMed Abstract | Publisher Full Text\n\nAruga M: Factors Affecting Feelings of School Avoidance in Japanese High School Students: A Longitudinal Study of 10th to 12th Graders, School Health.2020; 16: p. 22–32. 2020/06/03. 1880-2400. 2014. Publisher Full Text Reference Source\n\nÅslund C, Nordquist N, Comasco E, et al.: Maltreatment, MAOA, and delinquency: Sex differences in gene–environment interaction in a large population-based cohort of adolescents. Behav. Genet. 2010; 41(2): 262–272. PubMed Abstract | Publisher Full Text\n\nBagozzi RP, Moore DJ: Public service advertisements: Emotions and empathy guide prosocial behavior. J. Mark. 1994; 58(1): 56–70. Publisher Full Text\n\nBal PM, Butterman OS, Bakker AB: The influence of fictional narrative experience on work outcomes: A conceptual analysis and research model. Rev. Gen. Psychol. 2011; 15(4): 361–370. Publisher Full Text\n\nBandura A: Self-efficacy: Toward a unifying theory of behavioral change. Psychol. Rev. 1977; 84(2): 191–215. PubMed Abstract | Publisher Full Text\n\nBanerjee SC, Greene K: Role of transportation in the persuasion process: Cognitive and affective responses to Antidrug narratives. J. Health Commun. 2012; 17(5): 564–581. PubMed Abstract | Publisher Full Text\n\nBatson CD, Klein TR, Highberger L, et al.: Immorality from empathy-induced altruism: When compassion and justice conflict. J. Pers. Soc. Psychol. 1995; 68(6): 1042–1054. Publisher Full Text\n\nBaumeister RF, Campbell JD, Krueger JI, et al.: Does high self- esteem cause better performance, interpersonal success, happiness, or healthier lifestyles?. Psychol. Sci. Public Interest. 2003; 4: 1–44. Publisher Full Text\n\nBerger KW: Communications. Annals of Otology, Rhinology & Laryngology. 1977; 86(2): 260–260. Publisher Full Text\n\nBlagg NR, Yule W: The behavioural treatment of school refusal: A comparative study. Behav. Res. Ther. 1984; 22(2): 119–127. Publisher Full Text\n\nBusselle R, Bilandzic H: Fictionality and perceived realism in experiencing stories: A model of narrative comprehension and engagement. Commun. Theor. 2008; 18(2): 255–280. Publisher Full Text\n\nChan HY, Lo TW: Quality of life of the hidden youth in Hong Kong. Appl. Res. Qual. Life. 2014; 9(4): 951–969. Publisher Full Text\n\nChan G: Hidden Youth and the Virtual World: The Process of Labeling and Empowerment. London: Routledge; 2016. Publisher Full Text\n\nChan GH: Application and effectiveness of play therapy using an online-game intervention for hidden youth. Br. J. Soc. Work. 2019; 50(7): 2116–2134. Publisher Full Text\n\nChristensen H, Reynolds J, Griffiths KM: The use of e-Health applications for anxiety and depression in young people: Challenges and solutions. Early Interv. Psychiatry. 2011; 5: 58–62. PubMed Abstract | Publisher Full Text\n\nCook TD, Flay BR: The persistence of experimentally induced attitude change. Adv. Exp. Soc. Psychol. 1978; 1–57. Publisher Full Text\n\nConner M, Norman P: Predicting and changing health behaviour: A social cognition approach. Conner M, Norman P, editors. Predicting and changing health behaviour: Research and practice with social cognition models. 3 Edn.Maidenhead: Open University Press; 2015; pp. 1–29.\n\nCoplan A: Empathic engagement with narrative fictions. J. Aesthet. Art Critic. 2004; 62(2): 141–152. Publisher Full Text\n\nCoplan A: Caring about characters: Three determinants of emotional engagement. Film Philos. 2006; 10: 1–19. Publisher Full Text\n\nCramer P: Defense mechanisms: 40 years of empirical research. J. Pers. Assess. 2014; 97(2): 114–122. PubMed Abstract | Publisher Full Text\n\nCrist DA, Rickard HC, Prentice-Dunn S, et al.: The relaxation inventory: Self-report scales of relaxation training effects. J. Pers. Assess. 1989; 53(4): 716–726. PubMed Abstract | Publisher Full Text\n\nCuijpers P, Reijnders M, Huibers MJH: The role of common factors in psychotherapy outcome. Annu. Rev. Clin. Psychol. 2019; 15: 207–231. Publisher Full Text\n\nDalager JK: Spiral of cynicism: The press and the public Good. Joseph B. Cappella, Kathleen hall Jamieson<i>Free speech and false profits: Ethics in the Media</i>. Ted Schwarz. J. Polit. 1998; 60(2): 526–528. Publisher Full Text\n\nDeighton J, Romer D, McQueen J: Using drama to persuade. J. Consum. Res. 1989; 16(3): 335. Publisher Full Text\n\nDeighton J: The consumption of performance. J. Consum. Res. 1992; 19(3): 362–372. Publisher Full Text\n\nDeterding S, Dixon D, Khaled R, Nacke L: From game design elements to gamefulness. Proceedings of the 15th International Academic MindTrek Conference on Envisioning Future Media Environments - MindTrek ’11. 2011. Publisher Full Text\n\nDe Vignemont F, Singer T: The empathic brain: How, when and why?. Trends Cogn. Sci. 2006; 10(10): 435–441. PubMed Abstract | Publisher Full Text\n\nDillard J, Peck E: Affect and Persuasion Emotional Responses to Public Service Announcements. Commun. Res. 2000; 27: 461–495. Publisher Full Text\n\nDillard JP, Shen L: On the nature of reactance and its role in persuasive health communication. Commun. Monogr. 2005; 72(2): 144–168. Publisher Full Text\n\nDixon P, Bortolussi M, Sopčák P: Extratextual effects on the evaluation of narrative texts. Poetics. 2015; 48: 42–54. Publisher Full Text\n\nDumtrache SD: The effects of a cinema-therapy group on diminishing anxiety in young people. Procd. Soc. Behv. 2014; 127: 717–721. Publisher Full Text\n\nDunlop SM, Wakefield M, Kashima Y: Pathways to persuasion: Cognitive and experiential responses to health-promoting mass media messages. Commun. Res. 2009; 37(1): 133–164. Publisher Full Text\n\nDunbar RI, Teasdale B, Thompson J, et al.: Emotional arousal when watching drama increases pain threshold and social bonding. R. Soc. Open Sci. 2016; 3(9): 160288. PubMed Abstract | Publisher Full Text\n\nEagly AH, Chaiken S: The psychology of attitudes. Harcourt Brace Jovanovich College Publishers; 1993.\n\nEntertainment Software Association: 2015. 2015 Essential Facts about Computer and Video Game Industry.Reference Source\n\nEgger HL, Costello JE, Angold A: School refusal and psychiatric disorders: A community study. J. Am. Acad. Child Adolesc. Psychiatry. 2003; 42(7): 797–807. Publisher Full Text\n\nEscalas JE, Stern BB: Sympathy and empathy: Emotional responses to advertising dramas. J. Consum. Res. 2003; 29(4): 566–578. Publisher Full Text\n\nFairburn CG, Patel V: The impact of digital technology on psychological treatments and their dissemination. Focus. 2018; 16(4): 449–455. PubMed Abstract | Publisher Full Text\n\nFarranda P, Perry J, Lee C, et al.: Adolescents’ preference towards self-help: implications for service development. Primary Care & Community Psychiatry. 2006; 11(2): 73–79. Publisher Full Text\n\nFatahi N, Bardideh M, Talebi Bahman Biglou R, et al.: The effectiveness of narrative therapy on reducing behavior problems and improving self-perception in students. Quarterly Journal of Child Mental Health. 2021; 7(4): 297–312. Publisher Full Text\n\nFleming T, Stasiak K, Moselen E, et al.; Revising computerized therapy for wider appeal among adolescents: Youth perspectives on a revised version of SPARX.2020. Publisher Full Text\n\nFreidlin P, Littman-Ovadia H, Niemiec RM: Positive psychopathology: Social anxiety via character strengths underuse and overuse. Personal. Individ. Differ. 2017; 108: 50–54. Publisher Full Text\n\nGarris R, Ahlers R, Driskell JE: Games, motivation, and learning: A research and practice model. Simul. Gaming. 2002; 33(4): 441–467. Publisher Full Text\n\nGebbers T, Wit J, Appel M: Transportation into narrative worlds and the motivation to change health-related behavior. International. J. Commun. 2017; 11.\n\nGee JP: What video games have to teach us about learning and literacy. Comput. Entertain. 2003; 1(1): 20–20. Publisher Full Text\n\nGerrig RJ: Experiencing narrative worlds: On the psychological activities of reading. Yale University Press; 1993.\n\nGerrig RJ, Prentice DA: The representation of fictional information. Psychol. Sci. 1991; 2(5): 336–340. Publisher Full Text\n\nGilbert DT: “How mental systems believe”: Reply. Am. Psychol. 1992; 47(5): 670–671. Publisher Full Text\n\nGilbert DT, Tafarodi RW, Malone PS: You can’t not believe everything you read. J. Pers. Soc. Psychol. 1993; 65(2): 221–233. Publisher Full Text\n\nGoldberg DP, Hillier VF: A scaled version of the general health questionnaire. Psychol. Med. 1979; 9(1): 139–145. Publisher Full Text\n\nGoldstein H: Starting where the client is. Soc. Casework. 1983; 64(5): 267–275. Publisher Full Text\n\nGoldstein TR: The pleasure of unadulterated sadness: Experiencing sorrow in fiction, nonfiction, and “in person.”. Psychol Aesthet Crea. 2009; 3(4): 232–237. Publisher Full Text\n\nGosschalk PO: Behavioral Treatment of Acute Onset School Refusal in a 5-year old Girl with Separation Anxiety Disorder. Educ. Treat. Child. 2004; 27(2): 150–160. Reference Source\n\nGreen MC, Brock TC: The role of transportation in the persuasiveness of public narratives. J. Pers. Soc. Psychol. 2000; 79(5): 701–721. PubMed Abstract | Publisher Full Text\n\nGreen MC, Brock TC: In the mind’s eye: Transportation- imagery model of narrative persuasion. Green MC, Strange JJ, Brock TC editors. Narrative impact: Social and cognitive foundations. Mahwah, NJ: Lawrence Erlbaum Associates Publishers; 2002; 315–341\n\nGreen MC, Brock TC, Kaufman GF: Understanding media enjoyment: The role of transportation into narrative worlds. Commun. Theory. 2004; 14(4): 311–327. Publisher Full Text\n\nGreen MC, Donahue JK: Simulated worlds: Transportation into narratives. Markman KD, Klein WMP, Suhr JA, editors. Handbook of Imagination and Mental Simulation. Hove: Psychology Press; 2009; 241–256.\n\nGregory WL, Cialdini RB, Carpenter KM: Self-relevant scenarios as mediators of likelihood estimates and compliance: Does imagining make it so?. J. Pers. Soc. Psychol. 1982; 43(1): 89–99. Publisher Full Text\n\nHamari J, Koivisto J, Sarsa H; Does Gamification work? -- A literature review of empirical studies on Gamification.’ 2014 47th Hawaii International Conference on System Sciences. 2014. Publisher Full Text\n\nHanley GP, Iwata BA, McCord BE: Functional analysis of problem behavior: A review. J. Appl. Behav. Anal. 2003; 36(2): 147–185. PubMed Abstract | Publisher Full Text\n\nHarris PL: The work of the imagination. Malden, MA: Blackwell; 2000.\n\nHense J, Mandl H: Learning in or with games? Quality criteria for digital learning games from the perspectives of learning, emotion, and motivation theory. Proceedings of the IADIS International Conference on Cognition and Exploratory Learning in the Digital AgePublisher. Sampson DG, Spector JM, Ifenthaler D, et al., editors. Madrid (Spain): IADIS; 2012.\n\nHovland CI, Weiss W: The influence of source credibility on communication effectiveness. Public Opin. Q. 1951; 15: 635–650. Publisher Full Text\n\nHuffman JC, DuBois CM, Healy BC, et al.: Feasibility and utility of positive psychology exercises for suicidal inpatients. Gen. Hosp. Psychiatry. 2014; 36(1): 88–94. PubMed Abstract | Publisher Full Text\n\nJohnson DR: Transportation into a story increases empathy, prosocial behavior, and perceptual bias toward fearful expressions. Pers. Indiv. Differ. 2012; 52(2): 150–155. Publisher Full Text\n\nJohnson D, Horton E, Mulcahy R, et al.: Gamification and serious games within the domain of domestic energy consumption: A systematic review. Renew. Sust. Energ. Rev. 2017; 73: 249–264. Publisher Full Text\n\nJones MD: Cultural characters and climate change: How heroes shape our perception of climate science. Soc. Sci. Q. 2013; 95(1): 1–39. Publisher Full Text\n\nJones BA, Madden GJ, Wengreen HJ: The FIT game: Preliminary evaluation of a gamification approach to increasing fruit and vegetable consumption in school. Prev. Med. 2014; 68: 76–79. PubMed Abstract | Publisher Full Text\n\nKam TH: The common sense that makes the ‘otaku’: Rules for consuming popular culture in contemporary Japan. Jpn Forum. 2013; 25(2): 151–173. Publisher Full Text\n\nKaryotaki E, Efthimiou O, Miguel C, et al.: Internet-Based Cognitive Behavioral Therapy for Depression: A Systematic Review and Individual Patient Data Network Meta-analysis. JAMA Psychiat. 2021; 78(4): 361–371. PubMed Abstract | Publisher Full Text\n\nKato TA, Teo AR, Tateno M, et al.: Can Pokémon GO rescue shut-ins (hikikomori) from their isolated world?. Psychiatry Clin. Neurosci. 2017; 71: 75–76. PubMed Abstract | Publisher Full Text\n\nKeen S: A theory of narrative empathy. Narrative. 2006; 14: 207–236. Publisher Full Text\n\nKessler RC, Avenevoli S, Ries Merikangas K: Mood disorders in children and adolescents: An epidemiologic perspective. Biol. Psychiatry. 2001; 49(12): 1002–1014. Publisher Full Text\n\nKim E, Ratneshwar S, Thorson E: Why narrative ads work: An integrated process explanation. J. Advert. 2017; 46(2): 283–296. Publisher Full Text\n\nKoyama A, Miyake Y, Kawakami N, et al.: Lifetime prevalence, psychiatric comorbidity and demographic correlates of “hikikomori” in a community population in Japan. Psychiatry Res. 2010; 176(1): 69–74. PubMed Abstract | Publisher Full Text\n\nKondo N, Sakai M, Kuroda Y, et al.: General condition of hikikomori (prolonged social withdrawal) in Japan: Psychiatric diagnosis and outcome in mental health welfare centres. Int. J. Soc. Psychiatry. 2013; 59(1): 79–86. Publisher Full Text\n\nKross E, Berman MG, Mischel W, et al.: Social rejection shares somatosensory representations with physical pain. Proc. Natl. Acad. Sci. 2011; 108(15): 6270–6275. PubMed Abstract | Publisher Full Text\n\nKubo H, Urata H, Sakai M, et al.: Development of 5-day hikikomori intervention program for family members: A single-arm pilot trial. Heliyon. 2020; 6(1): e03011. PubMed Abstract | Publisher Full Text\n\nKuosmanen T, Fleming T, Newell J, et al.: A pilot evaluation of the SPARX-R gaming intervention for preventing depression and improving wellbeing among adolescents in alternative education. Internet Interv. 2017; 8: 40–47. PubMed Abstract | Publisher Full Text\n\nLanders RN: Developing a theory of Gamified learning. Simul. Gaming. 2014; 45(6): 752–768. Publisher Full Text\n\nLanglands RL, Jorm AF, Kelly CM, et al.: First aid for depression: A Delphi consensus study with consumers, carers and clinicians. J. Affect. Disord. 2008; 105(1-3): 157–165. PubMed Abstract | Publisher Full Text\n\nLau Y, Htun TP, Wong SN, et al.: Therapist-supported internet-based cognitive behavior therapy for stress, anxiety, and depressive symptoms among postpartum women: A systematic review and meta-analysis. J. Med. Internet Res. 2017; 19(4): e138. PubMed Abstract | Publisher Full Text\n\nLee YS, Lee JY, Choi TY, et al.: Home visitation program for detecting, evaluating and treating socially withdrawn youth in Korea. Psychiatry Clin. Neurosci. 2013; 67(4): 193–202. PubMed Abstract | Publisher Full Text\n\nLi J, Theng Y, Foo S: Game-based digital interventions for depression therapy: A systematic review and meta-analysis. Cyberpsychol. Behav. Soc. Netw. 2014; 17(8): 519–527. PubMed Abstract | Publisher Full Text\n\nLyon AR, Cotler S: Toward reduced bias and increased utility in the assessment of school refusal behavior: The case for diverse samples and evaluations of context. Psychol. Sch. 2007; 44(6): 551–565. Publisher Full Text\n\nLocke EA: Social foundations of thought and action: A social-cognitive view. Acad. Manag. Rev. 1987; 12(1): 169–171.\n\nManninen S, Tuominen L, Dunbar RI, et al.: Social Laughter triggers endogenous opioid release in humans. J. Neurosci. 2017; 37(25): 6125–6131. PubMed Abstract | Publisher Full Text\n\nMantani A, Kato T, Furukawa TA, et al.: Correction: Smartphone cognitive behavioral therapy as an adjunct to pharmacotherapy for refractory depression: Randomized controlled trial. J. Med. Internet Res. 2018; 20(8): e11702. PubMed Abstract | Publisher Full Text\n\nMar RA, Oatley K, Hirsh J, et al.: Bookworms versus nerds: Exposure to fiction versus non-fiction, divergent associations with social ability, and the simulation of fictional social worlds. J. Res. Pers. 2006; 40(5): 694–712. Publisher Full Text\n\nMar RA, Oatley K, Peterson JB: Exploring the link between reading fiction and empathy: Ruling out individual differences and examining outcomes. Commun. 2009; 34(4): 407–428. Publisher Full Text\n\nMariu KR, Merry SN, Robinson EM, et al.: Seeking professional help for mental health problems, among New Zealand secondary school students. Clin. Child Psychol. Psychiatry. 2011; 17(2): 284–297. PubMed Abstract | Publisher Full Text\n\nMaruyama S, Sato H, Morimoto K: Relationship between working-life satisfaction, health practices and primary symptoms/problems. Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene). 1991; 45(6): 1082–1094. PubMed Abstract | Publisher Full Text\n\nMatsuguma S, Niemiec RM: Hikikomori from the perspective of overuse, underuse, and optimal use of character strengths: Case reports. Int. J. Appl. Posit. Psychol. 2020; 6(3): 219–231. Publisher Full Text\n\nMazzocco PJ, Green MC, Sasota JA, et al.: This story is not for everyone: Transportability and narrative persuasion. Soc. Psychol. Personal. Sci. 2010; 1(4): 361–368. Publisher Full Text\n\nMcNair DM, Lorr M, Droppleman LF: Profile of Mood States. San Diego: Educational and industrial Testing Service; 1971.\n\nMeerwijk EL, Ford JM, Weiss SJ: Brain regions associated with psychological pain: Implications for a neural network and its relationship to physical pain. Brain Imaging Behav. 2012; 7(1): 1–14. PubMed Abstract | Publisher Full Text\n\nMehrabian A, Epstein N: A measure of emotional empathy. J. Pers. 1972; 40(4): 525–543. Publisher Full Text\n\nMerry SN, Stasiak K, Shepherd M, et al.: The effectiveness of SPARX, a computerised self help intervention for adolescents seeking help for depression: randomised controlled non-inferiority trial. BMJ. 2012; 344(3):e2598–8. PubMed Abstract | Publisher Full Text\n\nMirzoeff N: An Introduction to Visual Culture(2009-06-28) Paperback – January 1.2009.\n\nMoffitt CE, Chorpita BF, Fernández SN: Intensive cognitive-behavioral treatment of school refusal behavior. Cogn. Behav. Pract. 2003; 10: 51–60. Publisher Full Text\n\nMojdeh S, Zamani M, Kooshki AM, et al.: Effect of watching a movie on family members’ anxiety level during their relatives’ surgery. Iran. J. Nurs. Midwifery Res. 2013; 18(4): 329–332. PubMed Abstract\n\nNakamura M, Kondo I, Kubota A, et al.: School-attendance problems, subjective symptoms and lifestyle factors: The Shizuoka health and lifestyle survey of students. Jpn. J. Public Health. 2010; 57: 881–890. (in Japanese with English abstract). PubMed Abstract\n\nOatley K: Why fiction may be twice as true as fact: Fiction as cognitive and emotional simulation. Rev. Gen. Psychol. 1999; 3(2): 101–117. Publisher Full Text\n\nOatley K: Emotions and the story world of fiction. Green MC, Strange JJ, Brock TC, editors. Narrative impact: Social and cognitive foundations. Mahwah: Lawrence Erlbaum; 2002; 39–70.\n\nOsanai H, Kusumi T: Reliability and validity of the Narrative Transportation Scale in Japanese. Jpn JPers. (In Japanese with English abstract.). 2016; 25(1): 50–61.\n\nPanto F, Saito T, Morita N, et al.: The correlation between enjoying fictional narratives and empathy in Japanese Hikikomori. F1000Res. 2021; 10: 776. Publisher Full Text\n\nPelowski M, Akiba F: A model of art perception, evaluation and emotion in transformative aesthetic experience. New Ideas Psychol. 2011; 29(2): 80–97. Publisher Full Text\n\nPennant ME, Loucas CE, Whittington C, et al.: Computerised therapies for anxiety and depression in children and young people: A systematic review and meta-analysis. Behav. Res. Ther. 2015; 67: 1–18. PubMed Abstract | Publisher Full Text\n\nPennington N, Hastie R: Explanation-based decision making: Effects of memory structure on judgment. J. Exp. Psychol. Learn. Mem. Cogn. 1988; 14(3): 521–533. Publisher Full Text\n\nPetty RE, Cacioppo JT: Communication and Persuasion: Central and peripheral routes to attitude change. New York, NY: Springer; 1986.\n\nPhillips BJ, McQuarrie EF: Narrative and Persuasion in fashion advertising. J. Consum. Res. 2010; 37(3): 368–392. Publisher Full Text\n\nPrentice DA, Gerrig RJ, Bailis DS: What readers bring to the processing of fictional texts. Psychon. Bull. Rev. 1997; 4: 416–420. Publisher Full Text\n\nProctor C, Maltby J, Linley PA: Strengths use as a predictor of well-being and health-related quality of life. J. Happiness Stud. 2010; 12(1): 153–169. Publisher Full Text\n\nPrzybylski AK, Rigby CS, Ryan RM: A motivational model of video game engagement. Rev. Gen. Psychol. 2010; 14(2): 154–166. Publisher Full Text\n\nPrzybylski AK, Weinstein N: Violent video game engagement is not associated with adolescents’ aggressive behaviour: Evidence from a registered report. R. Soc. Open Sci. 2019; 6(2): 171474. PubMed Abstract | Publisher Full Text\n\nRadway J: Books and Reading in the Age of Mass Production: The Book-of-the-Month Club, Middlebrow Culture and the Transformation of the Literary Field in the U.S.1997; 1926–1940.\n\nReinhart AM, Marshall HM, Feeley TH, et al.: The persuasive effects of message framing in organ donation: The mediating role of psychological reactance. Commun. Monogr. 2007; 74(2): 229–255. Publisher Full Text\n\nRosenberg M: Society and the adolescent self-image. Princeton, NJ: Princeton University Press; 1965.\n\nSaito K: Psychiatry on school refusal in children and adolescents. Tokyo: Kongoshuppan; 2006. (in Japanese).\n\nSaito T: Otaku to Hikikomori (tokushu,tomodachi ga dekinai ko). Child Study. 2009; 63(16): 108–113.\n\nSaito K: Hikikomori no hyouka: shien ni kansuru gaidorain. Tokyo: Japan’s Ministry of Health, Labour and Welfare; 2010.\n\nSaito T: Shakaiteki hikikomori: Owaranai shishunki. (Societal hikikomori: Unending adolescency). Tokyo: PHP-Kenkyujo; 1998.\n\nSaito T: Chuukounen Hikikomori. Gentoushashinsho. 2020.\n\nSakakibara M, Teramoto Y, Tani I: Development of a short-form self-report measure to assess relaxation effects. Shinrigaku Kenkyu. (In Japanese with English abstract.). 2014; 85(3): 284–293. PubMed Abstract | Publisher Full Text\n\nSeligman LD, Ollendick TH: Cognitive-behavioral therapy for anxiety disorders in youth. Child Adolesc. Psychiatr. Clin. N. Am. 2011; 20(2): 217–238. PubMed Abstract | Publisher Full Text\n\nSchunk DH, Meece JL, Pintrich PR: Motivation in education: Theory, research, and applications. Pearson College Division; 2013.\n\nSlater MD: Entertainment education and the persuasive impact of narratives. Green MC, Strange JJ, Brock TC, editors. Narrative impact: Social and cognitive foundations. Lawrence Erlbaum; 2002; 157–181.\n\nShiv B, Edell Britton JA, Payne JW: Does elaboration increase or decrease the effectiveness of negatively versus positively framed messages?. J. Consum. Res. 2004; 31(1): 199–208. Publisher Full Text\n\nSmith JE, Meyers RJ: Motivating Substance Abusers to Enter Treatment: Working With Family Members. New York: Guilford Press; 2004.\n\nSpielberger CD: Review of profile of mood states. Prof. Psychol. 1972; 3(4): 387–388. Publisher Full Text\n\nSteindl C, Jonas E, Sittenthaler S, et al.: Understanding psychological reactance. Z. Psychol. 2015; 223(4): 205–214. PubMed Abstract | Publisher Full Text\n\nStrange JJ, Leung CC: How anecdotal accounts in news and fiction can influence judgments of a social problem’s urgency, causes, and cures. Personal. Soc. Psychol. Bull. 1999; 25(4): 436–449. Publisher Full Text\n\nSurmelian LEON: Techniques of Fiction Writing: Measure and Madness Hardcover. New York: Doubleday; 1969; pp. Blurb. 0385063911.\n\nSuzuki Y, Kino K: Development of the multidimensional empathy scale (MES). Jpn. J. Educ. Psychol. 2008; 56(4): 487–497. Publisher Full Text\n\nTal-Or N: How Co-viewing affects attitudes: The mediating roles of transportation and identification. Media Psychol. 2016; 19(3): 381–405. Publisher Full Text\n\nTajan N, Hamasaki Y, Dax NP: Hikikomori: The Japanese Cabinet Office’s 2016 Survey of acute social withdrawal. Asian Pac J. 2017; 15(5): 5017.\n\nTaylor M: Strategies of dissociation: A mimetic dimension to social problems in Japan. Anthropoetics. 2006; 12(1).\n\nTateno M, Teo AR, Ukai W, et al.: Internet addiction, smartphone addiction, and Hikikomori trait in Japanese young adult: Social isolation and social network. Front. Psych. 2019; 10. PubMed Abstract | Publisher Full Text\n\nTokuda K: The Validity of Temporary Mood Scale. Ritsumeikan ningen kagaku kenkyū. 2011; 22: 1–6.\n\nTOYOTA Foundation: the Report of Research Fund program in 2016.2018. 23. Nov.2019 Obtained. Reference Source\n\nUmegaki T: nihongohan rōzenbāgu jisonshin shakudo no nakara yomi-ban no no, Nihon gyōkai riron sō 閣論 Bunshū, 2002, 44-kan, dai 44-kai-kai-kai-shū-shū, p. 223 -, Kōkai-bi 2017/03/30, onrain ISSN 2424-1571, insatsu ISSN 2189-5538.Publisher Full Text Reference Source\n\nU.S. Bureau of Labor Statistics. Reference Source\n\nvan Laer T , de Ruyter K , Visconti LM, et al.: The extended transportation-imagery model: A meta-analysis of the antecedents and consequences of consumers’ narrative transportation. J. Consum. Res. 2014; 40(5): 797–817. Publisher Full Text\n\nVan Leeuwen L, Van Den Putte B, Renes RJ, et al.: Do narrative engagement and recipients’ thoughts explain the impact of an entertainment-education narrative on discouraging binge drinking?. Media Psychol. 2016; 20(2): 194–220. Publisher Full Text\n\nWang J, Calder BJ: Media transportation and advertising. J. Consum. Res. 2006; 33(2): 151–162. Publisher Full Text\n\nWeaver J, Zillmann D: Effect of humor and tragedy on discomfort tolerance. Percept. Mot. Skills. 1994; 78(2): 632–634. PubMed Abstract | Publisher Full Text\n\nWells GL, Gavanski I: Mental simulation of causality. J. Pers. Soc. Psychol. 1989; 56(2): 161–169. Publisher Full Text\n\nWerbach K, Hunter D: For the Win: How Game Thinking can Revolutionize your Business. Wharton Digital Press; 2012.\n\nWise J: Depression in children: Offer digital CBT as first line treatment, says NICE. BMJ. 2019; 364: l364. PubMed Abstract | Publisher Full Text\n\nWheeler SC, Green MC, Brock TC: Fictional narratives change beliefs: Replications of Prentice, Gerrig, & Bailis (1997) with mixed corroboration. Psychon. Bull. Rev. 1999; 6(1): 136–141. Publisher Full Text\n\nWouters P, van Nimwegen C , van Oostendorp H , et al.: A meta-analysis of the cognitive and motivational effects of serious games. J. Educ. Psychol. 2013; 105(2); 249–265. Publisher Full Text\n\nYamashita K: Relationship between the motivation to attend school and serum lipid levels in high school students. Journal of the Japanese Association of Rural Medicine. 1998 (in Japanese with English abstract); 47: 30–35. Publisher Full Text\n\nYılmaz M, Yılmaz U: The relation between social learning and visual culture. lnternational Electronic Journal of Elementary Education. 2019; 11(4): 421–427. Publisher Full Text\n\nYokoyama T, Kawasaki A, Mitsumiya T, et al.: Impact of online workshop for youth empowerment: Applying C-BED to Hikikomori support in Japan. Education. Quarterly Reviews. 2019; 2(4). Publisher Full Text\n\nZahn-Waxler C, Radke-Yarrow M: The origins of empathic concern. Motiv. Emot. 1990; 14(2): 107–130. Publisher Full Text\n\nZichermann G, Cunningham C: Gamification by design: Implementing game mechanics in web and mobile apps. O’Reilly Media; 2011.\n\nZunshine L: Why we read fiction: Theory of mind and the novel. Columbus: The Ohio State University Press; 2006."
}
|
[
{
"id": "140523",
"date": "08 Jul 2022",
"name": "Peter Bower",
"expertise": [
"Reviewer Expertise Comparative effectiveness research"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to comment on this interesting paper\nI have no specific expertise in this clinical area and have reviewed this largely in terms of trial methodology and reporting. I hope others can comment on the introduction who have expertise in the clinical phenomenon under consideration\nThe title is slightly odd as it discusses children, but the people in the study are all over 20 with an average age of 35. This might be clarified. Did the participants find the content acceptable?\nThe introduction is very detailed and long, far longer than is conventional, and I wondered if that was necessary. The discussion was also quite dense and would benefit from greater structure and use of paragraphs\nThis is described as a pilot trial but the main presentation is on the outcomes (described as a ‘preliminary assessment of effectiveness and compliance’), whereas many pilot trials are delivered in terms of other issues to do with the feasibility of the study. I think this work needs to be placed more clearly in the context of current thinking on these issues (https://pilotfeasibilitystudies.biomedcentral.com/).\nWas any pre-study power calculation done? This needs to be clarified. How was the ‘target’ of 67 derived?\nThe aim is stated to be ‘amongst youngsters’, but this is not the target of recruitment and this needs to be clear. I assume this pilot used an adult audience for ‘proof of concept’ although I was surprised that the content was appropriate for people up to 60 years of age.\nThere needs to be clarity about numbers. The number of people in the trial is the number randomised (n=61). Loss to follow up is normal but needs to be distinguished. The study did not enroll 40 patients (page 9 of the pdf), it enrolled 61 of which 40 completed the study\nIt would be helpful to know how many people were recruited from each referral source, although those data may not be available.\nThe manuscript needs to be clearer about details such as the randomisation process and how concealment of allocation was ensured. I do not understand how the process led to such imbalance at baseline (37:24) and this needs to be explained and discussed. It does suggest an issue if the programme was set to 1:1\nI do not understand the CONSORT, as ‘FOLLOW UP’ suggests that no-one was lost to follow up or failed to complete the intervention, but the box above suggests that 21 did not complete. There is a huge imbalance in loss here between arms. A standard intent-to-treat analysis would analyse outcome data from non-completers. Did anyone not complete the intervention, but still provide outcome data? All this needs to be clarified and understood if we are to make sense of the results, because at present it looks like bias will be present in any analysis that loses more than 50% of one group, and none of the other.\nIt is generally not recommended to test for differences at baseline (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1116277/), and these data should be provided descriptively. Baseline data should be provided for ALL patients randomised to assess the success of the randomisation (which is done with descriptive data). The authors could then look at differences between ‘completers’ and ‘non-completers’ in baseline data to assess potential bias due to loss to follow up.\nData need to be consistently presented in terms of the number of decimal places.\nThe reason for the use of both the t-test and ANCOVA needs to be clarified. ANCOVA controlling for the baseline score on the outcome and for any pre-specified prognostic factors would be the norm in trial analysis, although they would generally be for a primary assessment of effectiveness, rather than a pilot\nAlthough the moderator analysis using the median split is theoretically interesting, the trial is not really big enough to provide a strong test (most trials are not) and a median split is likely to exacerbate these problems. The authors could consider removing this analysis, or should be very cautious about its interpretation. Again, there are published guidelines about conduct and reporting of subgroup analyses in trials (Sun et al Credibility of claims of subgroup effects in randomised controlled trials: systematic review. BMJ 2012; 344: e1553, Sun et al. Subgroup Analysis of Trials Is Rarely Easy (SATIRE): a study protocol for a systematic review to characterize the analysis, reporting, and claim of subgroup effects in randomized trials. Trials 2009; 10: 101) which could be referred to, although I think any subgroup analysis in a pilot is probably not appropriate\nAlthough compliance is an aim, I am not sure any data are provided on this beyond the limited data in the CONSORT, and this needs to be clarified.\nThere is the basis for an interesting pilot study here, but the presentation and analysis needs to be brought into line with current conventions and some significant ambiguities need to be clarified if readers are to assess this paper properly.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "251519",
"date": "08 May 2024",
"name": "Michelle Colder Carras",
"expertise": [
"Reviewer Expertise I am a public health scientist specializing in video games and mental health. I have additional expertise in public health informatics",
"including development and evaluation of digital health interventions. I am also somewhat of a US-based Otaku",
"although never Hikikomori or Futoko."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary This pilot RCT compared an interactive novel genre intervention to a traditional psychoeducational intervention in the treatment of individuals with severe symptoms of isolation and school refusal. Mental health and emotional response were evaluated at baseline and post-intervention. Student t-tests revealed intervention effects for emotional transportation (reduced in intervention group and relaxation (higher in intervention group), but ANCOVA controlling for group and emotional transportation also found lowered empathy in the intervention group post-intervention. Overall, the manuscript provides a description of an intriguing intervention, but this is not communicated clearly and concisely per suggested guidelines for scientific communication (see APA style and grammar guidelines). Although there is no way to know if this is the case here, the paper could be improved by consulting guidelines for turning a dissertation chapter into a scientific article. Again, the APA has suggestions, e.g. “Limit the introductory text to material relating to the immediate context of your research questions and hypotheses.”: https://apastyle.apa.org/style-grammar-guidelines/research-publication/dissertation-thesis\n\nIt would be useful to be specific throughout the paper about the measures. It seems that Narrative transportation, narrative engagement and emotional transportation may be used interchangeably in the text and tables.\n\nPeer Review Form – “No” or “Partly” responses\nIs the work clearly and accurately presented and does it cite the current literature?\nSee discussion of succinctness\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nSee discussion of choice of ANCOVA\n\nAre the conclusions drawn adequately supported by the results?\nIt is difficult to find the conclusions and how they link to the results\n\nIntroduction There is an overly-detailed background for the rationale behind developing the intervention. The manuscript would be much stronger and clearer if this could be made more succinct. See APA guidelines mentioned above: Currently it reads like a dissertation thesis chapter rather than a clear and logical background section designed to set up the rationale and methods for the study. For example, a previous game, SPARX, is described in 7 sentences. See APA guidelines mentioned above, e.g. ““Limit the introductory text to material relating to the immediate context of your research questions and hypotheses.” https://apastyle.apa.org/style-grammar-guidelines/research-publication/dissertation-thesis Making paragraphs shorter, ensuring each paragraph has a clear theme sentence, and using the inverted funnel approach to writing the introduction will help with this.\nGiven that Hikikomori and Futoko are the primary targets of intervention, these terms should be described earlier on in the paper. As a scientist with a background in mental health and a deep interest in school refusal, I would be curious to know how the standard of care in Japan relates to approaches used with youth showing behavior disorders in other countries, such as the strengths-based wrap-around approach and Multisystemic Therapy. This would help understand the generalizability and transferability of this intervention to other settings.\nGiven that the authors have previous work in this area, that deserves a bit more discussion. How does this RCT flow from the previous work?\nThe final paragraph of the introduction should be especially strong and succinct, presenting the rationale for the intervention and the methods used to assess it.\nThe introduction section is lacking a clear background of the development of the game. There is no way of knowing how this was accomplished and whether appropriate user-centered design was used. Many digital health interventions ultimately fail because they lack a human-centered design approach and don’t meet the needs of the target population. It would be appropriate to describe how the intervention was theorized and designed. There are appropriate guidelines for this, and it will greatly help future systematic reviews that include this paper.\nMethods It is wonderful that the study used broad criteria to recruit individuals, but including individuals with past social withdrawal experience needs more support. Is Hikkikomori considered an absorbent state? If not, wouldn’t it be expected that recovery from Hikkikomori would make it such that the intervention would have little to no effect?\nMeasures The link given to justify a score of >=5 on the GHQ goes to an article in the reference section about the SF-36; could the authors please review that reference?\nBackground information about measured constructs is better left in the Introduction (e.g., links between high or low self-esteem and other factors).\nPsychometric statistics are not routinely included; some measure of internal consistency in the sample should be reported. Formatting of the description of the internal consistency of subscales of the MES could be clarified, as a row of numbers with decimals is not easy to link to specific subscales.\nRecruitment: It would be good to provide more description of “sites dedicated to Hikikomori and school refusal subjects”.\nProcedure: Was there any ability to ascertain the timing of using the intervention or control parts of the website and completing the questionnaires? This would be very useful for validating timing of the measures.\nAdditional justification for a one-week measurement period is warranted, as often the lessons learned in interventions take longer to internalize and have an effect.\n\nIn the data analysis section, the description of the post-hoc ANCOVA is a bit confusing, particularly “score of emotional transportation at T1 as median split as fixed factors”.\nResults: The amount of dropout seems to differ between groups. Is there data to show when the dropout occurred? A missing data analysis would help determine if there are differences that would affect the analysis assumptions and interpretation of results.\nThe note about the three of five subscales of the MES being used could be moved to the measures section.\nThe discussion of the ANCOVA results as describing whether effects occur “through” enhancement of emotional transportation does not seem to fit the purpose of ANCOVA. It should be discussed how the mediation through emotional transportation fits within the use of a t-test + ANCOVA, or whether mediation is not the relationship/hypothesis testing being described by the analysis.\nThe reporting of t-tests is confusing. Why is it that sometimes 1-tailed and sometimes 2-tailed t tests are used? Checking the results for relaxation with Stata showed some differences from what is reported in the text; perhaps the t-test results need further scrutiny.\nIn the discussion of the many statistical tests, there is no need to repeat the same information in table and text. The text could be used to summarize the tables or point out results that were statistically significant or unexpected.\n\nOverall, it seemed like the intervention group had worsening in some areas. This should be discussed as a potential harm in the contexts of intervention risks. lower emotional transportation on t-test (2-tailed) Higher relaxation on t-test than control (1-tailed) Lower emotional transportation post-test on ANCOVA Lower narrative engagement post-test on ANCOVA By group and emotional transportation-effects on Empathy (lower), self-esteem, post on ANCOVA\n\nTable 6: It would be good to clarify that both group and emotional transportation median split are the covariates.\nLast sentence of page 14 is missing a variable name—relaxation, I think—just before “(Table 6)”.\nDiscussion: Succinctness is vital here. Much of the discussion would benefit from removing extraneous description. For example, the first sentence of the discussion is a succinct recap, but the following 4 sentences repeat the background information and could be cut.\nInstead of describing results of statistical testing as “mean values… showed a slight tendency to improve”, a more precise “mean values improved, but the difference did not reach statistical significance” would better convey the findings.\nI found it very difficult to understand the majority of the discussion due to the length and lack of a clear structure. Rather than succinct links between the study findings and prior literature, there seems to be extensive additional background information presented here. The impact of a Discussion section can be increased if it has a rapid and clear flow, for example,\nHere is one finding, succinctly presented [e.g., the intervention group had lower emotional transportation]. This was unexpected/does not support our hypothesis because… This conflicts with work by another person, perhaps because… Yet this is similar to work by another person, perhaps because… The implications of this situation are… Here is a second finding, succinctly presented. This supports our hypothesis that… This conflicts with work by another person, perhaps because… Yet this is similar to work by another person, perhaps because. The implications of this situation are…\n\nThe limitations section is very clear and well thought out. It’s surprising that it wasn’t possible to know when the questionnaire was completed if it was answered online; perhaps that could be explained.\nIt’s heartening to see the publicly available game and data; the authors are to be applauded! I did try to download and play the game, but the download file did not contain any way to start it when unizpped on a Mac running Sonoma 14.4\nAlso, I would like to apologize to the authors for the length of time it took to review this—email changes interfered with keeping track of this review.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-574
|
https://f1000research.com/articles/10-552/v1
|
09 Jul 21
|
{
"type": "Case Report",
"title": "Case Report: Systemic lupus erythematous associated with thrombotic thrombocytopenic purpura, a diagnostic challenge",
"authors": [
"Horacio Suárez-Ale",
"Elizabeth Fabian-Aquino",
"Virgilio E. Failoc-Rojas",
"Vicente A Benites-Zapata",
"Felipe Ignacio-Cconchoy",
"Horacio Suárez-Ale",
"Elizabeth Fabian-Aquino",
"Vicente A Benites-Zapata",
"Felipe Ignacio-Cconchoy"
],
"abstract": "Thrombotic thrombocytopenic purpura (TTP) is an uncommon microangiopathic disease and often occurs as a complication of systemic lupus erythematous (SLE). However, this probable causal relationship has not been completely proven. The diagnostic differentiation of both diseases is difficult in the first instance because they share similar characteristics that may overlap. We present a case of a 32-year-old woman with antecedents of epilepsy since she was 12 years old. The patient was admitted to the emergency room with a clinical picture of headaches, fever, paleness in the skin and mucosa, confused state, paresthesia, and transient spasticity of the extremities. The laboratory results revealed Coombs negative direct autoimmune hemolytic anaemia, severe thrombocytopenia, significant elevation of the enzyme lactate dehydrogenase, and presence of schistocytes ++ in the peripheral film. In addition, positive antinuclear antibodies and positive anti-native DNA in titers of 1/320 and 1/160, respectively, were found. Renal function was conserved. We concluded that it was a case of TTP associated with SLE and indicated treatment with plasmapheresis and methylprednisolone pulses, obtaining a satisfactory response (normalization of biomarker levels, health condition) after the second session of plasmapheresis. Diagnosis of both SLE and TTP is often difficult to achieve; however, adequate correlation of clinical manifestations and laboratory tests, along with the help of partial therapeutic interventions, may lead to good clinical response.",
"keywords": [
"Systemic Lupus Erythematous",
"Thrombotic Thrombocytopenic Purpura",
"plasmapheresis",
"adamts-3 protein",
"human"
],
"content": "Introduction\n\nThrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) that can be classified as idiopathic or in association with other pathological processes such as neoplasias, infections, and autoimmune diseases such as systemic lupus erythematous (SLE).1 Its classical presentation and characteristics are the pentad composed of: fever, neurological disorder, renal dysfunction, microangiopathic hemolytic anemia, and thrombocytopenia.1,2 The occurrence of TTP associated with SLE has an immunological basis related to the formation of antibodies that inhibit or diminish the function of a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 (ADAMTS13), and the increase in serum level of the inhibitor of metalloprotease ADAMTS3. The occurrence of both entities at the same time is a rare presentation; generally, TTP is a complication in patients with SLE.2,3\n\nThe clinical picture of both entities is somewhat similar because they share clinical characteristics that can overlap. It is difficult to make the diagnostic differentiation in the first instance, which delays the decision with regards to the correct treatment. This is important because the prognosis is more ominous when both entities appear at the same time, either as an association, or a secondary complication. We present a clinical case of a woman with a clinical presentation of SLE and TTP that was difficult to diagnose.\n\n\nCase presentation\n\nWe report a case of a 32-year-old woman of mixed ancestry and with no specific occupation who was admitted to the hospital as an emergency because she was presenting with a confused state, paresthesia, and transient spasticity of the extremities that lasted for 30 minutes. She also reported she had a fever of 38°C for three days before admission. As important antecedents she reported headaches, dizziness, sporadic ecchymosis on the legs, and oral ulcers since she was a teenager, which she did not consider important. She suffered from epilepsy since she was 12 years old for which she has followed irregular treatment with carbamazepine. She also has an obstetric antecedent of three pre-term labors between 32 and 35 weeks. Among family antecedents we can mention that her mother is epileptic, the grandmother on her mother´s side has lupus, and her youngest daughter had convulsions at three months of age.\n\nOn physical examination, a confused state, slight malar erythema, and ecchymosis on the legs and arms were found. The osteomuscular articular system and the cardiovascular and pulmonary systems had no alterations and she was hemodynamically stable. On admission, blood test showed hemoglobin: 7.5 g/dL, reticulocytes: 11.92%, and platelet count: 10,000/mm3; biochemical tests showed lactate dehydrogenase (LDH): 1,741 U/L, total bilirubin: 0.9 mg/dL, C-reactive protein (CRP) level: 0.79 mg/L, globular sedimentation rate (GSR): 77 mg/L, urea: 16 mg/dL (normal range: 11-20 mg/dL), and creatinine: 0.9 mg/dL (normal range: 0.7-1.5 mg/dL). Peripheral blood smear showed positive schistocytes (++). Brain CT-scan showed no alterations. Because of the hematological and biochemical alterations reported, 300 mL of platelet concentrates were transfused five times, elevating the platelet count to 40,000/mm3 with a rapid decline on the second day. This made us suspect that it was a case of thrombotic microangiopathy (TMA) with hemolytic anemia. We indicated autoantibodies tests in which we found negative antiphospholipid antibodies, positive antinuclear antibodies in titers of 1/320, and positive anti-native DNA in titers of 38.24 IU/mL. On the third day after admission, the platelets decreased to 9,000/mm3 and the patient presented with a sudden neurological disorder with language disturbance, paresthesia in lower extremities, and confused state, totally recovering in few hours; an emergency brain CT-scan was performed, which showed no significant changes. The diagnosis of SLE was confirmed, as well as TTP, based on the two positive results of the systemic autoantibodies, along with severe thrombocytopenia, microangiopathic hemolysis, and the neurological disorder. We began treatment with methylprednisolone pulses of one gram IV every 24 hours for three days; however, three days after the beginning of treatment, the level of platelets and red blood cells decreased to 7,000 mm3 and 6.8 g/dL, respectively, so we decided to begin plasma exchanges (plasmapheresis) using fresh frozen plasma with a volume of 2,000 mL. After the first plasma exchange, a significant increase in the level of platelets was evidenced, together with the reduction of LDH; so, four exchanges were completed, obtaining, five days after the last exchange, a normalization of the platelets and LDH levels: 243,000/mm3 and 374 U/L, respectively (Figure 1). Hemoglobin levels also began to raise to 9.5 g/dL, and there was a normalization of total bilirubin levels (0.28 mg/dL) and CRP (0.18 mg/dL). The patient had no clinical evidence of neurological symptoms, with platelets: 277,000/mm3 (normal range: 150,000-400,000/mm3) and hemoglobin: 12.8 g/dL (normal range: 11.9-13.5 g/dL). She was discharged four weeks after hospitalization with a medical prescription of prednisolone at a dose of 0.5 mg/kg/day PO for four weeks and her usual anticonvulsants (valproic acid: 30 mg/kg/day and carbamazepine: 15 mg/kg/day). There were no significant adverse effects.\n\nLDH: Lactate dehydrogenase.\n\nThirteen months after discharge, the patient was in good health, became pregnant, and had a satisfactory delivery with normal levels of platelets and hemoglobin.\n\n\nDiscussion\n\nTTP occurs in about 2% of patients with SLE.2,3 TTP manifestation after SLE has been more frequent than both appearing simulteanously.4 This case report is about a young woman who appears for the first time with SLE associated with TTP.\n\nTTP shares clinical and laboratory characteristics with SLE, which makes the diagnosis and proper treatment difficult and delayed,5 with a resulting elevation of mortality. Mortality due to TTP is greater than 80%, but when the appropriate treatment is followed with plasma exchange, the survival rate is greater than 80%. On the other hand, when TTP is present in patients with SLE, the episode is usually severe and lethal with a mortality rate of 34.1-62.5%.6–8 In this case report, the diagnosis was made by anamnesis and laboratory tests; the patient achieved clinical improvement and survived. The classical clinical pentad in the presentation of TTP: microangiopathic hemolytic anemia (MHA), thrombocytopenia, neurological disorder, renal dysfunction, and fever was not observed in this case; this has been observed previously, but it is not frequent to find this pentad currently.7,8 TTP does not usually present alone but is associated with or in concomitance with other pathologies, either autoimmune, neoplastic, or infectious. Sometimes, the treatment of concomitant pathologies in TTP can mitigate or mask some components of the classical clinical pentad. In addition, the poor specificity of the initial clinical manifestations of the TTP such as the neurological deficit associated with ischemia (headaches, consciousness disorders), and fatigue and abdominal pain associated with hemorrhage, make its diagnosis a challenge.5,8\n\nA cohort study that evaluated the clinical characteristics and prognostic factors of 105 cases of TTP associated with SLE found that the occurrence of the neurological disorder alone or accompanied by renal disorder was significantly higher in the group of patients that died than in the ones that survived, suggesting that the neurological and renal deficits could be a possible risk factor for mortality in patients with TTP and SLE.7 In this clinical case, the patient presented with sensory disorder and a confused state but recovered immediately and the analysis of images did not show cerebral lesions. The absence of kidney involvement in our patient could be because the clinical presentation of TTP was before or simultaneous to one of SLE, a presentation described as the least frequent in all cases reported to date.8,9 The appropriate treatment with plasma exchange and adequate hydroelectrolytic management probably prevented kidney involvement. This is an interesting situation because in most cases in which SLE appeared first, there was kidney involvement accompanying other clinical manifestations of TTP; this could explain the relative resistance to indicated treatments including plasma exchange in the cases reported, which showed a high mortality rate.6\n\nSeveral studies have found that treatment with glucocorticoids and plasma exchange can achieve remission of 65.7% in patients with SLE and TTP7,8 and it has been observed that some treatment options such as rituximab are used for refractory cases, achieving a good prognosis.3,7,8 In this case, the initial treatment was followed with methylprednisolone pulses of 1 g/day because it was focused mainly on active SLE complicated with TTP. However, the pulses were not favorable because two consecutive days after having received them, the clinical picture, mainly the neurological one, persisted and the hematological clinical picture with anemia and thrombocytopenia was worse, so plasma exchange was performed. With this management, the platelet figures increased significantly and there was a decrease in serum LDH levels. The response was positive after four plasma exchanges with platelet levels of 243,000/mm3.\n\nThe clinical and hematological evolution of the present case, which was favorable and rapid, contrasts with most of the cases reported in which there was a delay in the response and a high mortality rate despite the use of methylprednisolone pulses, plasma exchange, and other options such as the use of rituximab.3,7,8 The explanation to this particular situation could be that, excluding the positive serology in this patient (that is, the ANA and anti-native DNA antibody), the presentation of the clinical characteristics was not compatible with SLE but mainly with TTP, which could lead us to assume that SLE, for the moment, would be only serological and that its clinical manifestations could become clear in the future.\n\nPlasma exchange independent of ADAMTS13 activity is important and is recommended until the first platelet counts appear within normal limits for two consecutive days.10 TTP should always be considered in patients with hemolytic anemia and thrombocytopenia; however, in young women, SLE and TTP can occur simultaneously.\n\nThe strength of this case report relies on the uncommon presentation of both SLE and TTP, which adds more information about the clinical picture and possible outcomes. The main limitation was the lack of the ADAMTS13 activity and inhibitor tests, which are not used routinely but may have helped to confirm the diagnosis of TTP. The diagnosis of both conditions was even more challenging considering the differential diagnosis of epilepsy and the irregular use of medication for this neurological disorder.\n\n\nConclusion\n\nTTP associated with SLE is not a common presentation. It represents a challenge for diagnosis and treatment because it can be fatal if it is not treated on time. The peculiarity of this case is that the clinical presentation was almost exclusively one of TTP because it had only the neurological manifestations and positive serologic findings of ANA and anti-DNA that are present in cases of SLE. Plasma exchange and corticosteroids can be used successfully and the patients can achieve remission with treatment; in cases resistant to treatment, modulators of monoclonal antibodies like rituximab are frequently used. Our patient with SLE and TTP had a good response to the platelet replacement and methylprednisolone and her evolution has been favorable.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.",
"appendix": "References\n\nKnobl P: Thrombotic thrombocytopenic purpura. Memo. 2018; 11(3): 220–226. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLansigan F, Isufi I, Tagoe CE: Microangiopathic haemolytic anaemia resembling thrombotic thrombocytopenic purpura in systemic lupus erythematosus: the role of ADAMTS13. Rheumatology (Oxford, England). 2011; 50(5): 824–829. PubMed Abstract | Publisher Full Text\n\nAbu-Hishmeh M, Sattar A, Zarlasht F, et al.: Systemic Lupus Erythematosus Presenting as Refractory Thrombotic Thrombocytopenic Purpura: A Diagnostic and Management Challenge. A Case Report and Concise Review of the Literature. Am J Case Rep. 2016; 17: 782–787. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi J, Jiang JJ, Wang CY, et al.: Clinical features and prognosis of patients with thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus: a review of 25 cases. Ital J Pediatr. 2019; 45(1): 55. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShah AA, Higgins JP, Chakravarty EF: Thrombotic microangiopathic hemolytic anemia in a patient with SLE: diagnostic difficulties. Nat Clin Pract Rheumatol. 2007; 3(6): 357–362. PubMed Abstract | Publisher Full Text\n\nLetchumanan P, Ng HJ, Lee LH, et al.: A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus. Rheumatology (Oxford, England). 2009; 48(4): 399–403. PubMed Abstract | Publisher Full Text\n\nJiang H, An X, Li Y, et al.: Clinical features and prognostic factors of thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus: a literature review of 105 cases from 1999 to 2011. Clin Rheumatol . 2014; 33(3): 419–427. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChangcharoen B, Bolger DT Jr: Thrombotic thrombocytopenic purpura as an initial presentation of systemic lupus erythematosus with acquired ADAMTS 13 antibody. BMJ Case Rep. 2015; 2015. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPan YX, Wang HY, Shang YT, et al.: Clinical Analysis of 12 cases of Systemic Lupus Erythematosus Associated with Thrombotic Thrombocytopenic Purpura. Zhongguo shi yan xue ye xue za zhi. 2017; 25(4): 1147–1150. PubMed Abstract | Publisher Full Text\n\nGonzalez NS, Lorenzo N, Parodis Y, et al.: Thrombotic thrombocytopenic purpura in a new onset lupus patient? Immunol Res. 2017; 65(2): 454–458. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "97915",
"date": "15 Nov 2021",
"name": "Katerina Pavenski",
"expertise": [
"Reviewer Expertise TTP and other thrombotic microangiopathies",
"therapeutic apheresis and trasnfusion medicine"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a case report of a 32yo female with a new diagnosis of presumably immune TTP. The case is not unique but still may have value to the readers with appropriate revisions. I summarize my feedback below:\nTitle Based on reading this case report, I am not convinced that your patient fulfils the diagnostic criteria for SLE. She clearly has positive autoimmune serology but does not appear to have any clinical features of SLE. Finding of positive autoimmune serology is not uncommon in patients with iTTP, and some of these patients eventually develop SLE and some of them will not.\nAbstract\nSuggest to change \"TTP often occurs as a complication of SLE\" to \"TTP sometimes is associated with SLE\". The latter statement is more accurate.\n\nRe-word \"direct Coombs negative hemolytic anemia\". You surely do not mean \"autoimmune\" hemolytic anemia which is associated with spherocytes on film and RBC autoantibodies.\n\nWhat is \"conserved\" renal function? Do you mean her renal function was at baseline on the basis of measuring her serum creatinine, or serum creatinine was in normal range? Was urinalysis done?\n\nWas troponin done to rule out cardiac involvement?\n\nADAMTS13 activity and inhibitor were not done in this case but are required to confirm diagnosis. Please discuss this limitation and way to mitigate it (i.e. in resource constrained circumstance, can use a prediction score - such as PLASMIC) to predict chance of having low ADAMTS13.\nIntroduction\nThe classical pentad occurs in under 10% of cases of TTP. It is therefore important to question TTP when there is MAHA, thrombocytopenia and no obvious explanation and not wait for the pentad.\n\nCompletely disagree with statement \"generally, TTP is a complication in patients with SLE\". In most patients, iTTP is not associated with SLE or any other disorder. Indeed, to see SLE and TTP is not common at all.\nCase presentation\nWhat is meant by mixed ancestry?\n\nDoes \"irregular treatment\" with carbamazapine mean inconsistent compliance?\n\nWas there any history of obstetrical complications? Were antecedent births live and healthy? Were there any pregnancy losses?\n\nWhy were platelets transfused and repeatedly - 5 times? Based on lab work provided, very high chance of this being TTP (for e.g., if use PLASMIC score) and platelet transfusions are considered contra-indicated in patients with TTP (risk of worsening thrombosis) unless there is a life-threatening bleed. Was she seriously bleeding?\n\nWhy was plasma exchange not started right away or only after worsening of clinical and labs? Based on presenting labs, very high index of suspicion that this was TTP...why PEX was stopped after 4 treatments? Standard of care is usually daily PEX until platelets are normal for at least 2 consecutive days.\n\nDiscussion\nI disagree with \"TTP does not usually present alone\". In fact, in majority of cases, TTP presents alone, with no other diseases.\n\nI understand that there was a diagnostic uncertainty about her initial diagnosis: SLE vs TTP. And that treatment of SLE was appropriately steroid pulse. However, based on her presenting picture (fragmentation hemolysis and thrombocytopenia and evidence of target organ damage - neurological) TTP could not be ruled out and as such (SLE or not) she should have received PEX or risk mortality or further organ damage. For every day delay in starting TPE, risk of death increases (Van de Louw et al., 20211). This should be the message of this case report.\n\nI also would encourage the authors to include the statement about importance of getting ADAMTS13 activity test. If APLA, other autoimmune sophisticated serology could be done by the lab, so could be ADAMTS13. And this test is very important precisely because it is so difficult to differentiate TTP from other diseases, especially if more than one disease is present.\n\nRe sentence, \"TTP should always be considered...however in young women SLE and TTP can occur simultaneously\": This is not the reason to delay TTP treatment. TTP is most likely in young women and so is SLE. TTP should always be considered and treatment should be started, whether SLE is also suspected and especially in young women.\nConclusion Really, conclusion should be that SLE and TTP can occur together (albeit not frequently) and this makes diagnosis more difficult. However, considering the severe consequences of leaving TTP untreated (death, major organ damage), patient should be treated expediently as TTP with PEX and steroids while diagnosis is being sorted out.\nPlease consider my suggestions and good luck.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "8278",
"date": "25 May 2022",
"name": "Virgilio E Failoc-Rojas",
"role": "Author Response",
"response": "Title Based on reading this case report, I am not convinced that your patient fulfils the diagnostic criteria for SLE. She clearly has positive autoimmune serology but does not appear to have any clinical features of SLE. Finding of positive autoimmune serology is not uncommon in patients with iTTP, and some of these patients eventually develop SLE and some of them will not. Author Response: In fact, the patient met the criteria for SLE, but we did not detail the clinical manifestations. The patient had a history of epileptic seizures and oral ulcer, and on admission presented with malar erythema. Given the initial suspicion of SLE, subsequent immunological tests confirmed the diagnosis (positive antinuclear antibodies in titers of 1/320, and positive antinuclear DNA in titers of 38.24 IU/mL). We have sought to clarify the diagnostic process of SLE in the text. Abstract 1. Suggest to change \"TTP often occurs as a complication of SLE\" to \"TTP sometimes is associated with SLE\". The latter statement is more accurate. Author Response: Thank you. We have changed the statement. 2. Re-word \"direct Coombs negative hemolytic anemia\". You surely do not mean \"autoimmune\" hemolytic anemia which is associated with spherocytes on film and RBC autoantibodies. Author Response: We have re-worded the phrase. 3. What is \"conserved\" renal function? Do you mean her renal function was at baseline on the basis of measuring her serum creatinine, or serum creatinine was in normal range? Was urinalysis done? Author Response: We clarified this term. Yes, urinalysis was done and showed that serum creatinine was in the normal range. 4. Was troponin done to rule out cardiac involvement? Author Response: Yes, troponin was done and ruled out cardiac involvement. 5. ADAMTS13 activity and inhibitor were not done in this case but are required to confirm diagnosis. Please discuss this limitation and way to mitigate it (i.e. in resource constrained circumstance, can use a prediction score - such as PLASMIC) to predict chance of having low ADAMTS13. Author Response: Thank you, this limitation was discussed briefly. Introduction 1. The classical pentad occurs in under 10% of cases of TTP. It is therefore important to question TTP when there is MAHA, thrombocytopenia and no obvious explanation and not wait for the pentad. Author Response: Thank you for your comment. We agreed with this idea; this was pointed out in the text. 2. Completely disagree with statement \"generally, TTP is a complication in patients with SLE\". In most patients, iTTP is not associated with SLE or any other disorder. Indeed, to see SLE and TTP is not common at all. Author Response: Thank you. We clarified this statement, as the message was to explain that TTP might occur after SLE as a complication, in the context of the rare presentation of both entities. Case presentation 1. What is meant by mixed ancestry? Author Response: This was a term referred to as mestizo. We changed this term for sake of clarity. 2. Does \"irregular treatment\" with carbamazapine mean inconsistent compliance? Author Response: Yes, it does. To clarify the term, we changed it to “has been treated inconsistently with carbamazepine”. 3. Was there any history of obstetrical complications? Were antecedent births live and healthy? Were there any pregnancy losses? Author Response: The patient had three preterm delivery events. All births were live and healthy and there were no pregnancy losses. This was added in the text. 4. Why were platelets transfused and repeatedly - 5 times? Based on lab work provided, very high chance of this being TTP (for e.g., if use PLASMIC score) and platelet transfusions are considered contra-indicated in patients with TTP (risk of worsening thrombosis) unless there is a life-threatening bleed. Was she seriously bleeding? Author Response: Treatment was defined after consultation with experts based on clinical and platelet levels. We agree that this treatment is not the most appropriate but in the limited circumstances of the hospital it was the most accepted option. 5. Why was plasma exchange not started right away or only after worsening of clinical and labs? Based on presenting labs, very high index of suspicion that this was TTP...why PEX was stopped after 4 treatments? Standard of care is usually daily PEX until platelets are normal for at least 2 consecutive days. Author Response: The reason immediate treatment with plasma exchange was not performed was that TTP was not initially suspected, and the availability of treatment was not immediate to provide timely care. In addition, treatment with PEX was momentarily suspended after four treatments because, by expert consensus, the patient showed a favorable pattern in which the platelet level was increasing, and the DHL concentration was decreasing. Finally, upon seeing a consistent improvement, it was decided not to restart the plasma exchange. This response was also added to the text. Discussion 1. I disagree with \"TTP does not usually present alone\". In fact, in majority of cases, TTP presents alone, with no other diseases. Author Response: Thank you for your comment. We agree with this statement and have therefore revised the term in the text. 2. I understand that there was a diagnostic uncertainty about her initial diagnosis: SLE vs TTP. And that treatment of SLE was appropriately steroid pulse. However, based on her presenting picture (fragmentation hemolysis and thrombocytopenia and evidence of target organ damage - neurological) TTP could not be ruled out and as such (SLE or not) she should have received PEX or risk mortality or further organ damage. For every day delay in starting TPE, risk of death increases (Van de Louw et al., 20211). This should be the message of this case report. Author Response: Thank you for this insightful comment. We recognize that this was a limitation and agree that PTT should have been appropriately ruled out regardless of the diagnosis of SLE. We have added this message in the text. 3. I also would encourage the authors to include the statement about importance of getting ADAMTS13 activity test. If APLA, other autoimmune sophisticated serology could be done by the lab, so could be ADAMTS13. And this test is very important precisely because it is so difficult to differentiate TTP from other diseases, especially if more than one disease is present. Author Response: Thank you for your kind suggestion. Indeed, ADAMTS13 activity testing is a critical step in the diagnosis of TTP. However, many hospitals in Peru lack these and other sophisticated tests due to cost. With this in mind, we have added a statement on the importance of ADAMTS13 so that it may benefit the proper clinical management of PTT in future events. 4. Re sentence, \"TTP should always be considered...however in young women SLE and TTP can occur simultaneously\": This is not the reason to delay TTP treatment. TTP is most likely in young women and so is SLE. TTP should always be considered and treatment should be started, whether SLE is also suspected and especially in young women. Author Response: Thank you. The sentence was modified. We agree that in young women with these characteristics, one should think about TTP regardless of concomitant disease, and in the face of this suspicion act in a timely manner. Conclusion Really, conclusion should be that SLE and TTP can occur together (albeit not frequently) and this makes diagnosis more difficult. However, considering the severe consequences of leaving TTP untreated (death, major organ damage), patient should be treated expediently as TTP with PEX and steroids while diagnosis is being sorted out. Author Response: Thank you for your suggestion. We have modified this section to convey a more precise conclusion."
}
]
},
{
"id": "100435",
"date": "11 Jan 2022",
"name": "Ahmet Emre Eşkazan",
"expertise": [
"Reviewer Expertise TTP",
"Hematology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI have reviewed the manuscript. Although relatively rare, SLE and TTP may occur in the same patient, and although the case was well-presented, I do not think that this case does add anything new to what we have already known on this subject. As the authors stated, there are no ADAMTS13 activity, antigen, and antibody results. This, especially the anti-ADAMTS13 antibody result, is really important to distinguish hereditary TTP from immune-mediated TTP. In addition, the direct antiglobulin test is also lacking. In the longer-term follow-up, the patient did not receive any treatment for SLE, which is quite interesting.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-552
|
https://f1000research.com/articles/11-573/v1
|
25 May 22
|
{
"type": "Method Article",
"title": "Ensemble method for cluster number determination and algorithm selection in unsupervised learning",
"authors": [
"Antoine Zambelli"
],
"abstract": "Unsupervised learning, and more specifically clustering, suffers from the need for expertise in the field to be of use. Researchers must make careful and informed decisions on which algorithm to use with which set of hyperparameters for a given dataset. Additionally, researchers may need to determine the number of clusters in the dataset, which is unfortunately itself an input to most clustering algorithms; all of this before embarking on their actual subject matter work. After quantifying the impact of algorithm and hyperparameter selection, we propose an ensemble clustering framework which can be leveraged with minimal input. It can be used to determine both the number of clusters in the dataset and a suitable choice of algorithm to use for a given dataset. A code library is included in the Conclusions for ease of integration.",
"keywords": [
"Clustering",
"Consensus Clustering",
"Ensemble",
"Gaussian Mixture",
"Hierarchical Clustering",
"K-means",
"Number of Clusters",
"Spectral Clustering",
"Unsupervised Learning"
],
"content": "Introduction\n\nUnsupervised learning - one of the main branches of machine learning - is the study of previously unlabelled datasets. With the hope of gaining new insights into their data and its structure, researchers can attempt to group or segment their data based on similarities between the data points in an exercise called clustering.\n\nClustering problems have been studied in-depth, with applications in the fields of computational biology, operations research and social sciences1–3 to name a few. Quite a few algorithms are available for use, including in popular open-source libraries.4,5 However, these problems have often required human intervention on the part of the researcher. Naturally, this severely limits automation and is prone to human-error.\n\nThe need for researcher input is due mainly to two problems: determining the number of clusters in the dataset, and choosing an algorithm to cluster with. Both can produce highly inaccurate results if poorly selected.\n\nThe canonical approach to determining the number of clusters in a dataset is to take an “elbow method” approach. We detail this in the Problem section. In short, it attempts to cluster the dataset with different numbers of clusters and compare the outputs, looking for an elbow in the curve of results. However, this has inherent shortcomings. A researcher must still choose which algorithm and which set of hyperparameters to use.\n\nWhile hierarchical clustering algorithms (HCA) can be used to automatically find the number of clusters with reasonable accuracy in some cases,6 using this method means we miss out on using the many other algorithms that have been developed, even if they would be better suited to our dataset.\n\nA large number of sophisticated methods have been explored as well.7 One of the more famous approaches was developed by Monti, et al.8 - called consensus clustering. Many of these methods (including Monti) suffer from a high level of complexity and abstraction, often based on the idea of partitioning the data.9,10 Essentially, they attempt to cluster many different subsets of the data under different cluster numbers and then select the most stable ones.\n\nApart from usability stemming from their complexity, many of these methods can get computationally intensive (including memory requirements). Lastly, as noted in Ref. 11, they do not generally perform well when it comes to estimating the number of clusters. As a final note, these approaches also suffer from the need for researcher input as to the choice of algorithm and parameters. We consider it prudent, therefore, to explore the topic further.\n\nIn this paper, we propose an ensemble approach to answering the following questions: How many clusters are in the dataset, and which algorithm-hyperparameter choice is best for this data? Our approach outputs the number of clusters, as well as both a model choice and a set of hyperparameters to use with the model. Note that we do not define ensemble in the sense of a collection of partitions, but rather separate algorithms, as seen in Ref. 12.\n\nLuckily, several of the graph-based methods mentioned above - including consensus clustering and its improvements - are actually complementary to our proposed method, and we see no reason why they could not be combined, albeit with a bit of work. Consensus clustering takes as input a model and its hyperparameters, but has no framework for choosing a suitable model. Likewise, this first discovery we are presenting does not account for any data partitions.\n\nWhile we leave the task of truly combining our approach with existing methods to future work, we present evidence of the benefits of accounting for model and hyperparameter choices in Monti’s consensus clustering, and we invite the reader to consider the possibilities as they read through our work. In the following section, we look at the problem in more detail, exploring the three main areas that must be addressed. In the Methods we define our algorithm or workflow. We then discuss results, present typical usage in the Discussion, and finally summarize our approach and findings in the Conclusions.\n\nAs mentioned, the central issue we are facing is that of finding the number of clusters in our dataset. While we have previously stated that the choice of algorithm and hyperparameter set is important, we found it was often overlooked in the literature, being taken as a given or covered at a high level.13 So, we set out to compute some baseline performance changes that choosing the algorithm and hyperparameter set can have. We found that, in fact, this choice had a very large impact on predicting the number of clusters in a dataset, and were ourselves quite startled by the magnitude of these variations.\n\nPerhaps the most common approach to determining the number of clusters is to use the elbow method.14,15 This involves making many attempts at clustering, and then picking the one that seems to fit best. More directly, the workflow is:\n\n1. Choosing a clustering algorithm and parameter set.\n\n2. Clustering the data into n clusters for n∈2⋯N.\n\n3. For each N−1 attempts, computing a metric (ex: BIC).\n\n4. Finding the elbow in the curve of metric values, the x-axis value is our number of clusters.\n\nNote that automatically finding the elbow can be done in several ways, such as the minimum absolute second derivative, the point of best linear fit, or as we will use here, the triangle method.\n\nIntuitively, we can view these methods through the lens of Information Theory. Namely, the curve represents the amount of information explained as we increase the number of clusters. As we begin getting diminishing returns, we say that we are no longer explaining the data, and have too many clusters (hence the cutoff at the elbow).\n\nOur approach will rest on this method and principle, but will tackle its three weaknesses - the choices that were implicitly made: algorithm, hyperparameters and metric. Many of the difficulties are discussed at a high-level in Ref. 13. We are essentially tackling Step 2 (and partially Step 1) in Figure 1 in their Conclusion.\n\nFor now, let’s quantify exactly how important these choices are. Using the elbow method as a baseline, we computed some accuracy statistics on 100 randomly-generated three-cluster datasets, detailed in the Performance section. We defined accuracy as correctly determining the number of clusters we have (in this case 3). For each algorithm, we looked at performance across a broad range of hyperparameters and metrics, detailed in the Full dataset section.\n\n\nMethods\n\nOur data consisted of 100 two-dimensional three-cluster collections of 30,000 points each. The data was drawn from a standard normal distribution, with cluster centers randomly places between −5−5 and 55. Specifically, the data was constructed using the scikit-learn function make_blobs (Figure 2):\n\nThe first step many researchers will take to successfully cluster their data is to choose a clustering algorithm (step 1 in the traditional workflow above). A variety of inherently distinct algorithms exist, from Spectral methods to HCA and Density-Based Spatial Clustering of Applications with Noise (DBSCAN). The issue at this step is that different algorithms can be better suited to different datasets,16 and this can be very difficult to determine ahead of time. While there are some generally accepted behaviors - ie, Spectral clustering works well on non-convex datasets4 - we can also see this experimentally.\n\nFor each algorithm, hyperparameter and metric choice, we computed the accuracy of our predicted number of clusters on the 100 datasets, giving us M accuracy readings. For example, for one algorithm with two possible metrics and three hyperparameter values, we would have six accuracy readings for the clustering algorithm. If the choice of algorithm did not matter, then we would get the same statistics across different algorithms. The table below shows the statistics for those M readings for K-means, Gaussian mixture model (GMM), HCA and spectral:\n\nAs we can see, different algorithms obtain rather different results (whether the mean or max performance). The performance of the spectral and HCA algorithms, which are clearly ill-suited to our datasets, is particularly interesting. On the other hand, we can see that there is some combination of metrics and hyperparameters for which GMM does quite well with a 91% accuracy. Its standard deviation is quite high though, suggesting that different metrics and hyperparameters can lead to quite different results.\n\nThe second choice traditionally faced by researchers is hyperparameters (implicitly contained in step 2 of the traditional workflow). Generally referred to as hyperparameter tuning, this can greatly improve the performance of a model. Let’s examine the effect of hyperparameters in our experimental setup from the Simulated data section. Let’s hold the choice of metric constant (selecting inertia I - more on this in the Choice of metric section). This gives us:\n\nTable 2 shows us that the choice of hyperparameters, independent of other choices, can lead to large differences in performance. For instance, a judicious choice of hyperparameters in our K-means algorithm can lead to an 18% increase in performance. Similarly, a poor choice for Spectral leads to a staggering 86% drop. Unfortunately, we have no way of knowing ahead of time which parameter selection will yield the best results in a clustering problem (given an absence of ground truth).\n\nFurther, hyperparameters explain some of the variation we saw in Table 1 but not all. A quick look at the various statistics shows us we are missing another piece: the minimum performance seen by the K-means algorithm is now 71% instead of the rather shocking 8%. This indicates one more component to the problem.\n\nstd: standard deviation; min: minimum; max: maximum.\n\nstd: standard deviation; min: minimum; max: maximum.\n\nFinally, we arrive at the last choice we have to make: which metric to use (step 3 in the aforementioned workflow). Previous work by the author showed that in the case of HCA, different metrics performed differently,6 but there hasn’t been much work on this topic in general. However, we can once again examine this experimentally. In the same experimental setup as we used above, let’s examine the performance of algorithms for a fixed selection of hyperparameters across different metrics.\n\nEvery algorithm used the Inertia and Silhouette Score metrics.4 HCA also used the maximum Difference and Elbow metrics from.6 K-means and GMM also used the Akaike information criterion (AIC) and Bayesian information criterion (BIC) metrics.4 For the table of results, we took the first set of hyperarameters for that algorithm, denoted by the superscript 0.\n\nOnce again, we can see variations in performance within each algorithm-hyperparameter choice, here based solely on the choice of metrics. It turns out that much like we saw in Table 1 with HCA and Spectral, there is a weak element: the Silhouette Score.\n\nstd: standard deviation; min: minimum; max: maximum.\n\nThough not obvious from this table, further investigation shows that it has an average accuracy across all algorithms and hyperparameters of only 12%. By cutting the number of algorithm-hyperparmeter combinations we’ve amplified its effect, and are seeing it drag performance down across the board, something we couldn’t know ahead of time.\n\nThe problem is now apparent: we need to find a way to filter out the many possibly bad choices in algorithms, hyperparameters and metrics if we are to find the number of clusters in a dataset with reasonable accuracy.\n\nAs we saw in the previous section, we know there are some winning combinations of algorithm-hyperparameter-metric, but we must now figure out how to find them ahead of time. At a high level, our approach uses a fairly simple ensemble method. We clustered the dataset using all the combinations we could think of and selected our predicted number of clusters from all the results combined.\n\nThis section’s structure will follow the workflow of our algorithm, split into: set construction, building the ensemble, and voting. While we have found a preferred approach on our test dataset, we present several alternatives to each step of the workflow. First, however, the reader must endure some exposition of notation to be used throughout.\n\nSuppose we work with an ensemble of algorithms, denoted by the set\n\nThese would be the clustering algorithms such as K-means, GMM, etc.\n\nEach algorithm can have a set of hyperparameters associated with it. Let that be written as\n\nFurther, each hij can be comprised of several elements. For instance for GMM, h01 could be the covariance type and regularization parameter: DIAGONAL10−6, and h11=DIAGONAL10−5. If it helps, think of each hij as a set of kwargs passed into a model object.\n\nLastly, let’s write the set of metrics (inertia, AIC, etc) used as\n\nNow, given A, ℋj and ℳj, we have ∀j∈0N\n\nWe admit the notation is somewhat opaque, but by constructing our actual test sets it should be illustrated nicely.\n\nWorkflow\n\nNow that we have defined our A, ℋ and ℳ sets - and obtained our P sets - we must compute the clusterings.\n\nThis is, quite simply, an exhaustive loop over all the elements of the respective P set, where we apply the elbow method as described in the Methods section. ∀j∈0N, and ∀p∈Pj,\n\n1. We take an element p∈Pj.\n\n2. We use the hyperparameter values from p to compute clusterings for a range of cluster numbers.\n\n3. We then use the metric found in p to get an elbow curve.\n\n4. We find the elbow in the curve.\n\nFor each p, we have now found a suitable number of clusters for our data. More formally, we have just computed\n\nNote that Cj is simply a set of integers that map back to specific elements in Pj. For K-means clustering a 3-cluster dataset, we might get\n\nWe can then combine the results into a collection and find the number of clusters and best algorithm-hyperparameter selection from there:\n\n1. Construct the ensemble set ℰ (we developed two approaches detailed in the Building the ensemble section).\n\n2. Vote on the number of clusters (we developed three approaches detailed in the Voting section).\n\nSet construction\n\nThe first step in the workflow is to construct our A, ℋ, and ℳ sets. Let’s build some actual test sets to illustrate the structure. These were used for computational results in the Results section, and might help clarify the notation in the meantime. These models were built from the scikit-learn and fastcluster libraries.\n\nFirst, let’s define the algorithms to look at:\n\nThese were selected based on their diverse natures. Ideally, one wants to choose a collection of algorithms that work well on different types of data. In this case, K-means is a fast and reasonably accurate algorithm for convex datasets, HCA is fundamentally different and does not take cluster numbers as inputs, GMM is well-suited to data with a roughly Gaussian distribution and Spectral has been known to do well with non-convex datasets.\n\nNow, the set of hyperparameters can get rather cumbersome to write out, but let’s explicitly list those ranges for K-means:\n\nThis gives us the following set of hyperparameters for K-means:\n\nFor brevity, we present the remaining sets based on their base ranges:\n\n(where, for Spectral, metric and n_neighbors are only used for precomputed, and gamma is ignored for precomputed).\n\nIn general, hyperparameters should be selected based on available information. If a researcher can somehow narrow the hyperparameter space through other knowledge, they should do so. In the absence of such information, as is our case here, we tried to choose hyperparameter ranges that span the space.\n\nObviously, some of these parameters can take on an infinite number of values (and we have limited computing resources), but we find it judicious to choose a smaller number of values across orders of magnitude to obtain a representative sample of reasonable values.\n\nNow that we have our A and ℋ sets, we need ℳ. Per algorithm, we have:\n\nIn other words, for K-means, we get:\n\nWhat remains now is to construct our ensemble collection ℰ.\n\nWe present two approaches for building the ensemble set ℰ in the following sections, and detail the rest of the workflow thereafter.\n\nRaw\n\nGiven our C sets, the most natural way to construct our ensemble is simply to check every possible combination, essentially a cross product of our sets. This gives us our ensemble of values\n\nFollowing the example from the previous section, ℰ would be comprised of four-tuples spanning all possible combinations. Each tuple would contain a “guessed” cluster number given a specific algorithm-hyperparameter-metric choice.\n\nIf we structured ℰ as a matrix, the first few rows might look like\n\nwhere the first column corresponds to guesses from K-means, the second from GMM, then HCA and Spectral algorithms.\n\nMode\n\nWhile the Raw approach detailed above is the simplest, we consider the fact that it ignores a potentially important point. The choice of metric, while critical to the workflow, is intrinsically an \"elbow-method\" parameter. This sets it apart from the choice of algorithm and hyperparameters, which would be necessary regardless of approach.\n\nWith this in mind, we consider another formulation which first takes the mode of the results across metrics. That is, for a given algorithm and hyperparameter configuration, we take as a result the most commonly guessed number of clusters across all metric choices. We define\n\nFrom this we can define our ensemble ℰ¯ in the same way as ℰ,\n\nHere, our matrix will be smaller than in the Raw approach. Each column still corresponds to an algorithm, but each entry is now the mode of the guesses produced by a set of hyperparameters.\n\nNow, given our matrix E, there are a few ways to combine the results and vote on them. As a toy example, consider this result for a three-cluster dataset:\n\nFull\n\nThe simplest approach would be to simply take the most common cluster number found in our ensemble. While straightforward, it doesn’t allow us to capture any additional information, nor filter out errors or biases in any way. Our toy example contains 11 2s and nine 3s; we would get an incorrect final result of R=2.\n\nColumn-First\n\nAnother naive approach would be to vote along algorithms, giving us 4 results, and then voting for the most common answer within those 4. One possible issue with this approach is the case where we have a few particularly ill-suited algorithms. Looking at the same example, we get\n\nand an incorrect final result of R=2.\n\nRow-First\n\nFinally, we can look to capture what we are calling the cohesion between the results, essentially, favoring their agreement. By first looking at the individual rows of our example we would have\n\nand therefore R=3.\n\nGiven that our set ℰ (or ℰ¯) covers all combinations of results, we are choosing to prioritize those cases where our different algorithm-parameter-metric results are cohesive (row-wise), before looking at their actual value (column-wise).\n\nWe present results for the three approaches in the next section.\n\n\nResults\n\nNow, we arrive at our results. In the following sections, we present the results of the six different approaches (Raw/Mode with Row/Column/Full) on 100 simulated datasets from Section 1. We compared our results to two benchmarks.\n\nThe first is the expected value from randomly sampling our result set 100 times; essentially the accuracy we could expect from choosing an algorithm, hyperparameters and metrics beforehand.\n\nThe second is the consensus clustering approach put forward by Monti et al.8 In this case, we used K-means and GMM and attempted to pass in both default hyperparameters (D) and the best performing hyperparameters (B) as determined by our method.\n\nHere, we define accuracy by comparing the predicted number of clusters for each of the 100 datasets - based on voting on the ℰ or ℰ¯ set - to the actual number of clusters (three in every case).\n\nOverall results are shown in Table 4.\n\nWhile there were differences in performance between the voting methods, the signal was somewhat muddled. In the case of the Raw construction the Row-first approach was best, while for a Mode construction a Full vote was preferable. Overall, the differences in voting performance were also small, providing at most a 3% increase. We don’t consider it prudent to declare one voting approach more beneficial than another.\n\nOn the other hand, the choice between using a Raw ensemble construction ℰ or a mode-based ℰ¯ set seems to be clearer. Using a mode construction improved performance across the board, yielding a 2−8% increase in accuracy.\n\nGiven a mode-based ℰ¯ set, the naive voting took the lead: it was overall the best performer with 93% accuracy. Additionally, we find it important to note that we actually outperformed even the maximum performance we saw in Table 1, which was 91%.\n\nGiven that the latter could only occur given a prefect guess as to which algorithm-hyperparameter-metric combination to use, we find it even more satisfying.\n\nTable 5 details our benchmark performance as defined in this section: consensus clustering and expected value from random sampling.\n\nNot unexpectedly, randomly guessing at possible solutions yielded unsatisfactory results. We note that it consistently scored above 50%, likely due to the fact that even poor algorithm configurations can still pick up some signal.\n\nConsensus clustering gave very unpredictable results, with a very large variance in performance - though it did peak at a respectable 87%. We reiterate our previous point, however, that it requires a choice of algorithm and hyperparameters as inputs, greatly reducing its effectiveness in practice.\n\nPerhaps the most interesting result to come out of benchmarking was the performance of consensus clustering with respect to hyperparameter selections that did very well in our method. In the case of GMM this led to a drastic drop in performance (30%), while for K-means we saw a 6% increase. This would indicate that while it is likely a non-trivial exercise to combine the approaches in a reasonable way, it could be worth further investigation.\n\n\nDiscussion\n\nNow that we have examined this problem and our proposed solution, we’d like to discuss some other elements. Namely, typical usage setups, and some simple approaches to selecting the best algorithm-hyperparameter combination in each case. As our colleagues in industry would ask, how do we use this in production?\n\nWe would like to note that the following algorithm selection methods in particular are merely simple approaches to get things off the ground. There are undoubtedly other ways to solve this and we encourage further work in this area.\n\nWe believe there to be two general use-cases depending mainly on computational constraints: the case where all our data can be processed at once, and the case where we must slice our data into subsets first.\n\nIf we look at the case where we must partition our data due to computational limitations, we find ourselves in essentially the same framework that we did throughout the paper. While we will leave it to the reader to determine the best way to sample subsets of their data while capturing all clusters, let’s examine how this ensemble framework would work.\n\nThroughout, we have looked at 100 simulated datasets as a means of getting accuracy metrics. Suppose now we take our large dataset and split it into 100 smaller, more manageable, datasets. We are now in the same situation as we were earlier in the paper: we would expect the number of clusters to be the same for each of the smaller datasets, and we would aggregate the results of 100 ensemble methods (albeit not with “accuracy”).\n\nEstimating the number of clusters\n\nNow that we have our 100 subsets, we can construct our E matrix for each one of them and vote on the number of clusters. This gives us 100 answers, one cluster number estimate per subset.\n\nFrom there, we could select the most common answer (i.e., the mode) as our global estimated number of clusters (instead of computing accuracy as we did in this paper). Having determined how many clusters our dataset has, we arrive at the question of choosing an algorithm.\n\nAlgorithm-hyperparameter selection\n\nStill within our 100 subset context, let’s examine how we could choose a best algorithm-hyperparameter combination. We reiterate that this is only one of what is likely many possible approaches.\n\nGiven our estimated number of clusters, all the answers estimated by each algorithm-hyperparameter-metric combination found in the subset E matrices can be stored. From there, the accuracy of each algorithm-hyperparameter-metric combination (relative to our global estimated number of clusters) can be computed. The best-performing combination can be taken as a reasonable way of clustering future data from the same dataset.\n\nIndeed, in our simulated case, this approach correctly identified that GMM is the best choice, and more specifically that the combination\n\nachieved the best results, with 91% accuracy. Readers will note this is indeed the top performance we can achieve as per Table 1.\n\nIt seems reasonable to assume that given more data drawn from the same dataset, this algorithm with these hyperparameters would do well at clustering it in a sensible way. We do note that it is possible to apply the logic presented in the Algorithm-hyperparameter selection section under Methods; in this case as well, such logic is included in the code library by default.\n\nNow let’s look at the simpler case where all of our data can be processed together as a single dataset.\n\nEstimating the number of clusters\n\nIn this happy scenario, estimating the number of clusters is relatively straightforward: we run a single workflow. We begin by constructing our E matrix. Then, we compute the results of voting, which directly gives us the predicted number of clusters in our data.\n\nIn this case there is no need for any aggregation as we have a single outcome from the vote.\n\nAlgorithm-hyperparameter selection\n\nWhen it comes to identifying the right choice of combination, however, we can’t proceed as we did in the subset case. Given that we have no way of computing accuracy, we will instead look for the “most stable” choice. Once more, this is simply a first approach and that future work could likely result in improvements.\n\nFor each algorithm-hyperparameter combination, we look at its predictions across metrics (which are not needed for future clustering). For example, suppose that on the first dataset from our simulated data the GMM combination\n\nobtained results of [3, 3, 3, 3] across its four metrics, whereas\n\nobtained. [3, 4, 2, 3]\n\nIn this example, we would favor the combination that was most often correct: [3, 3, 3, 3]. Note that we are essentially looking for stability and insensitivity to metric choice.\n\nIf we extend this comparison to every algorithm-hyperparameter combination, we arrive at a suitable combination choice to use for future clustering. We note, however, that given the small number of metric choices, this approach is less likely to yield a unique best choice.\n\nIf that is the case, any of the top-ranked combinations may be selected, as they are equally likely to achieve desirable results - as per this stability framework.\n\n\nConclusion\n\nWe have developed a workflow with six possible configurations for determining the number of clusters in an unlabeled dataset, while offering a flexible basis for determining the optimal choice of algorithm and associated hyperparameters. While certain methods already exist, such as for agglomerative hierarchical clustering and consensus clustering, they each present difficulties in the field that our approach addresses.\n\nFistly, we no longer require researchers - who may not be subject matter experts in unsupervised learning, but rather their own domains - to provide such specific inputs as particular algorithms and hyperparameter-metric configurations. Instead, given reasonably spanning ranges of hyperparameters, and a diverse selection of algorithms, we can reliably predict the number of clusters present with more than 90% accuracy.\n\nWe also obtained - at very little cost - a reasonably suitable choice for which algorithm and which hyperparameters to use to further cluster the data. While not every situation will require clustering of additional incoming data from the same distribution, combination performance findings are sure to be beneficial to researchers.\n\nLastly, it is our hope that the simple algorithmic structure of this approach can lead to reliably simple integration into commonly used software libraries - thereby removing another barrier to entry. The code used for this framework can be found on GitHub.\n\nIn the future we hope to explore several avenues of work related to this approach. This includes studying other means of measuring cohesion (other than a row-first approach). We would also like a process to automatically track the ensemble set as it is populated and to adjust the hyperparameter space dynamically. This could allow for faster computations and less noise in the resulting ensemble. Finally, a careful and constructive combination of consensus clustering and our ensemble method.\n\n\nData availability\n\nZenodo: antoinezambelli/ensemble-clustering: v1.0.0, https://github.com/antoinezambelli/ensemble-clustering/tree/v1.0.0\n\nAnalysis code available from: https://github.com/antoinezambelli/ensemble-clustering\n\nArchived analysis code as at time of publication: https://github.com/antoinezambelli/ensemble-clustering/tree/v1.0.0\n\nLicense: MIT",
"appendix": "Acknowledgments\n\nWe thank Dr. Alexandra Cunliffe for her help in reorganizing the paper for better clarity.\n\n\nReferences\n\nMcGuirl M, Smith S, Sandstede B, et al.: Detecting shared genetic architecture among multiple phenotypes by hierarchical clustering of gene-level association statistics. Genetics. 06 2020; 215 (2): 511–529. 1943-2631. PubMed Abstract | Publisher Full Text\n\nSong X, Li W, Ma D, et al.: An enhanced clustering-based method for determining time-of-day breakpoints through process optimization. IEEE Access. 2018; 6: 29241–29253. Publisher Full Text\n\nCaoli AJ: Machine learning in the analysis of social problems: The case of global human trafficking. The British University in Dubai, (Dissertation). 2019.Reference Source\n\nPedregosa F, Varoquaux G, Gramfort A, et al.: Scikit-learn: Machine learning in Python. J. Mach. Learn. Res. 2011; 12: 2825–2830.\n\nMüllner D: fastcluster: Fast hierarchical, agglomerative clustering routines for r and python. J. Stat. Softw. 2013; 53(9): 1–18. Publisher Full Text\n\nZambelli AE: A data-driven approach to estimating the number of clusters in hierarchical clustering. F1000Res. 2016; 5(ISCB Comm J): 2809. PubMed Abstract | Publisher Full Text\n\nVega-Pons S, Ruiz-Shulcloper J: A survey of custering ensemble algorithms. Int. J. Pattern Recognit. Artif. Intell. 2011; 25(3): 337–372. Publisher Full Text\n\nMonti S, Tamayo P, Mesirov J, et al.: Consensus clustering: A resampling-based method for class discovery and visualization of gene expression microarray data. Mach. Learn. 2003; 52: 91–118. Publisher Full Text\n\nAlqurashi T, Wang W: Clustering ensemble method. Int. J. Mach. Learn. Cybern. 2019; 10: 1227–1246. Publisher Full Text\n\nYu Z, Wong H-S, Wang H: Graphbased consensus clustering for class discovery from gene expression data. Bioinformatics. 09 2007; 23(21): 2888–2896. 1367-4803. PubMed Abstract | Publisher Full Text\n\nȘenbabaoğlu Y, Michailidis G, Li JZ: Critical limitations of consensus clustering in class discovery. Sci. Rep. 2014; 4: 6207. Publisher Full Text\n\nYi J, Yang T, Jin R, et al.: Robust ensemble clustering by matrix completion. 2012 IEEE 12th International Conference on Data Mining. 2012; pages 1176–1181. Publisher Full Text\n\nHandl J, Knowles J, Kell DB: Computational cluster validation in post-genomic data analysis. Bioinformatics. 08 2005; 21(15): 3201–3212. PubMed Abstract | Publisher Full Text\n\nDangeti P: Statistics for Machine Learning. Packt Publishing;2017.\n\nShi C, Wei B, Wei S, et al.: A quantitative discriminant method of elbow point for the optimal number of clusters in clustering algorithm. J. Wireless Com. Network. 2021; 2021. Publisher Full Text\n\nGordon A: Classification. CRC Press;1999."
}
|
[
{
"id": "147137",
"date": "11 Aug 2022",
"name": "Dong Huang",
"expertise": [
"Reviewer Expertise Ensemble clustering",
"Multi-view clustering",
"Large-scale clustering"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper proposes a new ensemble clustering framework that is able to determine the number of clusters and the suitable choice of the algorithm to use for a given dataset.\nThis work aims to automatically find the number of clusters in ensemble clustering. Yet the related works should be enriched. For example, the ensemble clustering by factor graph (ECFG) algorithm finds the number of clusters via probabilistic formulation, which should also be discussed. Furthermore, the references are mostly outdated, where only one paper is published after 2020. Some recent works, such as multidiversified ensemble clustering, ensemble clustering via fast propagation of cluster-wise similarities, and ultra-scale ensemble clustering, should be discussed.\nIn the experiments, k-means, GMM, HCA, and spectral clustering are used as baselines. However, I would like to see further experimental comparison between the proposed algorithm and some other ensemble clustering algorithms.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
},
{
"id": "220274",
"date": "17 Dec 2023",
"name": "Ana Estela Antunes da Silva",
"expertise": [
"Reviewer Expertise Artificial Intelligence",
"Machine Learning"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper presents a real problem for users of machine learning algorithms which apply the task of clustering. One of the problems is choosing the number of groups, as well as the best algorithm to be applied to the problem. As a solution to this problem, authors propose an ensemble approach to answering the following questions: How many clusters are in the dataset, and which algorithm-hyperparameter choice is best for this data? Their approach outputs the number of clusters, as well as both a model choice and a set of hyperparameters to use with the model. This problem is very relevant and a tool with these characteristics can be of great importance.\nIn order to explain the answers for which I selected \"partially\", I present the points below.\nOn page 3 the author says:\n“While we leave the task of truly combining our approach with existing methods to future work, we present evidence of the benefits of accounting for model and hyperparameter choices in Monti’s consensus clustering, and we invite the reader to consider the possibilities as they read through our work”. This sentence does not make it clear what will be presented in the article. Phrases like this compromise the reading of the article. I suggest rewriting, according to the Results, on page 11, a subsection that says: “The second is the consensus clustering approach put forward by Monti et al.8 In this case, we used K-means and GMM and attempted to pass in both default hyperparameters (D) and the best-performing hyperparameters (B) as determined by our method”.\n2. Figure 1, on page 4, is a central figure for the article. I suggest explaining each of the steps more formally. For example, what is N? In step 3, which metric is the author referring to?\n3. Also, I don't think the elbow method (Figure 1) should be in the Introduction section, but rather in the Methods section. The entire methodology should have been explained according to the detailed steps of the method, including the explanation of the metrics.\n4. On page 4, the sentence “Using the elbow method as a baseline, we computed some accuracy statistics on 100 randomly generated three-cluster datasets…” It is necessary to explain which are the “accuracy statistics” and why the author decided to use them.\n5. On page 4, the sentence “For each algorithm, we looked at performance across a broad range of hyperparameters and metrics, detailed in the Full dataset section.”\n6. The author uses the word metric in a generic way without explaining what type of metric she/he is referring to.\n\n7. It is not clear the information from table 1, on page 5. Is the mean and SD of the 100 datasets with K-means? I suggest that the explanation above in Table 1 be revised. For example, the meaning of the sentence “If the choice of algorithm did not matter, then we would get the same statistics across different algorithms” is not clear.\n8. To facilitate understanding of the methodology itself, the subtitles in the Methods section should be more explanatory. For example: Simulated data ==> Data used in the experiments of our method. Choice of algorithm==> Selection of the most adequate clustering algorithm. Choice of hyperparameters ==> Here it is not clear whether this choice involves number of parameters or type of parameters or both. A most adequate subtitle would help.\n9. Table 2 shows the execution of algorithms with different parameter choices, however, which and how these choices were made is not clear. If the objective was not to discuss these choices, but to highlight that different choices can lead to different results, I suggest that this is made clearer in the text.\n10. The Set Construction subsection, on page 8, could be called: Ensemble Algorithm. All the following subsections should be summarized in an algorithmic body so that the steps performed can be understood in general at first. Then, each part of the algorithm could be detailed. This way, you can get an idea of how the steps are done in sequence.\n11. The subtitle \"Building the ensemble\" should be \"Approaches for building the ensemble\". The subtitles Raw, Mode, Voting etc. could also be revised.\n12. Regarding the Results section, did the authors consider adopting other datasets with more than two attributes? How would the method behave with unstructured data, such as text for example?\n13. I'm not sure the Discussion section addressed the ensemble results. It seemed to me that other forms of experiments were presented, which had not been mentioned in the Methods section. If sliced data sets were to be addressed, it should have been presented in the Methods section.\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
},
{
"id": "235165",
"date": "26 Jan 2024",
"name": "Luca Coraggio",
"expertise": [
"Reviewer Expertise Cluster Analysis",
"Model-based clustering",
"Classification"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe work addresses a relevant research question in cluster analysis, which has long been and stays an open-question, namely determining the optimal clustering solution, with a focus on the selection of a clustering algorithm along with its hyperparameters.\nThe author addresses the problem by developing an ensemble method, where multiple clustering algorithms are fitted on the data (or subsamples), using different hyperparameters and cluster-validation measures. Essentially, each clustering algorithm comes with a set of hyperparameters and cluster-validation indexes (generically called \"metric\" by the author). For each hyperparameters configuration, the clustering algorithm is fitted on the data, and an optimal number of clusters is determined for all of the validation indexes adopted for the specific algorithm. Thus, each algorithm-hyperparameters-metric returns an optimal number of clusters. These are used in a cartesian product with solutions from other algorithms to obtain the ensemble matrix. This is used with three selection methods proposed by the author to derive the overall best number of clusters, and the best algorithm-hyperparameter configuration that produces it.\nI really appreciated the emphasis posed on the hyperparameters selection, which is often overlooked in research. It is also praiseworthy the effort of developing a data-driven procedure aimed at practitioners (potentially, from other fields), which is both easy to understand and to apply.\nAlbeit, as it stands now, the work presents some critical issues which need to be addressed. Significantly expanding the experimental analysis could help to dismiss most of the concerns. In what follows, I outline 3 major points, and a series of other comments.\nM1. As it is presented, the proposed ensemble procedure mixes together extremely different clustering methodologies and validation indexes --- typically used in different problems --- failing to explain or provide enough supporting evidence of the overall validity of the procedure. It is well known that different clustering algorithms imply different cluster concepts (Hennig et al., 20151), but this fact, while acknowledged by the author, seems to be totally disregarded in the application. This is evident from comparing, in the same ensemble, methods like GMM and hierarchical clustering with single linkage, which are after very different clustering shapes: the former being more adequate with elliptical-symmetric shapes, the latter being more similar to density-based methods. In real applications, two different clustering algorithms might be capturing different aspects along which the data are clustered, both of which might be perfectly valid. This might imply looking at two different cluster concepts (e.g. a elliptical-symmetric clusters, and clusters of density-connected points). Having these methods compared in the same ensemble might lead to lose valid solutions simply because outnumbered by solutions of the other type. More empirical evidence would help dissipating this concern. At least in the case of different cluster concepts, I think it would be more prudent to report multiple solutions to the researcher, which he/she can later investigate and validate with domain-specific knowledge. This also leads me to my second point below.\nM2. Considering point 1 above, creating a major categorization (columns of the ensemble matrix) based on the algorithmic implementation of some clustering methods seem to be rather arbitrary. This choice seems to be dictated more by the software-related considerations rather than statistical ones. For example, consider two different implementations of Gaussian Mixture Models (e.g. Mclust (Scrucca et al., 20232) and Otrimle (https://cran.r-project.org/web/packages/otrimle/index.html)) and a single algorithm for a hierarchical clustering with single linkage. It is not difficult to find data examples where GMM would be inappropriate compared to the HCA: to make an example using a library known to the author, the \"make_moon\" data generating process from Python's scikit-learn is a good one (it consists of \"moon-shaped\" clusters, which are quite a departure from elliptical-symmetric shapes; a density-based approach would be better suited here). The GMM algorithm would most likely pick an excessively high number of clusters to fit the underlying data density well, struggling to capture the true clusters. Even if the HCA would do well, it might well be outnumbered by the \"wrong\" solutions simply because two GMM implementations are compared with a single HCA. This problem is likely even more evident for the Column-first strategy proposed by the author.\nM3. One last major issue is the lack of a sufficient experimental analysis. The procedure proposed by the author is purely backed-up by experimental evidence. As there is no formal argument on the effectiveness of the proposed ensemble procedure, it is very important to expand on this section considering more and more challenging experimental designs. The author presents an extremely simple clustering problem, where clusters are reasonably well separated, spherical Gaussian and with ten thousand points each, in two dimensions. This example alone is not at all sufficient to prove the general validity of any methodology. I suggest considering, at least, experimental designs where spectral clustering and/or HAC would be better suited as compared to K-means and GMM; with a far lower number of points (< 1000); and with more than 2 dimensions. Some real data sets could also be considered for benchmarking.\nHere are a list of other comments/suggestions:\nPage 1: \"While we leave the task... we invite the reader to consider possibilities as they read through our work.\" I would strongly suggest removing or rephrasing this. I think is not the job of the reader to think of possible/future applications as much as it is the job of the author to point-out viable ones. I think that having this statement depicts questionable the extent of the author's contribution, and may confuse the reader about what is actually being done and what is left as a sketch of future (feasible?) work.\n2. Table 1, Table 2, Table 3 are presented to show that different settings (algorithms, hyperparameter, or metric) may lead to different results; emphasis is put on the striking difference in performances across some entries. However, in the tables is not clear what the exact settings being compared are. I would suggest specifying those to make more sense of the differences in the presented figures. For example, Table 2 gives very different results as compared to Table 1, why? What is the exact setting here?\n3. In the experimental analysis, the author evaluates the solutions with the accuracy index based on the selected number of clusters across 100 data sets. While a 3-cluster-solution might have the exact same number of clusters of the true data generating process, these cluster might be totally off with respect to the true ones. I think that reporting the misclassification error (or the ARI index) as well might provide a better description of the solution's performances.\n4. Each clustering algorithm uses potentially different validation indexes (metric) to select the final number of clusters. Different validation indexes value some aspects more then other in assessing the clustering solutions. If the same validation metric is over-represented across different clustering algorithms, this could introduce a bias in the selection of the optimal solution from the ensemble. Further discussion or empirical evidence should be provided. (Linked to M1).\n5. (Linked to point 4 above) From the manuscript, in the case of Gaussian Mixture Models, BIC (or AIC) seems to be used to select the number of clusters among GMMs with the same covariance parameterization. It is not clear why BIC is not used pooling together GMMs with both different covariance parameterization and number of clusters. It should be used like this, as BIC allows to penalize for model complexity. Otherwise, poorer solution might be over-represented in the ensemble, hampering the overall performance.\n6. (Example for M1 and M2) Consider clustering a 2-class moon-dataset (see M2) with two GMM algorithms (GMM1: implementing covariance parameterization; GMM2: implementing eigen-ratio constraint), and consider HAC. An ensemble might look like: GMM1 GMM2 HAC 9\n\n9\n\n2 10\n\n9\n\n2 8\n\n9\n\n2 ... In such cases, an overly-complex solution might be selected just because an inappropriate clustering method (GMM) was over-represented in the ensemble.\n7. The author should discuss how to break ties. Suppose obtaining an ensemble of the form ALGO1 ALGO2 7\n\n2 7\n\n2 7\n\n2 ... What should be the selected number of clusters, and algorithm-hyperparameter in this case?\n8. Page 4. I would suggest describing the data generating process in more details. E.g. a 3-components standard-Gaussian mixture model, with equal mixing probabilities.\n9. In general, number of clusters are hyperparameters to many clustering algorithms. A remark should be made to distinguish them from other hyperparameters, and possibly this choice should be discussed in greater details. This issue is linked with point 5: with some clustering procedures it might be better to select the optimal solution comparing a validation index across both varying number of clusters and other hyperparameters.\n10. Page 7: \"If it helps, think of each h as a set of kwargs passed into a model object\". I would suggest removing this phrase. This assumes that the reader is familiar with Python. \"kwargs\" is not generally adopted by all programming languages. \"model object\" has no statistical meaning in the way it is used here. This phrase anchors the work to the Python niche and mind-set.\n11. Page 8: eq 11. These writings should be explained. \"np.geomspace\" assumes that the reader is familiar with Python; that she is familiar with the common \"np\" alias given to the numpy package; that she is familiar with the numpy package and functions. I would suggest to simply replace \"np.geomspace\" with its output (the following line). Once again, this anchors the manuscript to the Python niche, in my opinion.\n12. Page 10: presentation of E matrix. I think it would be a nice visual aid to present the E matrix first in the form of tuples as shown in (18), and then substituting the number of clusters.\n13. Page 10: \"The choice of metric...parameter\". The phrase is confusing. The \"elbow-method\" is not a metric, but rather a selection method.\n14. Page 10: \"Here, our matrix will be smaller than in the Raw approach\". It could be nice to provide dimensions for the E matrix, both in the row approach and in the \"mode\" approach.\n15. Page 11: the author should specify which E matrix (row or mode) is being used in the computation of Full/Column-first/Row-first solution.\n16. Page 11: Result section - \"The first... sampling our result set 100 times\". It is not clear to me what is being sampled and from what distribution.\n17. Page 11: Results section. The author mentions passing \"default parameters\"; it would be better to specify what the default values are.\n18. Table 4: are the difference in accuracy statistically significant?\n19. Page 12: what is a possible explanation that causes the methodology to outperform Table 1 results at a value of 93% accuracy against a 91% from Table 1?\n20. Page 12: \"Perhaps the most interesting...investigation\". This results is quite worrying in terms of future applications with consensus clustering. Presenting further experimental evidence might help.\n21. Since the proposed procedure involves forming numerous clustering solutions, it would be nice if the author commented on computational aspects of the proposed ensemble strategy.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-573
|
https://f1000research.com/articles/11-571/v1
|
25 May 22
|
{
"type": "Research Article",
"title": "Does the autism phenotype differ when selecting groups by neurodevelopmental versus genetic diagnosis? An observational study comparing autism and sex chromosome trisomy",
"authors": [
"Alexander C Wilson",
"Dorothy V M Bishop",
"Dorothy V M Bishop"
],
"abstract": "Background: Autism is diagnosed on the basis of social and non-social behavioural features that are assumed to cluster together, and assumed to be distinct from other aspects of development, such as language ability. It is unclear, however, if these assumptions are valid. This study presents a novel approach to answering this question by investigating whether correlations between autism features are similar for groups selected on behavioural versus genetic diagnosis.\nMethods: The autism phenotype was assessed by diagnostic interview in young people aged 7 to 14 diagnosed with autism (N=61) or sex chromosome trisomy (SCT; N=49). Data were analysed by confirmatory factor analysis and MANOVA.\nResults: Autism features showed a similar factor structure and were distinct from language ability in both groups. However, the SCT group was more likely to show clinically-significant difficulties in just some aspects of autism and a lower level of non-social autism features for their social-communication disabilities.\nConclusions: We suggest the group differences emerged because autism diagnostic criteria do not map exactly on the autism phenotype as it manifests “naturally”. Conventional diagnostic criteria for autism miss those with uneven profiles of difficulty and those with relatively low levels of restricted and repetitive behaviours and interests.",
"keywords": [
"Autism",
"autism phenotype",
"sex chromosome trisomy",
"diagnostic criteria",
"language"
],
"content": "Introduction\n\nAutism, like other neurodevelopmental disabilities, is diagnosed on the basis of a cluster of behavioural features that are assumed to group together as a single “entity” underpinned by specific neurocognitive mechanisms. In the case of autism, these features cluster across two domains: (1) social interaction and communication, and (2) non-social features including preference for routine, highly focused interests, repetitive behaviours and sensory processing differences (American Psychiatric Association, 2013). While autistic-like traits vary continuously through the population, it is assumed that there is a threshold where these traits become “clinically significant” and a diagnosis is deemed useful. Autism is also defined by what it is not: although autistic individuals may also have disabilities affecting core language (speech, syntax, vocabulary, etc.), these are not a cardinal feature of autism and where they occur are assumed to be separate from autism, forming a so-called “co-occurring” disability. Characterising neurodevelopmental disability in this way raises longstanding questions about diagnostic validity: specifically, about how we ought to lump and split neurodevelopmental features across different diagnostic categories. In the case of autism, does it reflect a natural category where social and non-social features go together? And likewise, is this category ultimately distinct from language ability?\n\nWhen autism is defined in terms of a combination of social and non-social features, we implicitly adopt a model such as that shown as Model A in Figure 1. Here, the black circles denote non-autistic individuals, for whom social and non-social features are only weakly associated, and the red circles denote those with autism, for whom both social and non-social features co-occur. A positive score on each scale denotes impairment. The dotted lines denote possible cut-offs that could be used diagnostically, and which would do a good job at identifying the subset of red dots as those in the top right quadrant. Another possibility, however, is that reality corresponds to model B, in which there is no distinctive autism subgroup, but rather a wide variation in the distribution of social and non-social features. Even though there is no distinctive autism subset in model B, we can still place cut-offs to identify those in the top right quadrant. Note that in model B, but not in model A, there are numerous people who score above threshold on either social or non-social features, but not both.\n\nIn model A, there is a distinctive autism subgroup in addition to the general population. In this autism subgroup (shown as red circles), social and non-social features closely co-occur. By contrast, among non-autistic people (shown as black circles), social and non-social features are only weakly associated. In model B, there is no distinctive autism subgroup, but rather a wide variation in the distribution of social and non-social features across the population.\n\nThere are a couple of sources of information which are consistent with model B rather than model A. First, some individuals show an uneven profile of difficulties, with social communication problems but a relative absence of other autistic features. This includes individuals with pragmatic language impairment (Gibson et al., 2013) and pervasive developmental disorder – not otherwise specified (Mandy et al., 2011). The dissociation is not entirely clear-cut, however, because such individuals may show some evidence of elevated but subthreshold autism features in the non-social domain too. A more secure source of information is from factor-analytic studies, and these provide evidence for two dimensions of autism features, rather than a single autism “entity”. Empirical studies consistently find separable social and non-social factors when assessing questionnaire and interview-based data on autistic individuals (see Shuster et al., 2014 for a review). Clinical assessments indicate a moderate correlation between social and non-social features of autism in autistic groups (e.g. 0.44 in over 600 autistic children, Mandy et al., 2014). In contrast, in general population groups, correlations tend to be low, although these are based on non-clinical measures relating to autistic-like traits rather than autism features per se (e.g. Svedholm-Häkkinen et al., 2018). In addition, genetically-informative studies indicate that these domains are highly heritable, but that genetic influences on the domains are relatively independent (Ronald et al., 2006). While these results consistently come to the same conclusion about the separability of autistic features into social and non-social domains, there are possible issues to consider regarding the samples and measures.\n\nWith respect to samples, it may not be optimal to rely either on autistic or general population groups. Autistic individuals will necessarily show elevated difficulties in both domains as this is required for diagnosis, and so there will effectively be a selection bias towards those with both social and non-social impairments. On the other hand, in general population groups, there may be an issue around generalisability and validity of measures. It has been found that genetic influence on autistic-like traits is shared across general population and autistic groups (e.g. Robinson et al., 2016), and so we can be confident that it is valid to study autistic-like traits across the general population. However, it might be the case that autistic-like traits are not directly equivalent to the clinical features of autism. It is clear that the questionnaires used for screening and measuring autistic-like traits in the general population (such as the Autism-Spectrum Quotient; Baron-Cohen et al., 2001) do not necessarily map well on to clinical assessments used to support an autism diagnosis (such as the Autism Diagnostic Observation Schedule; Lord et al., 2012). For instance, an epidemiological study of autism prevalence found a correlation of just 0.24 between these measures in a sample of over 600 adults oversampled for possible autism (Brugha et al., 2012). This underscores the possible limitations of relying on general population samples for understanding the relationship between the different domains of autism features, as studies of such samples will not contain individuals with clinically-significant difficulties, and are likely to rely on non-clinical questionnaire measures. Pulling together the limitations explored here, a more optimal approach might be to measure autism features in the social and non-social domains using a clinical assessment in a sample that has elevated likelihood of developmental disability but has not been selected on the basis of their neurodevelopmental presentation. Instead of neurodevelopmental presentation, we can select on the basis of aetiology. We will present results from children with a sex chromosome trisomy to illustrate this approach.\n\nLanguage problems introduce a further layer of complexity into the diagnosis of autism. There is a greater risk of language difficulties among autistic people compared to the general population (Kwok et al., 2015), and a significant proportion of autistic individuals (perhaps 30%) are minimally verbal (Tager-Flusberg & Kasari, 2013). Language difficulties may accentuate autism features, given that verbal ability impacts on scores on autism diagnostic assessments (Hus et al., 2014), and such difficulties predict a range of later outcomes for autistic people (Magiati et al., 2014). As language functioning is so heterogeneous and relevant to outcome in autism, DSM-5 suggests making use of a specifier in autism diagnosis indicating whether language impairment is present or not (American Psychiatric Association, 2013).\n\nWhen considering language problems, we need to distinguish between different aspects. Individuals can have problems with understanding or producing grammatical sentences or learning new vocabulary, but these core language difficulties can be dissociated from problems with language use (pragmatics), which are a cardinal feature of autism. Some autistic people may present with social communication problems in the absence of language difficulties or indeed with advanced language development (Baird & Norbury, 2016; Lam & Yeung, 2012). This dissociation between social communication and language is also captured in the theoretical models, which typically attribute the social difficulties in autism to cognitive constructs, such as “theory of mind”, while under-emphasising language (e.g. Baron-Cohen, 2000). Nevertheless, empirical evidence indicates that pragmatic difficulties in autism typically co-occur with core language difficulties, as reviewed by Andres-Roqueta and Katsos (2017) and Matthews et al. (2018). Furthermore, children who are selected on the basis of having language impairments tend to have elevated social communication difficulties (Leyfer et al., 2008; Norbury et al., 2004). This raises the possibility that dissociations between pragmatics and core language skills may have been exaggerated, with core language problems going under-recognised in autistic individuals because the pragmatic difficulties are more striking and obvious.\n\nA sample selected on the basis of a clinical diagnosis will necessarily show elevated levels of the traits relevant to the diagnosis – i.e. in the case of autism, social communication difficulties and restrictive and repetitive behaviours and interests (RRBIs). This may make social communication difficulties and RRBIs appear more connected than they really are and may also underplay relationships with other neurodevelopmental features. A reverse situation is also possible where selecting a sample with clinically-significant difficulties, i.e. with a diagnosis of autism, may deflate relationships between neurodevelopmental domains due to restricted variance. To summarise, it is possible that an autistic sample will lead us to see a biased picture of the relationships between different neurodevelopmental domains. To assess whether this is the case, we can compare (1) a sample that meets behavioural criteria for autism to (2) a sample selected on aetiological rather than behavioural grounds – in the case of this study, individuals with a genetic variation linked to neurodevelopmental disability. Effectively, in the first sample, we have a group where biases of the diagnostic system may be causing features of neurodevelopmental disability to cluster or fail to cluster; whereas, in the second sample, we have a genetically-defined group where we might see more accurately how nature lumps and splits features of neurodevelopmental disability. This second sample might not represent how such features cluster continuously across the population, but it does give us confidence that there might be neurocognitive reasons rooted in genetics that lead to particular patterns of neurodevelopmental traits. Having selected autistic and genetically-defined samples, we then compare the relationships between different neurodevelopmental traits across the groups. Where we see no discrepancies, we can infer that the diagnostic system maps on appropriately to the structure of neurodevelopmental disability as it manifests “naturally”. If there are differences, there may be sources of bias that are worth investigating further.\n\nFor the genetically-defined sample, the present study investigated a group of young people with a sex chromosome trisomy. Sex chromosome trisomy occurs where an individual has an additional X or Y chromosome; karyotypes include 47,XXX (Trisomy X), 47,XXY (Klinefelter’s Syndrome) and 47,XYY (Jacob’s Syndrome). These are common genetic variations occurring in about one of 650 to 1000 same sex births depending on the karyotype (Morris et al., 2008). All three karyotypes are associated with increased probability of neurodevelopmental disability, including delayed early milestones, language and literacy difficulties, executive dysfunction, autism, ADHD and anxiety (see van Rijn, 2019 for a review). The phenotype is variable, and many individuals will not show indications of neurodevelopmental disability, meaning that the majority of individuals with an SCT are likely to go undiagnosed (Abramsky & Chapple, 1997). Those who are diagnosed typically fall into two subgroups: (1) individuals identified incidentally on the basis of routine prenatal screening and (2) individuals identified postnatally following clinical investigations due to medical or behavioural concerns, who will therefore typically show a more severe phenotype than those diagnosed prenatally (Wilson et al., 2019). These issues around clinical ascertainment mean that individuals with a milder phenotype will typically be underrepresented in research samples, whereas clinically referred individuals will be overrepresented. The result is that mean scores for neurodevelopmental disability will be inflated compared to the true population level. This is highly problematic for research that aims to identify the “typical” phenotype in SCTs; however, for the purpose of the present study, this is less of an issue, as we are interested not in mean scores but in variances and covariances – how variability in one domain relates to variability in another domain of neurodevelopmental disability.\n\nIn the present study, we compared the structure of neurodevelopmental disability across samples defined by behavioural vs genetic diagnoses. We hypothesised that autism features would cluster differently across groups, and that language ability would show different relationships with autism features across groups. In terms of the clustering of autism features, we predicted that young people in the SCT group might be more likely to show elevated features in just one domain (e.g. just social communication), leading to greater dissociations in this group. As for language ability, we predicted that the link between language and social communication may be attenuated in the autistic group if the presence of an autism diagnosis selects for individuals whose communication problems are more attributable to social-cognitive rather than linguistic factors.\n\nThese issues surrounding clustering of neurodevelopmental traits are of theoretical interest, but there is also a practical issue here worth exploring: how does an individual’s specific clustering of difficulties, as represented by their diagnostic label, influence the clinical and educational support given? In particular, is support sometimes more dependent on the label than the actual functional difficulties the individual is experiencing? We therefore asked whether young people with an autism diagnosis and young people with an SCT, when controlling for level of difficulties, received different levels of special educational needs (SEN) support.\n\n\nMethods\n\nThe study was granted ethical clearance in November 2018 by the Medical Science Interdivisional Research Ethics Committee [R59912] at the University of Oxford.\n\nWe recruited families of young people aged 7;0 to 14;11 years who were diagnosed with a sex chromosome trisomy and/or autism spectrum condition. Families were recruited through social media and support groups, including Autistica, the National Autistic Society, Unique - Rare Chromosome Disorder Support Group, the Klinefelter Syndrome Association and The Association for X and Y Chromosome Variations. Exclusion criteria included: (1) severe and uncorrected sensory impairment, (2) history of neurological illness or brain injury, (3) nonverbal or word/phrase-level speech, and (4) English spoken as an additional language. To screen for limited language, families were asked “We would like to know whether your child can speak in sentences such as ‘I didn’t go the park because it rained’ and ‘I think the film was really good’. Your child may make mistakes when using sentences, but can they at least sometimes use sentences like these?” To be included in the study, families needed to say ‘yes’ or ‘maybe’ in response to this question.\n\n110 families entered the study; 49 were in the SCT group and 61 in the autistic group. In the SCT group, all families reported that the SCT diagnosis followed chromosomal microarray testing. Families in this group reported the following additional diagnoses: autism (n = 10), ADHD (n = 10), specific language impairment/developmental language disorder (n = 20), dyslexia (n = 8), dyspraxia/developmental coordination disorder (n = 7), and anxiety (n = 7). Most families were recruited specifically for this study, though seven had participated in our previous study (Wilson et al., 2019). In the autistic group, all families reported that the autism diagnosis followed a clinical interview with the family and behavioural observation of the child, mostly within multidisciplinary services including psychologists, paediatric doctors and speech and language therapists. Families in the autistic group reported the following additional diagnoses: ADHD (n = 13), specific language impairment/developmental language disorder (n = 6), dyslexia (n = 6), dyspraxia/developmental coordination disorder (n = 7), and anxiety (n = 12).\n\nA control group was not recruited for this study, although we assessed how performance of our sample on the language battery compared to a normative group of 390 young people recruited from mainstream school (Wilson & Bishop, 2022a). We ran a nonparametric MANOVA with the five language tests as dependent variables and autism diagnosis, trisomy diagnosis and age as predictors; both diagnosis variables were included as categoric variables coded as 0 or 1, allowing for the few young people with dual diagnoses. Controlling for age, MANOVA indicated that an autism diagnosis was not related to performance across the five language tests, p = .324, whereas an SCT diagnosis was linked to underperformance, p < .001.\n\nCaregivers completed an online survey in which they were asked about their child’s developmental history and completed two questionnaires, the Pediatric Symptom Checklist-17 (Gardner et al., 1999), and Children’s Communication Checklist (Bishop, 1998). Following the survey, we carried out a telephone-based assessment for autism features using the short version of the Developmental, Diagnostic and Dimensional Interview (3Di-sv; Santosh et al., 2009). In the final stage, young people were asked to complete an online battery of newly devised language tasks and a measure of nonverbal reasoning, the Animal Matrices. Families were offered several formats for this assessment session: with the first author at home, school or the University of Oxford, or in the family’s own time without a researcher present. All online aspects of the study were supported by Gorilla (https://gorilla.sc/). Consent from parents/guardians was sought at the beginning of each stage: on an online form at the beginning of the survey, using an oral consent script in the interview, and an online/paper form prior to the cognitive/language assessment. Young people gave assent to take part in the cognitive/language assessment, and ongoing assent was checked throughout all in-person sessions.\n\nChildren’s Communication Checklist (CCC; Bishop, 1998)\n\nIn this 70-item questionnaire about communication difficulties, caregivers indicate whether the statement “does not apply”, “somewhat applies” or “definitely applies” to their child (which are assigned scores of 0, 1 or 2 respectively). There is also a “can’t judge” option. The items are grouped into nine subscales covering structural aspects of language (speech and syntax), social aspects of language use, i.e. pragmatics (inappropriate initiation, coherence, stereotyped conversation, use of context, and rapport), and autistic features (social relationships and interests). Although an updated standardised version of this measure exists, this earlier form is integrated with the 3Di-sv, so was used in this study. As questionnaire responses were processed slightly differently to Bishop (1998), scoring is detailed below. Positively-worded items were reverse coded, and items were summed into composite scores, prorating for up to 20% of items where there were missing data. For the present study, only the structural language composite was analysed. Cronbach’s alpha for this composite was.93 [.91, .95].\n\nPediatric Symptom Checklist-17 (PSC-17; Gardner et al., 1999)\n\nThis is a screening questionnaire devised for use in primary healthcare for identifying children at risk of psychosocial problems. It consists of 17 items that caregivers report as applying to their child “never”, “sometimes” or “often” (scored as 0, 1 or 2 respectively). There are subscales for attentional (5 items), internalising (5 items) and externalising problems (7 items), with cut-offs of 7, 5 and 7 indicating clinically-significant difficulties in these areas. The cut-off on the full scale is 15 and translates to a t-score of 62. The cut-offs have been validated in a study of over 80,000 US families not in the care of a developmental paediatrician who were accessing primary healthcare; positive screening rates were 9 to 12% across the subscales and total scale. Where more than three items are left unanswered, the questionnaire is invalid; with three or fewer unanswered items, total scores are computed as normal, ignoring the missing items. Missing items invalidated total scores on the individual subscales.\n\nSpecial educational needs (SEN) provision\n\nDuring the survey, families were asked to describe any support their child received for their education, and also whether their child attended special school and/or had an Education, Health and Care Plan or similar statement of additional needs. Responses were coded on a 4-point scale: 0 = no or only occasional additional support; 1 = weekly low-intensity support in mainstream school, e.g. some one-to-one or additional group work; 2 = high-intensity support in mainstream school, e.g. has a dedicated teaching assistant for most lessons; 3 = attends special school. Home-schooling was coded as NA.\n\nShort version of the Developmental, Diagnostic and Dimensional Interview (3Di-sv; Santosh et al., 2009)\n\nThis is a 53-question informant interview for assessing and diagnosing autism, which was administered over the phone in approximately 30 to 40 minutes for each child. The questions are arranged in subscales that contribute to total scores for each of the dimensions of the autistic triad: social interaction, communication, and restricted and repetitive behaviour and interests (RRBIs). The three dimensions have clinically significant cut-offs at 10, 8 and 3. Alongside these continuous variables, an algorithm based on DSM-IV criteria outputs diagnostic classification as autistic or non-autistic. The original validation study showed 93% agreement in case-ness for autism with the Autism Diagnostic Interview-Revised (ADI-R; Lord et al., 1994).\n\nReceptive vocabulary\n\nParticipants hear a sequence of words and for each word, they are presented with four pictures on the screen. They are asked to “chose which picture goes best with the word”. Participants are given a point for each correct answer for a total score out of 39. Cronbach’s alpha [95% CI] in this sample was.78 [.71, .84]. This measure showed a correlation of.69 with a standardised vocabulary test (Wilson & Bishop, 2022a).\n\nReceptive grammar\n\nParticipants listen to sentences and decide if they are grammatical. There are four randomly ordered sentences, 23 items that do not follow typical syntax or use incorrect word forms (e.g. incorrect tenses) and 23 items that follow typical English grammar. Participants are given a point for each correct answer for a total score out of 50. Cronbach’s alpha [95% CI] in this sample was.87 [.83, .91].\n\nImplicature comprehension test\n\nParticipants watch a series of cartoon videos, with two characters producing a short utterance one after the other. Together the utterances form a conversational adjacency pair; in most cases, this is a question and answer. After this dialogue, participants hear a comprehension question, and they give a yes-no-don’t know response by clicking buttons on the screen. For 33 items, participants need to process implied meaning to answer the question, as the second character provides an indirect response to the first character. Participants are given a point for each correct answer for a total score out of 33. Cronbach’s alpha [95% CI] in this sample was.79 [.73, .84].\n\nChildren’s test of local textual inference\n\nParticipants hear two brief sections of a short story (about 90 words per part). After each section, they hear ten questions and four possible answers for each one. Participants click the correct option on the screen. As well as auditory presentation of all materials, everything is shown in text-based form on the screen. Participants are informed at the start that the short story sections will remain on the screen while they are answering questions about that section. Participants need to make inferences based on the short story to answer the questions. Participants are given a point for each correct answer for a total score out of 20. Cronbach’s alpha [95% CI] in this sample was.78 [.71, .84].\n\nSocial overtures\n\nParticipants hear a series of utterances spoken by a character to a conversational partner. Eleven are social overtures that attempt to engage the partner in a conversation (e.g. “I can’t believe what happened today.”) and twelve are not conversational bids (e.g. “I’m going to have a shower now.”). For each utterance, participants are asked whether the speaker wants a conversation or not, and to indicate their answer by clicking yes-no buttons. Participants are given a point for each correct answer for a maximum total of 23. Cronbach’s alpha [95% CI] in this sample was.84 [.79, .88].\n\nNonverbal reasoning (animal matrices)\n\nIn this non-verbal reasoning task, participants see a series of 2×2 matrices presented on the computer screen. In three of the boxes of each matrix, there are cartoon pictures of animals, and the fourth box is empty. The animals in the three boxes vary in systematic ways, and participants deduce which of five options fits in the empty box. Participants are given a point for each correct answer for a maximum total of 16. Cronbach’s alpha [95% CI] in this sample was.83 [.78, .88]. This measure showed a correlation of.70 with a standardised nonverbal reasoning test (Wilson & Bishop, 2022a).\n\nAll analysis was implemented using R software (R Core Team, 2020). Plots were generated using R packages ggplot2 (Wickham, 2016) and ggpubr (Kassambara, 2020). Data and scripts are available on the Open Science Framework: https://osf.io/qan7r/.\n\nWe considered how the autism phenotype manifested in the two groups using three methods. First, we carried out a categoric analysis in which we subdivided individuals based on whether they met autism criteria on one, two or all three dimensions of the 3Di-sv assessment. We tested whether there was a significant difference in the proportion of young people meeting criteria on just one or two dimensions between the SCT and autistic groups using a chi-square test. For our second analysis, we assessed whether autism features measured as continuous variables patterned differently across groups. This involved testing for factorial invariance of a latent “autism features” factor using multi-group confirmatory factor analysis implemented by R package lavaan with robust estimation (Rosseel, 2012). The three continuous variables produced in the 3Di-sv assessment for social interaction, communication and RRBIs were set to load on the factor. This structure was run separately in the two groups as we incrementally fixed the loadings, intercepts and residuals of the indicators to be the same across groups. Each increasingly constrained model was compared to the previous one using a chi-square test with Satorra-Bentler correction to test whether model fit was significantly affected. Where model fit declined, this would indicate a difference in how the autism phenotype manifested across groups. Finally, in our third analysis, we looked in more detail at the 3Di-sv, specifically at the subscale scores that contribute to the three autism dimensions. We tested whether some subscales contributed disproportionately to the autism phenotype when comparing groups. For each subscale, we used logistic regression to determine the odds that the groups would score differently on the subscale when controlling for total scores on the dimension to which the subscale belonged.\n\nNext, we assessed how language ability related to the autism phenotype across groups. Language ability was measured through parent-report on the CCC as well as performance on the language battery. See Figure 2 for raw data on the language battery. Among children who sat the battery, 3% of tests were not completed and these missing data were handled with multiple imputation implemented by R package mice (van Buuren & Groothuis-Oudshoorn, 2011). Then a factor score was extracted from the test battery using R package psych (Revelle, 2019). Analysis of eigenvalues indicated that one factor accounted for performance on the battery, and this explained 61% of variance across the five tests. We removed the effect of age on the language factor score using linear regression. To establish the influence of language on autism features, we used non-parametric MANOVA implemented by R package RVAideMemoire (Hervé, 2020). The dependent variables were the 3Di-sv dimensions (Social interaction, Communication and RRBIs), and the independent variables were language ability, group and the interaction. This analysis was run twice with language ability operationalised as the factor score extracted from the test battery first, and then parent-reported language difficulties on the CCC structural language scale.\n\nThe box-plots show first, second and third quartiles in the normative sample of children in mainstream school. Unfilled circles show young people in the autistic group, whereas coloured shapes show young people with a sex chromosome trisomy (SCT). The triangles show prenatally diagnosed SCTs and diamonds show postnatally diagnosed SCTs. Trisomy type is coded by colour: red for 47,XXX, gold for 47,XXY, and blue for 47,XYY.\n\nFinally, we tested whether the groups differed in the amount of special educational needs (SEN) provision they received, controlling for their level of difficulties. A two-stage multiple regression was run. In the first stage, we entered age, language test performance, 3Di-sv “autism features” and general psychosocial difficulties measured by the PSC-17, as control variables. (The 3Di-sv variable was extracted from the factor model described above. As the RRBI intercept varied between groups, this was allowed to differ when extracting factor scores). In the second stage of the multiple regression, SCT diagnosis was included as a further predictor.\n\n\nResults\n\nTable 1 shows a breakdown of the sample and descriptive statistics for all measures used in the following analyses. In the table, we break down mean scores in the SCT group by timing of diagnosis, as postnatally diagnosed individuals tend to show a more marked phenotype. However, for the analyses that follow, the SCT group is combined, as we are interested in clustering of features and variability rather than mean scores. As subdividing the SCT group by trisomy type (i.e. 47,XXX, 47,XXY and 47,XYY) was not viable due to small numbers, we leave aside the issue of trisomy type in the analysis, but raw data shown in Figures 2 and 3 are coded by trisomy type and timing of diagnosis for the reader’s interest.\n\nOn the psychometric measures, higher scores indicate greater difficulties, except for the language factor score and nonverbal reasoning where higher scores indicate higher performance.\n\nUnfilled circles show young people in the autistic group, whereas coloured shapes show young people with a sex chromosome trisomy (SCT). The triangles show prenatally diagnosed SCTs and diamonds show postnatally diagnosed SCTs. Trisomy type is coded by colour: red for 47,XXX, gold for 47,XXY, and blue for 47,XYY.\n\nFigure 3 shows raw data on the three dimensions of the 3Di-sv. We assessed the relative proportions of young people meeting autism criteria across these dimensions. As shown in Table 2, young people with an SCT were more likely to show uneven profiles, with clinically significant difficulties in just some aspects of the autism phenotype. 19 of 49 (39%) of the SCT sample met clinical criteria on just one or two of the autism dimensions of the 3di-sv, compared to 9 of 61 (15%) of the autistic sample; this difference was significant, Χ2 (1) = 7.05, p = .008.\n\nTable shows number of children (percentage of total).\n\nNext, we assessed whether the factor structure of autism features was the same across groups. See Table 3 for the outcome of this analysis. Model fit did not decline when fixing loadings across groups, indicating that the three dimensions of autism features clustered similarly in the autistic and SCT groups. Factor loadings [with 95% CIs] for the three dimensions were: Social interaction 0.83 [0.73, 0.92], Communication 0.88 [0.78, 0.97], and RRBIs 0.57 [0.41, 0.73]. The magnitude of the factor loadings indicates that RRBIs were somewhat less central to the autism phenotype, and this was the case equally across groups. However, one parameter did differ between the two groups: the intercept for RRBIs. This indicated that, controlling for Communication and Social interaction scores, the relative level of RRBIs differed (r = -0.27 [-0.45, -0.09], with lower scores in the SCT group).\n\nFinally, we took a more fine-grained approach to the 3Di-sv to assess whether groups endorsed the items contributing to the three dimensions differently. We used logistic regression to compute odds that the SCT group would score higher on each subscale when controlling for total scores at the dimension-level. As shown in Table 4, there was little evidence that groups differed in their presentation of the autism phenotype, as odds ratios tended to fluctuate around one as would be expected by chance. In general, these fluctuations were normally distributed as shown in Figure 4, and so attributable to random noise – but there was one outlying exception, the subscale pronoun errors. Young people in the SCT group were disproportionately likely to score higher on this subscale (by 2.66 times, p = .002) when controlling for overall autism communication phenotype, compared to young people in the autistic group. We tested whether this was due to greater language difficulties by covarying for language factor scores. This reduced the odds to 1.39, p = .446, indicating that language ability influenced group differences in this aspect of the autism phenotype.\n\nOdds values are shown for the SCT group scoring higher on a subscale compared to the autistic group when controlling for total scores on the dimension to which the subscale belongs. Subscales are on a 2-point scale, and odds represent a change in one point on the scale (i.e. between “never”, “sometimes” and “always”).\n\nThese odds ratios represent the likelihood that young people with a sex chromosome trisomy (SCT) will have an elevated score on a subscale when controlling for scores on the full scale to which the subscale belongs. Generally, the points fall along the line, indicating that the distribution of odds ratios does not differ from a normal distribution and that differences just reflect random noise. There is one outlying point in the top right (for the pronoun errors subscale) which seems to reflect a true difference between groups in presentation of the autism phenotype.\n\nFigure 2 shows raw data on the language measures, and Figure 3 shows scatter plots for the language factor score extracted from these measures against the 3Di-sv dimensions. MANOVAs indicated that the autism phenotype related to language ability measured both through test performance and parent report, with greater language ability predicting fewer autism features on the 3Di-sv dimensions. However, the effect size was relatively small (i.e. language ability explained only 6% of variance in autism features). As shown in Table 5, the group by language ability interactions were non-significant, indicating that the relationship did not differ between groups.\n\nIn the third research question, we asked whether there were systematic group differences in the level of SEN provision. The first stage of the regression indicated that level of disability explained 30% of variance in SEN provision, F (4, 82) = 10.09, p < .001. Addition of group membership in the second stage of regression was significant, F (1, 81) = 7.09, p = .009, and the full model explained 35% of variance in SEN provision. Controlling for the other variables entered in the regression, a trisomy diagnosis was associated with less SEN provision (0.64 units on the 4-point scale). See Table 6 for full results of the regression analysis.\n\n\nDiscussion\n\nThis study investigated the coherence of the autism phenotype: to what extent do autism features necessarily co-occur? And to what extent are autism features necessarily distinct from language? Are these relationships skewed if we simply focus on individuals with an autism diagnosis? Or do we see the same relationships even where a group is selected on the basis of a genetic rather than neurodevelopmental diagnosis? We approached these questions by comparing groups of young people with autism and young people with a sex chromosome trisomy (SCT).\n\nWe found no significant difference between the groups in terms of how different aspects of the autism phenotype related to each other. In both groups, social interaction and communication features showed a similar, moderate relationship with the non-social aspects of autism (RRBIs). This replicated previous observations that the social and non-social aspects of the autism phenotype are somewhat dissociable (Shuster et al., 2014). When modelling autism features in a factor analysis, we found that the factor loading for RRBIs was moderately high (0.57) but rather lower than for the other dimensions (both over 0.80). As noted above, this pattern of factor loadings did not differ across groups.\n\nLanguage difficulties showed only a weak relationship with the autism phenotype, explaining a small amount of variance (6%) in elevated autism features, and again this did not differ across groups. The weak relationship supports the view that the autism phenotype and language difficulties are relatively distinct, although certain autism-related behaviours may be more common when the individual has a language impairment. As such, the one subscale in the 3Di-sv assessment that was endorsed disproportionately across groups when controlling for total scores was a language-related one – pronoun errors – endorsed more frequently in the SCT group, probably due to the frequency of co-occurring language impairments in this group. However, more generally, language ability was only weakly related to autism features, and this was regardless of group. It was possible that communication difficulties among young people with an SCT may result from language problems, which commonly occur in SCTs (Bishop et al., 2019) and could mimic autism in this group. However, the lack of much relationship between autism features and language in both groups speaks against this view. Instead, it seems that social communication problems are likely to be more social-cognitive in nature than linguistic. Together these findings support the validity of the autism phenotype. Social difficulties tend to co-occur with RRBIs in autistic individuals; and this is to a similar degree in individuals at genetic risk for developmental problems but who have not been selected for autism; and language is a separate dimension of neurodevelopmental disability.\n\nHowever, there were some group differences in presentation of the autism phenotype. The SCT group was much more likely to show clinically-significant features in just some dimensions of the autism phenotype. This indicates that the social aspects of autism can manifest in the relative absence of the non-social aspects, and vice versa. The SCT group also tended to show RRBIs at a lower level compared to individuals in the autistic group with the same level of social interaction and communication features. This difference could be driven by the SCT or autistic group.\n\nOn the one hand, presence of an SCT may confer greater likelihood of social difficulties than the non-social aspects of the autism phenotype. However, there are certain caveats to bear in mind here. First, this might predict a dissociation between social and non-social difficulties specifically in the SCT group, but as noted above the factor loadings of different aspects of the autism phenotype did not significantly differ across groups. Also, as shown in Table 2, young people with an SCT who scored above threshold on just some aspects of the autism phenotype were as likely to show RRBIs above the clinical threshold as any other domain. Finally, we should be cautious about any suggestion that the SCT group shows a specific form of the autism phenotype, as there was substantial heterogeneity in presentation (see Figure 3). The exception to this was the 47,XYY group, in which universally high levels of autism features were observed. However, we should be tentative about this finding, as the sample size was small and all individuals in this group were postnatally diagnosed (and so more likely to show a marked phenotype).\n\nIf we instead consider whether the autistic group drove the differences, we might suggest that the autistic group “over-selected” for individuals with certain presentations: specifically, with clinically significant difficulties across the board and higher RRBIs than would be expected based on the individual’s social disabilities. Essentially, autism criteria may not map exactly onto the autism phenotype as it manifests “naturally”. In many ways, this is acknowledged in the diagnostic manuals, in which “atypical autism”, “pervasive developmental disorder – not otherwise specified” and “social (pragmatic) communication disorder (SPCD)” have allowed classification of individuals who do not quite meet autism criteria. There has, however, been debate about the utility and validity of these diagnoses (e.g. Norbury, 2014; Walker et al., 2004), and the current study simply underscores the view that diagnostic labels may not carve nature at the seams. Specific questions raised by findings in this study are (a) how to understand and support the difficulties of individuals with an uneven profile of autism features, and (b) how the level of RRBIs should be calibrated against the level of social and communication difficulties in diagnosing autism.\n\nWhat are the practical implications of these questions? A key issue is that different diagnostic labels may provide greater or lesser access to resources. Certainly, with regard to research, some neurodevelopmental conditions, e.g. autism, receive much greater research funding and are published on much more extensively than other neurodevelopmental conditions, e.g. dyslexia, dyspraxia and developmental language disorder (Bishop, 2010). It is less clear what the picture is in the clinical world; certainly, families sometimes express dissatisfaction about the limited resources channelled into diagnostic services and post-diagnostic support (Crane et al., 2016), although whether this differs by diagnostic label is unclear. In the present study, we found that young people in the SCT group received less special educational needs (SEN) support than young people in the autism group, after controlling for the level of difficulties they experienced (including language disability, autism features, and psychosocial difficulties). There are probably multiple reasons for this. The autism label may have greater currency in educational settings due to widespread knowledge about the condition and the existence of autism-specific services, whereas SCTs are relatively unknown among practitioners. In addition, SCTs may be perceived as rare conditions which require very specific support or conversely that they are genetic “and therefore nothing can be done” (but with this logic, we could say the same about autism, which is currently understood as having a genetic aetiology). If these perceptions are an issue, the advice to practitioners might be to focus not on the SCT label but instead on the difficulties affecting the young person’s day-to-day life, and support the young person with those difficulties using evidence-based interventions.\n\nThere are two limitations to bear in mind with this study. First, we used older DSM-IV criteria for autism rather than DSM-5. Autism features were assessed through the 3Di-sv clinical interview, which has been validated for discriminating DSM-IV cases and non-cases. The most important difference between DSM-IV and DSM-5 is the greater representation of sensory features in DSM-5 criteria. Very little is known about sensory reactivity in SCTs, so it is unclear whether this is likely to affect the level of similarity and difference between SCT and autistic groups. We should also note that our assessment was restricted to a single method, i.e. diagnostic interview with an informant, and did not involve direct observation of the young person. The second key limitation is that sample sizes were relatively modest. This limited the analytic methods we could use in the study and the possible subgroup analyses. We ran factor analyses using total scores on the three 3Di-sv dimensions rather than factor-analysing the items within the dimensions, as the latter method would have necessitated a much larger sample size. Nonetheless, we did assess whether families were more or less likely to endorse certain items across groups, and there was little evidence of this.\n\nThe other drawback of the small sample size was the limitation on subgroup analyses. It was not possible to run the main factor analysis in separate subgroups defined by trisomy type due to the small numbers. In the present sample, it did seem that the 47,XYY group showed a more severe phenotype than the 47,XXX and 47,XXY groups; however, we cannot be confident in this impression, due to the small numbers and possible confound of timing of diagnosis (as all children in this group were postnatally diagnosed whereas other groups showed a combination of pre and postnatally diagnosed). In addition, it should be noted that existing research does not provide strong reason to expect differences by trisomy type, as studies have typically shown significant variability of symptoms among SCTs but without any clear role to be played by the trisomy type (Bishop et al., 2019). This variability was also present in the current SCT sample – some children showed very little evidence of autism features whereas others showed elevated levels consistent with a diagnosis of autism (alongside their genetic diagnosis). This was often linked to timing of diagnosis, with postnatally-identified children showing more autism features, as one might expect based on the fact that many of these young people were diagnosed following investigations due to behavioural concerns.\n\nIn summary, this study supported the validity of the autism phenotype as comprising related social and non-social domains that were largely distinct from core language ability. However, we showed that the autism phenotype showed subtle differences when comparing a group diagnosed with autism to a group with genetic conditions conferring a heightened likelihood of neurodevelopmental disability. This supports the view that diagnostic criteria may not map exactly onto the autism phenotype as it manifests “naturally”, which may result in some individuals falling through the diagnostic cracks. Given the link we found between diagnostic label and the level of special educational needs provision, this may impact the support an individual can access.\n\n\nData availability\n\nOpen Science Framework. Data and scripts: children in clinical groups. DOI: https://doi.org/10.17605/OSF.IO/7WDVU (Wilson & Bishop, 2022b).\n\nThis project contains the following underlying data:\n\n- PARENT SURVEY\n\n- CCC.csv Children's Communication Checklist (Bishop, 1998), a parent-report questionnaire assessing structural and pragmatic aspects of language, as well as autistic features. File presents item-level responses to all items; then number of unscored items for the structural, pragmatic, social and interests subscales; then total scores on each subtest. Total raw scores and prorated total scores are given (where parents left up to 20% of items unscored for a subscale, scores were prorated by the mean score for the rest of the items in that subscale; where more than 20% of items were unscored, that subscale was recorded as invalid). Item-level responses are coded as follows: 0=does not apply; 1=applies somewhat; 2=definitely applies; NA=don't know/can't judge. Note that item-level scores have been reverse coded for positively-worded items.\n\n- PSC17.csv Pediatric Symptom Checklist, a parent-report questionnaire of general psychosocial impairment (https://www.massgeneral.org/psychiatry/treatments-and-services/pediatric-symptom-checklist). In addition to total scores, factor analysis supported the extraction of subscores for attention (5 items), internalising (5 items) and externalising difficulties (7 items; Gardner et al., 1999). For each of these subscales, the file presents item-level responses followed by two summary scores: subscale total and positive screen for impairment on that subscale. At the end of the file, total scores for the whole scale, positive screen for impairment on the whole scale, and number of missing items are shown. Where any items are left unscored for a subscale, total score for that subscale is recorded as invalid for that participant; for the categoric variables (impaired or not impaired), scores are provided if the participant would necessarily have screened positively or negatively irrespective of how the missing items were answered. Where three or fewer items are left unscored on the whole scale, total scores are calculated ignoring those unscored items; the whole scale is recorded as invalid if a participant leaves more than three items unanswered. Item-level responses as coded as follows: 0=never; 1=sometimes; 2=often; NA=unanswered.\n\n- participant.information.csv File presents data for each child in the following order: their study ID; gender; age at the time the parent completed the survey; the UK school year group they belong to based on their birthday; whether they completed most/all of the test battery (1=most/all tests completed; 0=one or fewer tests completed); whether they have an autism diagnosis; whether they have a diagnosis of a sex chromosome trisomy (SCT); whether an SCT diagnosis was prenatal (0=postnatal; 1=prenatal; NA=no trisomy diagnosis); the type of trisomy; whether they have been diagnosed with a language or literacy disability (e.g. SLI, DLD, dyslexia, etc.); and their level of SEN (special educational needs) support (0=none; 1=some low-intensity support in mainstream school; 2=high intensity support in mainstream school; 3=attends special school; NA=home-schooled).\n\n- PARENT INTERVIEW\n\n- 3di.csv The developmental, diagnostic and dimensional (3Di) assessment was administered over the phone (Santosh et al., 2009). The file presents scores on the Social Interaction, Communication, and Repetitive and Restrictive Behaviour and Interests (RRBIs) subscales (the Nonverbal Communication score is based on a subset of the Communication items). Autism case-ness is shown in the final column; 3Di criteria for autism are a Social Interaction score of 10 or over, plus a Communication score of 8 or over and/or an RRBI score of 3 or above.\n\n- TEST BATTERY (See Wilson and Bishop (2022a) for normative data and psychometric analysis of the test battery in almost 400 non-autistic children. Please note that a small number of items were dropped from the tests based on this psychometric analysis, and data for these items are not given in the files uploaded here. In addition, z-scores have been computed for some of the tests, and are included in files with \"z-score conversion\" in the title.)\n\n- Grammar.csv Receptive Grammar task, in which participants listen to sentences and decide if they are grammatical. They hear the following instructions: “Some of the sentences will sound good, but some of the sentences will sound bad. There might be a missing word. Or the wrong word might be used. Or the order of the words might be weird. If the sentence is good, click the green tick. If the sentence is bad, click the red cross”. There are 50 items: in 4 sentences the words are in a random order and should be easily rejected, 20 items are taken from McDonald (2006) and showed high accuracy in primary school children, and 26 items are a subset of our adult version of this test (Wilson et al., 2019); these latter items were chosen on the basis of high accuracy and high item-total correlations. Excluding the 4 randomly ordered sentences, 23 items do not follow typical syntax or use incorrect word forms (e.g. incorrect tenses) and 23 follow typical English grammar. Examples of incorrect items include: “The teacher told the story the children” and “I went out after I have eaten dinner”. There was one measured variable: the sum of items currently answered (out of 50). The file presents item-level accuracy and total scores.\n\n- Vocab.csv Receptive Vocabulary task, in which participants choose which of four pictures is related to a word. Participants hear a sequence of 39 words and for each word, they are presented with four pictures on the screen. They are asked to “chose which picture goes best with the word”. The words include nouns, verbs and adjectives, and vary in approximate age of acquisition from 5 to 12, with similar numbers of easy and harder words; two experienced teachers independently rated the ages at which they would expect 50% and 90% of children in a typical class to be familiar with the word. There was one measured variable: the sum of items correctly answered (out of 39). The file presents item-level accuracy and total scores.\n\n- Implicature.csv Implicature Comprehension Test, in which participants watch a series of cartoon videos, in each of which two characters produce a short utterance one after the other. Together the utterances form a conversational adjacency pair; in most cases, this is a question and answer. After this dialogue, participants hear a comprehension question, and they give a yes-no-don’t know response by clicking buttons on the screen. For 33 items, participants need to process implied meaning to answer the question, as the second character provides an indirect response to the first character. An example item includes: Character 1: “Could you hear what the police said?” Character 2: “There were lots of trains going past.” Comprehension Question: “Do you think she heard what the police said?” Correct Answer: “No.” There are also 10 items where the answer is more explicit; these serve as positive control items. An example item includes: Character 1: “Did you see the policemen earlier on?” Character 2: “I saw them standing on the platform.” Comprehension Question: “Do you think he saw the policemen?” Correct Answer: “Yes.” From these items, there were two measured variables: sum of implicature items correctly answered (out of 33) and sum of explicit-response control items correctly answered (out of 10). The file presents item-level accuracy and total scores.\n\n- Inference.csv Children's Test of Local Textual Inference, in which participants hear two brief sections of a short story (about 90 words per part). After each section, they hear ten questions and four possible answers for each one. “We don’t know” is an answer option for every question, and is the correct answer to four questions. Participants click the correct option on the screen. As well as auditory presentation of all materials, everything is shown in text-based form on the screen. Participants are informed at the start that the short story sections will remain on the screen while they are answering questions about that section. Participants need to make inferences based on the short story to answer the questions. The short story starts as follows: “Unfortunately, the family couldn’t go swimming. The sea was rougher and colder than expected. Instead, Billy spent the whole morning playing a ballgame with his sister, Susie.” An example question is: “What had Billy planned to do?” Participants chose their answer from the following options: “play a ballgame”, “go swimming”, “walk along the sea”, and “we don’t know”. There was one measured variable: the sum of items correctly answered (out of 20). The file presents item-level accuracy and total scores.\n\n- Overtures.csv Social Overtures task, in which participants hear 23 utterances spoken by a character to a conversational partner. Eleven are social overtures that attempt to engage the partner in a conversation (e.g. “I can’t believe what happened today.”) and twelve are not conversational bids (e.g. “I’m going to have a shower now.”). Participants listen to instructions explaining that “There are different reasons why we say things to other people. Sometimes, we want to start a conversation. We want the other person to ask us questions and say lots of things to us. Other times we just want to tell the other person something very quickly. We don’t always want to start a long conversation.” They are then asked for each sentence whether the speaker wants a conversation or not, and to indicate their answer by clicking yes-no buttons. There was one measured variable: the sum of items correctly identified as a social overture or not (out of 23). The file presents item-level accuracy and total scores.\n\n- Matrices.csv Animal Matrices nonverbal reasoning task, in which participants are presented with a sequence of 16 2×2 matrices on the computer screen. In three of the boxes of each matrix, there are cartoon pictures of animals, and the fourth box is empty. The animals in the three boxes vary along six dimensions: species, colour, size, number, direction faced, and position in the box. There are systematic relationships between the three animals, and participants need to deduce which of five options fits in the empty box. For example, the top two boxes may show red lions, one big and one small, and the bottom left box may show a big yellow horse; the correct option to fill the empty box would be a small yellow horse. There was one measured variable: the sum of items correctly answered (out of 16). The file includes item-level accuracy and total scores.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nOur warmest thanks to all the families and young people who took part in this research. Also, many thanks to the following organisations for their support in reaching out to families: Autistica, the National Autistic Society, Unique - Rare Chromosome Disorder Support Group, the Klinefelter Syndrome Association and The Association for X and Y Chromosome Variations.\n\n\nReferences\n\nAbramsky L, Chapple J:47,XXY (Klinefelter syndrome) and 47,XYY: Estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat. Diagn. 1997; 17(4): 363–368. PubMed Abstract | Publisher Full Text\n\nAmerican Psychiatric Association: Diagnostic and statistical manual of mental disorders. 5th ed.2013.\n\nAndrés-Roqueta C, Katsos N:The contribution of grammar, vocabulary and theory of mind in pragmatic language competence in children with autistic spectrum disorders. Front. Psychol. 2017; 8: 996. PubMed Abstract | Publisher Full Text\n\nBaird G, Norbury CF:Social (pragmatic) communication disorders and autism spectrum disorder. Arch. Dis. Child. 2016; 101(8): 745–751. Publisher Full Text\n\nBaron-Cohen S:Theory of mind and autism: A fifteen year review.Baron-Cohen S, Tager-Flusberg H, Cohe DJ, editors. Understanding other minds: Perspectives from developmental cognitive neuroscience. Oxford University Press;2000; pp. 3–20.\n\nBaron-Cohen S, Wheelwright S, Skinner R, et al.:The Autism-Spectrum Quotient (AQ): Evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. (2001). J. Autism Dev. Disord. 2001; 31(1): 5–17. PubMed Abstract | Publisher Full Text\n\nBishop DVM:Development of the Children's Communication Checklist (CCC): A method for assessing qualitative aspects of communicative impairment in children. J. Child Psychol. Psychiatry. 1998; 39(6): 879–891. PubMed Abstract | Publisher Full Text\n\nBishop DVM:Which neurodevelopmental disorders get researched and why?. PLoS One. 2010; 5(11): e15112. PubMed Abstract | Publisher Full Text\n\nBishop DVM, Brookman-Byrne A, Gratton N, et al.:Language phenotypes in children with sex chromosome trisomies [version 2; peer review: 3 approved]. Wellcome Open Res. 2019; 3(143): 143. PubMed Abstract | Publisher Full Text\n\nBrugha TS, McManus S, Smith J, et al.:Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychol. Med. 2012; 42(3): 647–656. PubMed Abstract | Publisher Full Text\n\nCrane L, Chester JW, Goddard L, et al.:Experiences of autism diagnosis: A survey of over 1000 parents in the United Kingdom. Autism. 2016; 20(2): 153–162. PubMed Abstract | Publisher Full Text\n\nGardner W, Murphy M, Childs G, et al.:The PSC-17: a brief pediatric symptom checklist with psychosocial problem subscales. A report from PROS and ASPN. Ambulatory Child Health. 1999; 5(3): 225–236.\n\nGibson J, Adams C, Lockton E, et al.:Social communication disorder outside autism? A diagnostic classification approach to delineating pragmatic language impairment, high functioning autism and specific language impairment. J. Child Psychol. Psychiatry. 2013; 54(11): 1186–1197. PubMed Abstract | Publisher Full Text\n\nHervé M:RVAideMemoire: Testing and plotting procedures for biostatistics. R package version 0.9-77.2020.Reference Source\n\nHus V, Gotham K, Lord C:Standardizing ADOS domain scores: Separating severity of social affect and restricted and repetitive behaviors. J. Autism Dev. Disord. 2014; 44(10): 2400–2412. PubMed Abstract | Publisher Full Text\n\nKassambara A:ggpubr: ‘ggplot2’ based publication ready plots. R package version 0.4.0.2020.Reference Source\n\nKwok EYL, Brown HM, Smyth RE, et al.:Meta-analysis of receptive and expressive language skills in autism spectrum disorder. Res. Autism Spectr. Disord. 2015; 9: 202–222. Publisher Full Text\n\nLam YG, Yeung SSS:Towards a convergent account of pragmatic language deficits in children with high-functioning autism: Depicting the phenotype using the pragmatic rating scale. Res. Autism Spectr. Disord. 2012; 6(2): 792–797. Publisher Full Text\n\nLeyfer OT, Tager-Flusberg H, Dowd M, et al.:Overlap between autism and specific language impairment: Comparison of Autism Diagnostic Interview and Autism Diagnostic Observation Schedule scores. Autism Res. 2008; 1(5): 284–296. PubMed Abstract | Publisher Full Text\n\nLord C, Rutter M, DiLavore PC, et al.: Autism Diagnostic Observation Schedule - Second Edition. Western Psychological Services;2012.\n\nLord C, Rutter M, Le Couteur A:Autism Diagnostic Interview—Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J. Autism Dev. Disord. 1994; 24(5): 659–685. PubMed Abstract | Publisher Full Text\n\nMagiati I, Tay XW, Howlin P:Cognitive, language, social and behavioural outcomes in adults with autism spectrum disorders: A systematic review of longitudinal follow-up studies in adulthood. Clin. Psychol. Rev. 2014; 34(1): 73–86. PubMed Abstract | Publisher Full Text\n\nMandy W, Charman T, Gilmour J, et al.:Toward specifying pervasive developmental disorder-not otherwise specified. Autism Res. 2011; 4(2): 121–131. PubMed Abstract | Publisher Full Text\n\nMandy W, Charman T, Puura K, et al.:Investigating the cross-cultural validity of DSM-5 autism spectrum disorder: Evidence from Finnish and UK samples. Autism. 2014; 18(1): 45–54. PubMed Abstract | Publisher Full Text\n\nMatthews D, Biney H, Abbot-Smith K:Individual differences in children’s pragmatic ability: A review of associations with formal language, social cognition, and executive functions. Lang. Learn. Dev. 2018; 14(3): 186–223. Publisher Full Text\n\nMcDonald JL:Beyond the critical period: Processing-based explanations for poor grammaticality judgment performance by late second language learners. J. Mem. Lang. 2006; 55(3): 381–401. Publisher Full Text\n\nMorris JK, Alberman E, Scott C, et al.:Is the prevalence of Klinefelter syndrome increasing?. Eur. J. Hum. Genet. 2008; 16(2): 163–170. PubMed Abstract | Publisher Full Text\n\nNorbury CF:Practitioner review: Social (pragmatic) communication disorder conceptualization, evidence and clinical implications. J. Child Psychol. Psychiatry. 2014; 55(3): 204–216. PubMed Abstract | Publisher Full Text\n\nNorbury CF, Nash M, Baird G, et al.:Using a parental checklist to identify diagnostic groups in children with communication impairment: A validation of the Children's Communication Checklist-2. Int. J. Lang. Commun. Disord. 2004; 39(3): 345–364. PubMed Abstract | Publisher Full Text\n\nR Core Team: R: A language and environment for statistical computing. R Foundation for Statistical Computing;2020.Reference Source\n\nRevelle W: psych: Procedures for personality and psychological research. Northwestern University;2019.Reference Source\n\nRobinson EB, St Pourcain B, Anttila V, et al.:Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat. Genet. 2016; 48(5): 552–555. PubMed Abstract | Publisher Full Text\n\nRonald A, Happé F, Bolton P, et al.:Genetic heterogeneity between the three components of the autism spectrum: A twin study. J. Am. Acad. Child Adolesc. Psychiatry. 2006; 45(6): 691–699. PubMed Abstract | Publisher Full Text\n\nRosseel Y:lavaan: An R package for structural equation modelling. J. Stat. Softw. 2012; 48(2): 1–36.Reference Source\n\nSantosh PJ, Mandy WP, Puura K, et al.:The construction and validation of a short form of the developmental, diagnostic and dimensional interview. Eur. Child Adolesc. Psychiatry. 2009; 18(8): 521–524. PubMed Abstract | Publisher Full Text\n\nShuster J, Perry A, Bebko J, et al.:Review of factor analytic studies examining symptoms of autism spectrum disorders. J. Autism Dev. Disord. 2014; 44(1): 90–110. PubMed Abstract | Publisher Full Text\n\nSvedholm-Häkkinen AM, Halme S, Lindeman M:Empathizing and systemizing are differentially related to dimensions of autistic traits in the general population. Int. J. Clin. Health Psychol. 2018; 18(1): 35–42. PubMed Abstract | Publisher Full Text\n\nTager-Flusberg H, Kasari C:Minimally verbal school-aged children with autism spectrum disorder: The neglected end of the spectrum. Autism Res. 2013; 6(6): 468–478. PubMed Abstract | Publisher Full Text\n\nvan Buuren S , Groothuis-Oudshoorn K:mice: Multivariate imputation by chained equations in R. J. Stat. Softw. 2011; 45(3): 1–67. Publisher Full Text Reference Source\n\nvan Rijn S :A review of neurocognitive functioning and risk for psychopathology in sex chromosome trisomy (47,XXY, 47,XXX, 47, XYY). Curr. Opin. Psychiatry. 2019; 32(2): 79–84. PubMed Abstract | Publisher Full Text\n\nWalker DR, Thompson A, Zwaigenbaum L, et al.:Specifying PDD-NOS: A comparison of PDD-NOS, Asperger syndrome, and autism. J. Am. Acad. Child Adolesc. Psychiatry. 2004; 43(2): 172–180. PubMed Abstract | Publisher Full Text\n\nWickham H: ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag;2016.\n\nWilson AC, Bishop D:A novel online assessment of pragmatic and core language skills: An attempt to tease apart language domains in children. J. Child Lang. 2022a; 49(1): 38–59. PubMed Abstract | Publisher Full Text\n\nWilson A, Bishop DVM:Data and scripts: children in clinical groups.2022b, May 19. Publisher Full Text\n\nWilson AC, King J, Bishop DVM:Autism and social anxiety in children with sex chromosome trisomies: An observational study [version 2; peer review: 2 approved]. Wellcome Open Res. 2019; 4(32). Publisher Full Text PubMed Abstract | Reference Source"
}
|
[
{
"id": "145590",
"date": "08 Aug 2022",
"name": "Lu Qiao",
"expertise": [
"Reviewer Expertise rare disease",
"genetic variants",
"genome-wide association study",
"multi-omics study and neurodevelopmental outcomes"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the paper titled “Does the autism phenotype differ when selecting groups by neurodevelopmental versus genetic diagnosis? An observational study comparing autism and sex chromosome trisomy”, Wilson et al. analyzed 61 young people diagnosed with autism and 49 with sex chromosome trisomy for whom the psychometric measures including autism phenotype, language ability, general psychosocial impairment and special educational needs support were available. The authors investigated the difference of autism phenotypes, different relationships of language ability with autism features and difference in the amount of special educational needs across above samples defined by behavioural versus genetic diagnoses. No significant difference of autism phenotypes between groups and autism features were distinct from language ability in both groups. Controlling for level of difficulties, SCT group received less special educational needs than autism group. This study supports that autism diagnostic criteria may not map exactly onto the autism phenotype.\nIn their paper, the authors did an excellent job controlling for prenatal or postnatal samples, age or school year, levels of difficulties, etc in the analysis. The neurodevelopmental abilities or autism features are highly correlated with age or school year, levels of difficulties or even diagnosed phrase, which are stated in the introduction. They detect the proportion, variances and covariances instead of mean score. They removed the effect of age on the language factor using linear regression or take age and language ability as independent variables. I believe these are very reasonable methods to solve the questions. One concern is small sample size in the multi-group confirmatory factor analysis. The other things that I liked about this paper are organized logically in the introduction and discussion part. The paper is generally well written and structured.\nBelow I have provided numerous remarks on the text or figures:\nIn the introduction part, adding more details in the relationship between SCT and autism especially in genetic and phenotype aspect would be constructive. I thought this may help us readers understand the purpose at the beginning of the paper.\n\nIn figure 1, is the model B showing the autism in general population? Is it more helpful to highlight autism in red to explain model B? What’s the reference of those two models?\n\nIn figure 3, can you show the scores on x and y axis to clarify the measure values?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "154704",
"date": "16 Dec 2022",
"name": "Nancy Raitano Lee",
"expertise": [
"Reviewer Expertise language",
"executive function",
"and social development among youth with neurogenetic syndromes"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to review “Does the autism phenotype differ when selecting groups by neurodevelopmental versus genetic diagnosis? An observational study comparing autism and sex chromosome trisomy” for F1000 Research. Wilson and Bishop pose a compelling question about the validity of the assumptions that underlie the autism diagnostic criteria (i.e., that social and non-social features of autism cluster together but are distinct from structural [i.e., non-social] language skills). They utilize a clever design by comparing associations among the triad (using DSM-IV as opposed to DSM-5 terminology) of autism symptoms and structural language skills in two samples – one defined by genotype (sex chromosome trisomies [SCTs]; n= 49) and the other by phenotype (those with behaviorally-ascertained autism diagnoses; n = 61). The authors report that autistic symptoms cluster together similarly in the behaviorally-defined autism group and the genetically defined SCT group. They also note that language skills do appear to be distinct from autism symptomatology in the two groups. However, they note two characteristics of the autism symptom presentation in youth with SCT that differ from those with behaviorally-ascertained autism: (a) those with SCT were more likely to show clinically significant elevations in some but not all ASD symptom clusters, and (b) those with SCT had lower levels of repetitive behaviors/restricted interests (i.e., non-social features of ASD).\nOverall, the research questions were clearly stated, the study was well-designed, and the research methods/statistical analyses employed were rigorous. In what follows, I note some questions I had that may be helpful for the authors to consider.\n\nAlthough I understand the use of the term ‘naturally’ when referring to the clustering of ASD features among youth with SCTs as opposed to behaviorally-defined ASD, I struggled a bit with the use of this terminology. Specifically, I was concerned that the reader who is naïve to autism research may wonder if this implies that behaviorally-defined ASD has less of a biological origin than ASD/ ASD features in those with SCTs (as ‘natural’ could imply that one group has a biologically driven symptom presentation and the other group does not). Is there another way to describe this distinction?\n\nI had a question about how exclusion criterion 3 (exclusion of those who were nonverbal or had phrase-level speech) may have impacted the pattern of findings. Upon reviewing the tests used to assess language, I understand why the authors imposed this exclusion to participation. However, I wonder if this influenced the findings. For example, had the authors permitted the inclusion of those with more limited language abilities, might you have seen less dissociability between language skills and social communication skills? By constraining structural language skills in the sample, could this have influenced associations observed between language skills and autism symptomatology. I don’t know that I have the answer, but this is certainly something I wondered as I read this paper and carefully considered the results.\n\nWhen discussing study findings, it may be beneficial to reference the literature on autism symptomatology in other neurogenetic disorders at heightened risk for ASD (e.g., fragile X syndrome, Down syndrome, Williams syndrome, Smith-Magenis syndrome). This could lead to an even richer discussion of the findings. Although studies of ASD symptomatology in these other neurogenetic syndromes may not have set out to evaluate the validity of the autism behavioral phenotype, per se, they are likely to speak to issues related to how autism symptoms cluster together in other neurogenetic syndromes as well as differences in symptom severity in the social and non-social aspects of ASD.\n\nAgain, thank you for the opportunity to review this very interesting manuscript!\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-571
|
https://f1000research.com/articles/11-570/v1
|
25 May 22
|
{
"type": "Research Article",
"title": "Financial logistics models based on systematic approach improving management solutions",
"authors": [
"Sergey Evgenievich Barykin",
"Irina Vasilievna Kapustina",
"Sergey Mikhailovich Sergeev",
"Sara Mehrab Daniali",
"Lyudmila Anatolievna Kopteva",
"Galina Nikolaevna Semenova",
"Igor Petrovich Pryadko",
"Alexey Mikhaylov",
"Pavel Baboshkin",
"Polina Datsyuk",
"Tomonobu Senjyu",
"Irina Vasilievna Kapustina",
"Sara Mehrab Daniali",
"Lyudmila Anatolievna Kopteva",
"Galina Nikolaevna Semenova",
"Igor Petrovich Pryadko",
"Alexey Mikhaylov",
"Pavel Baboshkin",
"Polina Datsyuk",
"Tomonobu Senjyu"
],
"abstract": "Background: Some firms with good growth opportunities and additional funds could have difficulties accessing external finance. One possible way to enhance their financial inclusion could be an exciting approach to planning the money reserve collected on a firm’s account. Methods: This article aims to disclose the introduction of financial logistics as the new theoretical field of management science. The authors present, in this paper, the key findings on the development of logistical models of an optimum money reserve calculation taking into account digital transformation and industry 4.0 technologies and optimization methods. Results: The monetary reserve models are analogies of models of storekeeping in supply chains. The specific area of the theoretical research of logistics is shown in this paper, which could be disclosed as the subject of financial logistics as a science. The authors consider the term “Financial Logistics” based on logistics theory and money demand. Conclusions: Authors suggest the methodology of studying the nature of both financial and material flows of resources by comparing the relevant formulas. From the researchers’ points of view, financial logistics could be defined as the theory of managing the cash flows based on the logistical models for calculating a corporation’s cash reserve. The authors find it interesting to expand the conditions for calculating financial flows since the uncertainty of external market conditions always influences actual commercial activity.",
"keywords": [
"Financial Inclusion",
"Logistics Models",
"Cash Balance",
"Financial Logistics",
"Optimal Order Size"
],
"content": "Introduction\n\nCurrently, industry 4.0 technologies and optimization methods (Spanos et al. 2014; Verny et al. 2020; Baruffaldi and Sternberg 2018; Brenner and Hummel 2017; Kayikci 2018; Tjahjono et al. 2017) allows to develop and implement new operating models (Tamás 2018) in various fields of logistics. The authors take into account the broad treatment of the term Financial Logistics, which could stand for multiple areas of consulting activities, including financial solutions for early-stage business's start-up, growth, and expansion, as well as “building platforms to assist companies in meeting their benchmark results”. The term financial logistics might be considered based on both theoretical points of view: logistics and demand for money.\n\nLogistics can be considered the science of managing material and related information and financial and service flows in an economic system from their origin to the place of consumption to achieve the system's goals with optimal resource costs.\n\nForming an optimal order batch model is one of the most critical problems of logistics, which is a crucial element of logistics theory in analyzing existing supply chains and designing optimal logistics systems. At the same time, to plan the balance of funds in the current account of the corporation, we can apply the idea of achieving a balance between the cost of placing an order and the cost of maintaining a stock of goods in the warehouse. The research results on the development of logistics models are presented in this article for calculating the optimal cash reserve. This article aims to disclose the introduction of financial logistics as the new theoretical field of management science.\n\nThe authors propose the combined approach concerning some critical issues from the theory of money demand by Bennet T. McCallum and Marvin S. Goodfriend (McCallum and Goodfriend 1987). The improvement of the classical logistical approach to finances is based on the critical papers by Sprenkle (Sprenkle 1969) (regarding the disadvantages of transactions demand for money models), Meltzer (Meltzer 1963) (considering the demand for money in relation to business firms), studying of the Maurice Allais’ priority of the Baumol-Tobin optimal cash balance model in the work (Baumol and Tobin 1989), Tobin (Tobin 1956) (the interest-elasticity of the demand for cash at a given volume of transactions), Morris (Morris 1971) (discussing the transactions demand for cash), Grace (Grace 1975) (examining the specification of the cost function in Baumol's and on Morris' transactions demand for cash), Karni (Karni 1973) (investigating possible interrelations among the volume of transactions, the rate of interest and the cost of cash withdrawal), Weitzman (Weitzman 1968) (commenting stochastic approach to exploring demand for money by firms) and cash management models (da Costa Moraes, Nagano, and Sobreiro 2015). Also, the authors find interesting the idea that the transactions should spend time depending on the technological innovations in the financial sphere. The researchers agree with Orazio Attanasio, Luigi Guiso, Tullio Jappelli (Attanasio, Guiso, and Jappelli 2002).\n\nThe authors suggest comparing formulas for calculating the optimal amount of cash reserve and various models of the optimal order size. Researchers are attempting to disclose a new systematic approach considering the shared nature of the material and financial flows. So, the methods used for defining the optimal order size in supply chain management could be implemented to manage financial flows.\n\nThe researchers suggest the following definition of financial logistics from the theoretical point of view: financial logistics could be defined as the theory of managing cash flows based on the logistical models for calculating the corporation’s cash reserve. This article presents the model for determining the monetary reserve, an analogy to the inventory management model in supply chains. The developed approach considers the theoretical fundamentals for comparing the optimal amount of cash reserve and various inventory management models, which improves both the theory and practice of financial planning.\n\n\nEvolution of logistics models for cash inventory management\n\nThis research aims to develop a systematic approach to managing financial flows based on the theoretical system previously implemented in supply chain management. The authors have implemented the logistics theory into determining a corporation’s cash reserve. We can develop the used methods based on the analogy of the theoretical approach that has been developed in logistics and supply chain management of optimal order size models. The article proves to extend the framework of the theory and methods that are widely known in supply chains management for a new research field spreading over both the financial management models and the logistics approach.\n\nThe authors show the specific area of the theoretical research of logistics which could be disclosed as financial logistics as a science.\n\nLogistics began in the 1950s. Although the logistics processes were carried out earlier in economic activity, they were performed separately, without any logistics management concept in the modern sense. The Optimal or Economical Order Quantity (EOQ) model is the most common model of applied logistics theory. According to Steven Nahmias (Nahmias 2007), interest in mathematical models for inventory management emerged in the first half of the 20th century. At the same time, in 1915, Ford Whitman Harris outlined a simple model for calculating the optimal order size, and this model was analyzed by R. H. Wilson in 1934 (Wilson 1934) (according to D. Erlenkotter (Erlenkotter 1989, 1990)).\n\nSince the 1950s, the idea of inventory management based on demand forecasting for individual groups of goods and raw materials is further spread in the sphere of circulation of financial flows.\n\nAn article by William Baumol published in the November 1952 issue of the Quarterly Journal of Economics (Baumol 1952) is the first work in money management. It should be noted that W. Baumol used the idea of minimizing the total costs of registration and storage of inventory, considering the opportunity costs of storing funds and the costs of attracting financial resources. The basic idea of the Baumol model is that there are opportunity costs of keeping money which is the interest income that can be generated on other assets. However, storing cash reserves allows you to reduce transaction costs. When the interest rate increases, the corporation will seek to reduce the funds due to the opportunity costs of storing money.\n\nWe can conclude that the period of development of logistics models for managing the corporation's financial resources begins since the publication of W. Baumol’s article, taking into account the opinion of Baumol and J. Tobin about the priority of this model in work (Baumol and Tobin 1989). In general, we can talk about another area of application of methods and models of logistics as a science of managing not only materials but also financial flows of the corporation.\n\nA study by Merton H. Miller and Daniel Orr is the subsequent work devoted to calculating the optimal cash balance. This study aimed at developing a model for managing cash reserves in an uncertain environment (published in the August 1966 issue of the Quarterly Journal of Economics (Miller and Orr 1966)). Another study provided the extension of the model for calculating the cash reserve of M. Miller and D. Orr, which was published in Miller and Orr (1968). The stochastic model assumes the probabilistic nature of the behavior of the corporation's cash flows, which is in contrast to the Baumol-Tobin model.\n\nBernell K. Stone, an Associate Professor of the master’s degree in Commercial and Industrial Activities and Public Administration at Cornell University, in 1972, proposed an extension of the Miller-Orr model, suggesting the possibility of predicting the net cash flow of a corporation (Stone 1972). The B. Stone model assumes that the corporation can expect the cash flow with a sufficient degree of certainty, in contrast to the stochastic model for calculating the optimal cash balance of M. Miller and D. Orr.\n\nImproving the logistics models of managing the corporation's financial resources has continued since the 1970s. Considering the possibility of postponing the payment to a later date by obtaining a deferral, an extension of the Baumol model was proposed by Rama Sastry, an Associate Professor at the Indian Institute of Research in Bangalore (Sastry 1970). The model developed by R. Sastry overcomes the disadvantage of the Baumol model of the absence of the possibility of deferred payment. According to the model, the Sastry objective function includes the costs of financial transactions and the opportunity costs of storing funds, as in the Baumol model, and the interest accrued by the corporation's counterparties on loan provided.\n\nIn the process of financial management, the corporation can use the credit line model developed by William A. Ogden and Srinivasan Sundaram and published in the Journal of Financial and Strategic decisions in the spring of 1998 (Ogden and Sundaram 1998). The interest rate on loans, as a rule, exceeds the return on short-term investments. This means that the cost of servicing the loan exceeds the opportunity cost of the funds received through the sale of securities. Borrowing reduces the number of transactions involving the sale of securities made to replenish the cash reserve. The credit line model allows you to calculate the optimal amount of cash received through the sale of securities and attracted by the credit line for a specific time.\n\nIt should be noted that financial resources interacting with material flows are also a controlled link and must obey the general laws of the logistics system. Although there are differences in calculating the optimal values of the cash balance and inventory of material resources, the models have some similarities, shown in Table 1. For example, the formula of W. Baumol corresponds to the Wilson formula used to determine the optimal order size in supply chains.\n\nThe correspondence of the symbols in the formulas for calculating the optimal values of stocks of material and financial resources is shown in Table 2.\n\n\nMethods\n\nAll the models considered (the model of calculating the cash reserve with the possibility of multiple financial investments, the model of the cash reserve taking into account lending and various financial assets, and the model of lending and financial investments with a limit on the number of interest payments) are based on the assumption of instant replenishment of the cash reserve. In some cases, the money is gradually transferred to the current account of the corporation. Therefore, it takes time to replenish the balance of funds in the existing version of the corporation.\n\nThe assumption of the model of W. Baumol was used. The balance of funds R, attracted to replenish the cash reserve, is reduced until stock is entirely exhausted. Consequently, it is assumed that the amount of cash Ri will decrease evenly in the interval t and then the subsequent replenishment of money at the end of the interval t. Ed𝑖 denotes the profitability of the i-th financial investment. Then, the total opportunity cost of the corporation from the termination of N financial investments will be\n\nIn this case, the equality is valid:\n\nSince the total cash reserve is equal to the sum of all potential investments (with the amount of Ri each) that remained unrealized.\n\nSuppose the corporation allocates R to investments in shares. In that case, it should determine the claims of li (as a percentage of R), reflecting the number of funds that can be allocated to a specific financial investment, i.e., for li in shares of a unit:\n\nThen, the total opportunity cost (analogous to the cost of storing tangible assets), formulated in the form (1), is equal to\n\nConsider the costs of attracting financial resources. In the model of W. Baumol, it is assumed that the costs associated with the transaction for the sale of securities are b rubles for the deal. However, there may be several financial assets, so it is logical to assume that the fixed costs of making transactions with different types of investments are not equal and can be indicated by bi rubles for the deal. Let us consider the case when the transaction costs contain a constant (bfi rubles per transaction) and the variable part (bvi∙R rubles per transaction); that is, the transaction costs are equal to\n\nLet us make the following assumptions.\n\n\n\n1. The corporation uses two types of assets, as in the previous models:\n\n(a) bank deposits and securities,\n\n(b) a stock of cash.\n\n2. The corporation’s costs for making transactions with securities and conducting operations for depositing or withdrawing money from a bank deposit do not depend on the transaction volume and include constant and variable parts.\n\n3. The constant intensity of the receipt of funds u rubles is known per day during the time interval t1 (Figure 1).\n\n4. The corporation that has accumulated a reserve of funds, that is, after the end of the time interval t1, spends the funds during the interval t2. At the same time, the intensity of the expenditure of funds is constant throughout the entire time interval t (t1 + t2) and is equal to v rubles per day.\n\nThus, over the period t1, the reserves increase with an intensity of (u – v) rubles per day. After t1 day, the receipt of funds Ropt, and the balance on the current account starts to decrease with an intensity of v rubles per day. The maximum size of the stock is equal to (u – v)t1 rubles for t1 day.\n\nRecall that the total costs of the corporation are equal to the sum of the costs of storing and raising funds. Consider the components of the total costs in the interval t:\n\n1) the opportunity cost of storing funds will be\n\n\n\n2) the cost of raising funds is equal to\n\nWrite down the expression for the total costs of the company in the period T:\n\nLet us take the derivative of F concerning R, equate it to zero, and get an expression for calculating the optimal size of cash receipts that are uniform over time. Ropt is equal to\n\nHaving calculated the optimal amount of cash inflow, we write down the expression for calculating the maximum balance of funds on the current account Rmax:\n\nThe developed model for calculating the considered cash flow is presented first and analogous to the production order model in supply chains (Economic Production Quantity, EPQ).\n\nLet us assume that a corporation has the opportunity to purchase securities of various yields (% per year): Ed1 = 24 %; Ed2 = 16 %; Ed3 = 10 %.\n\nShares (as a percentage of R) reflect the amount of funds that can be allocated for a specific financial investment, that is, for li in shares of a unit: l1 = 20 %; l2 = 35 %; l3 = 45 %.\n\nAt the same time, the fixed costs of making transactions by the corporation are equal, respectively (thousand rubles for each operation): bf1 = 2; bf2 = 3; bf3 = 4.\n\nVariable transaction costs (percentages of the transaction amount) are bv1 = 0,5; bv2 = 0,6; bv3 = 0,65.\n\nThe total amount of all payments to the corporation per year is 245,000 thousand Rubles. Moreover, the intensity of receipt of funds is accepted for 1,000 thousand Rubles per day, and the intensity of the expenditure of funds is 671.2 thousand Rubles per day. The funds are spent as they are credited to the corporation's current account.\n\nAt the same time, the fixed costs of raising funds from the sale of type i assets during the t1 interval (thousand rubles in the t1 interval) are bf1,t1=2; bf2,t1=3; bf3,t1=4.\n\nThe variable costs of raising funds from the sale of type i assets during the t1 interval are (percentages of the transaction amount) bv1,t1 = 0,5; bv2,t1 = 0,6; bv3,t1 = 0,65.\n\nThe model allows us to calculate the optimal receipts and the maximum balance of funds on the current account. Substituting the data in the formulas (9) and (10), we get the optimal value of uniform cash receipts of the Ropt 9,488.2 thousand rubles, and the size of the cash reserve Rmax is equal to 3,119.4 thousand Rubles during the year (Barykin 2022).\n\nMicrosoft Excel was used for this calculation example for the developed model.\n\n\nResults and discussion\n\nAuthors suggest discussing considered theoretical propositions as the introduction to the new field of the research. Studying the latest systematic approach as a subject of financial logistics is suggested.\n\nHowever, the calculated dependences reflect a particular deterministic case and assume linear profitability and interest rates. The authors find it interesting to expand the conditions for calculating financial flows since the uncertainty of external market conditions always influences actual commercial activity. The reasoning will be carried out by analogy with the calculations of reserves with uncertain demand. The basic equations and parameters also correspond to the financial indicators. To solve such a complicated problem and the list of considered indicators, it is necessary to introduce: ψz - the probability density function of the required stock of funds z. Then, to carry out the calculation, we will formulate the representation of the problem statement in the following form.\n\nIt is necessary to search for a solution that satisfies the condition:\n\nLz means costs due to uncertainty and are calculated for z≥0 as follows:\n\nSince it is also necessary to take into account the variant of the deficit, then for z<0 it can be written:\n\nThe presented mathematical formalisms are convenient for implementation on a computer. Using any of the add-ons for finding the optimal solution included in all packages of applied programs, the researcher can calculate the result in the form of an optimal solution from the condition:\n\nwhere θ means the lower limit of the probability of fulfilling the conditions for raising funds, ΨS means an expression for calculating the cumulative distribution function.\n\nExpressions are much clearer in the case of the discrete nature of monetary assets. Then these formalisms are transformed into sums of the following form:\n\nSince the calculation formulas given in Table 1 were built from the condition of linearity of dependencies both bz and EDz as well as EKRz, applying this assumption, it is possible to solve the resulting equations by differentiating the expression b⋅z+Lz and equating to zero:\n\nThis equality gives a simple result for linear dependencies: ΨS0=EKR−bEKR+ED.\n\nThe abovementioned expression can be used for approximate estimates, but to calculate economically significant indicators, it is necessary to use an algorithm based on formulas (1) - (4) of this research.\n\nThe researchers also suggest discussing the use of the proposed approach from the point of view of financial inclusion as providing greater access to financial services. A financial inclusion policy focuses on both the World Bank and the United Nations Development Programme (UNDP). The World Bank report on Financial Inclusion (World Bank 2013) describes when some firms have difficulties accessing financial resources due to principal-agent problems or transaction costs. Authors suppose that those firms could implement the proposed financial logistics approach to enhance their financial inclusion to get additional funds to finance working capital and fixed asset investments.\n\nExploring methods and models of financial logistics in reliance on different conditions could be a topic for future research. The new industry 4.0 technologies (e.g., cyber physics systems, big data, IoT, etc.) allow extending the field of financial logistics implementation based on the digital transformation of logistics (S. Y. Barykin, Bochkarev, et al. 2021; Shmatko et al. 2021) and digital twins (S. Y. Barykin, Kapustina, et al. 2021). Authors also argue that studying the developed approach is based on sustainability (Pouri and Hilty 2018; S. E. Barykin et al. 2021; Bevilacqua et al. 2020), and the digital transformation concept (Mikhaylov 2021) is a topic for future research.\n\n\nConclusion\n\nThis article presents a model developed by the authors for calculating the cash balance, allowing firms to determine the reserve of funds, enhancing their management solution. The development of financial flow management models based on the logistics methodology, including building analogies with models for determining the optimal order size, will improve planning the balance of funds and increase the efficiency of allocating funds.\n\nThe logistics approach is based on the search for a compromise between the fixed costs of transactions (for example, the sale of securities) and the costs of maintaining the cash balance and raising borrowed funds. Various models of cash balance management developed based on the logistics methodology are considered: the model of W. Baumol, the model of debt accumulation, the credit line, and the Miller-Orr model. It can be concluded that although there exist different models for managing the cash balance, there are currently no improvements to the models that allow for the other conditions of the corporation's financial flow planning. The researchers suggest the following definition of financial logistics from the theoretical point of view: financial logistics could be defined as the theory of managing the cash flows based on the logistical models for calculating the firm’s cash reserve.\n\nAuthors considered a systematic approach comprising both the theory of financial management and models of optimal order size in supply chain management. The firms can apply the idea of striking a balance between expenses for registration of the order and charges on the maintenance of a stock of the goods in a warehouse. The authors find it interesting to expand the conditions for calculating financial flows and consider the developed approach from the point of view of sustainability concept based on the multidisciplinary approach as a topic for future research, taking into account the uncertainty of external market conditions.\n\n\nData availability\n\nFigshare: Financial logistics model calculations.xls. https://doi.org/10.6084/m9.figshare.19640694.v1 (Barykin 2022).\n\nThis project contains the following underlying data:\n\n- Data file 1. Financial logistics model calculations.xls (example data with the relevant calculation of the developed model and visualization in MS Excel sheet)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nWe are thankful to the Ministry of Science and Higher Education of the Russian Federation for the financial support of this project.\n\n\nReferences\n\nAttanasio OP, Guiso L, Jappelli T: The Demand for Money, Financial Innovation, and the Welfare Cost of Inflation: An Analysis with Household Data. J. Polit. Econ. 2002; 110(2): 317–351. Publisher Full Text\n\nBaruffaldi G, Sternberg H: Chains in Chains - Logic and Challenges of Blockchains in Supply Chains. Proceedings of the 51st Hawaii International Conference on System Sciences. 2018; 3936–3943. Publisher Full Text\n\nBarykin SE: Financial logistics model calculations.xls. figshare. Dataset. 2022. Publisher Full Text\n\nBarykin SE, Borisoglebskaya LN, Provotorov VV, et al.: Sustainability of Management Decisions in a Digital Logistics Network. Sustainability. 2021; 13(16): 9289. Publisher Full Text\n\nBarykin SY, Bochkarev AA, Dobronravin E, et al.: The Place and Role of Digital Twin in Supply Chain Management. Acad. Strateg. Manag. J. 2021; 20(2): 1–19.Reference Source\n\nBarykin SY, Kapustina IV, Sergeev SM, et al.: Developing the Physical Distribution Digital Twin Model within the Trade Network. Acad. Strateg. Manag. J. 2021; 20(1): 1–18.Reference Source\n\nBaumol WJ: The Transactions Demand for Cash: An Inventory Theoretic Approach. Q. J. Econ. 1952; 66(4): 545. Publisher Full Text\n\nBaumol WJ, Tobin J: The Optimal Cash Balance Proposition: Maurice Allais’ Priority. J. Econ. Lit. 1989; 27(3): 1160–1162.Reference Source\n\nBevilacqua M, Bottani E, Ciarapica FE, et al.: Digital Twin Reference Model Development to Prevent Operators’ Risk in Process Plants. Sustainability. 2020; 12(3): 1088. Publisher Full Text\n\nBrenner B, Hummel V: Digital Twin as Enabler for an Innovative Digital Shopfloor Management System in the ESB Logistics Learning Factory at Reutlingen - University. Procedia Manuf. 2017; 9: 198–205. Publisher Full Text\n\nMoraes C, da Botelho M , Nagano MS, et al.: Stochastic Cash Flow Management Models: A Literature Review Since the 1980s. Guarnieri P, editor.Cham:Springer International Publishing;2015; 11–28. Publisher Full Text\n\nErlenkotter D: An Early Classic Misplaced: Ford W. Harris’s Economic Order Quantity Model of 1915. Manag. Sci. 1989; 35(7): 898–900. Publisher Full Text Reference Source\n\nErlenkotter D: Ford Whitman Harris and the Economic Order Quantity Model. Oper. Res. 1990; 38(6): 937–946. Publisher Full Text Reference Source\n\nGrace HS: Proper Specification of the Cost Function: A Comment on Baumol’s and on Morris’ Transactions Demand for Cash. Q. J. Econ. 1975; 89(4): 658. Publisher Full Text\n\nKarni E: The Transactions Demand for Cash: Incorporation of the Value of Time into the Inventory Approach. J. Polit. Econ. 1973; 81(5): 1216–1225. Publisher Full Text Reference Source\n\nKayikci Y: Sustainability Impact of Digitization in Logistics. Procedia Manuf. 2018; 21: 782–789. Publisher Full Text\n\nMcCallum B, Goodfriend M: Money: Theoretical Analysis of the Demand for Money. National Bureau of Economic Research Working Paper Series. Vol. No. 2157. Cambridge, MA.1987. Publisher Full Text\n\nMeltzer AH: The Demand for Money: A Cross-Section Study of Business Firms. Q. J. Econ. 1963; 77(3): 405. Publisher Full Text\n\nMikhaylov AY: Development of Friedrich von Hayekʼs Theory of Private Money and Economic Implications for Digital Currencies. Terra Economicus. 2021; 19(1): 53–62. Publisher Full Text\n\nMiller MH, Orr D: A Model of the Demand for Money by Firms. Q. J. Econ. 1966; 80(3): 413. Publisher Full Text\n\nMiller MH, Orr D: The Demand for Money by Firms: Extensions of Analytic Results. J. Financ. 1968; 23(5): 735. Publisher Full Text\n\nMorris RD: A Note on the Transactions Demand for Cash. Q. J. Econ. 1971; 85(3): 546. Publisher Full Text\n\nNahmias S: Análisis de La Producción y Las Operaciones. 5ta Edición ed.Mc Graw Hill;2007.Reference Source\n\nOgden WA, Sundaram S: A Model for Optimal Utilization of a Firm’s Line of Credit. J. Financ. Strateg. Decis. 1998; 11(1): 27–35.Reference Source\n\nPouri MJ, Hilty LM: Conceptualizing the Digital Sharing Economy in the Context of Sustainability. Sustainability. 2018; 10(12): 4453. Publisher Full Text\n\nSastry ASR: The Effect of Credit on Trasactions Demand for Cash. J. Financ. 1970; 25(4): 777. Publisher Full Text\n\nShmatko A, Barykin S, Sergeev S, et al.: Modeling a Logistics Hub Using the Digital Footprint Method—The Implication for Open Innovation Engineering. J. Open Innov. Technol. Mark. Complex. 2021; 7(1): 59. Publisher Full Text\n\nSpanos AC, Ponis ST, Tatsiopoulos IP, et al.: A New Hybrid Parallel Genetic Algorithm for the Job-Shop Scheduling Problem. Int. Trans. Oper. Res. 2014; 21(3): 479–499. Publisher Full Text\n\nSprenkle CM: The Uselessness of Transactions Demand Models. J. Financ. 1969; 24(5): 835–847. Publisher Full Text\n\nStone BK: The Use of Forecasts and Smoothing in Control-Limit Models for Cash Management. Financ. Manag. 1972; 1(1): 72. Publisher Full Text\n\nTamás P: Innovative Business Model for Realization of Sustainable Supply Chain at the Outsourcing Examination of Logistics Services. Sustainability. 2018; 10(1): 210. Publisher Full Text\n\nTjahjono B, Esplugues C, Ares E, et al.: What Does Industry 4.0 Mean to Supply Chain?. Procedia Manuf. 2017; 13: 1175–1182. Publisher Full Text\n\nTobin J: The Interest-Elasticity of Transactions Demand For Cash. Rev. Econ. Stat. 1956; 38(3): 241. Publisher Full Text\n\nVerny J, Oulmakki O, Cabo X, et al.: Blockchain & Supply Chain: Towards an Innovative Supply Chain Design. Projectics/Proyéctica/Projectique. 2020; n°n°26(2): 115–130. Publisher Full Text\n\nWeitzman M: A Model of the Demand for Money by Firms: Comment. Q. J. Econ. 1968; 82(1): 161. Publisher Full Text\n\nWilson RH: A Scientific Routine for Stock Control. Harv. Bus. Rev. 1934; 13(1): 116–128.Reference Source\n\nWorld Bank: Global Financial Development Report 2014: Financial Inclusion. Washington, DC:The World Bank;2013. Publisher Full Text"
}
|
[
{
"id": "138964",
"date": "07 Jun 2022",
"name": "Mohammad Maruf Hasan",
"expertise": [],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you so much for giving me the opportunity to read your article. It’s a good informative study, however, some points need to be clarified and suggestions incorporated.\nDo the authors mean that the term financial logistics could refer to the wide range of solutions based on the logistics theory and demand for money? This point needs a bit more elaboration in the text.\n\nThe author needs to elaborate on how the logistics approach could be implemented in financial solutions?\n\nMore explanation is needed on what could be considered a comprehensive treatment of the term “Financial Logistics”?\n\nCould an optimal order batch model be considered as a basis for a theoretical approach for some financial models?\n\nCan the authors prove that logistics models could be the fundamental base for calculating the optimal cash reserve of the company?\n\nThe logistic model and theory of money of demand seem to be ambiguous in the text. Does the proposed combined approach include the logistics models and the theory of money demand?\n\nCan you please suggest your definition of financial logistics?\n\nMy final question is, Could specialists in financial analytic managing financial flows implement the methods used for defining the optimal order size in supply chain management?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "138965",
"date": "09 Jun 2022",
"name": "Inna Evgenievna Barykina",
"expertise": [
"Reviewer Expertise Social Sciences"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAfter reviewing the research paper I paid attention to the scientific novelty of considering the financial logistics from theoretical points of view: logistics and demand for money. Authors define financial logistics as a new scientific field that could be described as the theory of managing the cash flows based on the logistical models. So, I can make a conclusion that the authors attempt to develop the approach for implementing the logistics theory for calculating the corporation’s cash reserve. Authors explore the model for determining the monetary reserve as an analogy to the inventory management model in supply chains. The findings of the authors are very interesting from a theoretical and practical point of view, but I’d suggest making some improvements. The authors should incorporate the following suggestions and revise the manuscript.\nReviewer’s Comments:\nThe abstract needs revision and restructuring. The abstract should be revised by adding the aim and future scope of the proposed work.\n\nThe term “Financial logistics” is used in the title as well as in the abstract. Does this definition stem from logistics or from the theory of financial management? It should be explained in the introduction.\n\nThe uncertainty of market conditions is a wide concept that is required to explain in this paper’s context.\n\nIt is advised to explain the nature of the financial logistics in the introduction section to understand the research problem.\n\nPaper novelty should be added at the end of the Introduction.\n\nIt is advised to explain the logical connection between financial logistics and the digital twin concept in the discussion section.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "138963",
"date": "24 Jun 2022",
"name": "Sher Zaman Khan",
"expertise": [
"Reviewer Expertise Digital Entrepreneurship",
"sustainable development goals",
"financial inclusion",
"CSR",
"Strategic Management",
"Intellectual capital",
"Entrepreneurial finance",
"business model innovation",
"sustainable competitive advantage ect."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you very much for providing me the opportunity to review this article which is submitted by the authors for possible indexing. Actually, the article is good enough. The title of the article is interesting and the overall contents and methodology of the article are rich in multiple aspects, however, I have some minor observations which need to be incorporated by the authors in a revised version of this article. For instance,\n\nThe theory of logistics is a broader concept, I want to get it clearer if the authors try to extend the framework of the theory and logistics methods to the sphere of managing financial flows? please clarify.\n\nAlthough the proposed approach is much more interesting than the latest one, however, it needs more clarification in the main text, either, the proposed approach could be implemented in deterministic and stochastic situations?\n\nA bit more clarification is needed on the work of William Baumol, published in 1952 entitled “The Transactions Demand for Cash: An Inventory Theoretic Approach.” Is this the first work in “Financial Logistics”?\n\nDo the authors assume that the formula of W. Baumol could be considered as an analogy to the Wilson optimal order size formula?\n\nI think the authors can link the credit line model to the optimal order size when the shortage is acceptable.\n\nSome more explanation is needed in the text on how the optimal order size model in supply chains could help develop the theoretical vision of the cash reserve in financial management?\n\nIf the authors can add some information on the uniform cash reserve model and how can it be extended to the theory of financial logistics?\n\nAuthors are supposed to develop the introduction to the new field of research. What could the authors suggest as topics for future research?\nIn the end, I conclude the entire quality and context of the article are rich enough and can be recommended to be accepted for indexing if the above-mentioned minor improvements are made positively. Regards\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-570
|
https://f1000research.com/articles/11-569/v1
|
25 May 22
|
{
"type": "Systematic Review",
"title": "Amiodarone versus beta-blockers for the prevention of postoperative atrial fibrillation after cardiac surgery: An updated systematic review and meta-analysis of randomised controlled trials",
"authors": [
"Radhyaksa Ardaya",
"Jenni Pratita",
"Nusaibah Nadia Juliafina",
"Farhan Haidar Fazlur Rahman",
"Kevin Leonardo",
"Jenni Pratita",
"Nusaibah Nadia Juliafina",
"Farhan Haidar Fazlur Rahman",
"Kevin Leonardo"
],
"abstract": "Background: Amiodarone and beta-blockers are widely used as prophylaxis for postoperative atrial fibrillation (AF). The current recommendations from society guidelines are inconclusive, leading to differing practices among physicians. This meta-analysis aimed to compare the efficacy of both agents in preventing postoperative AF after cardiac surgery. Methods: We explored online medical databases, such as CINAHL, CENTRAL, MEDLINE, and EMBASE for randomised controlled trials (RCTs) comparing amiodarone and beta-blocker for prevention of AF after cardiac surgery. Outcomes analysed in this study were AF number of events and duration, hospital stay, and mean ventricular rate. Heterogeneity was assessed using the I² test, and publication bias was analysed using Egger’s test. Results: In total, eight RCTs comprising 1370 patients met the inclusion criteria. Pooled analysis showed that patients in both groups had no significant difference in both AF episodes (RR 0.83, 95% CI 0.66 to 1.04, p=0.10) and AF duration (SMD 0.46, 95% CI -1.14 to 2.05, p=0.57). Furthermore, secondary outcome analysis on mean ventricular rate and mean hospital length of stay in both groups showed no significant difference (MD -4.48, 95% CI -14.36 to 5.39, p=0.37 and MD 0.29, 95% CI -0.06 to 0.63, p=0.11, respectively). Conclusions: Amiodarone and beta-blockers are equally effective in preventing postoperative atrial fibrillation after cardiac surgery, with no difference in AF episode and duration, mean ventricular rate, and hospital length of stay.",
"keywords": [
"Atrial fibrillation",
"cardiac surgery",
"amiodarone",
"beta-blockers"
],
"content": "Introduction\n\nAtrial fibrillation (AF) is a common complication after cardiac surgeries with incidence ranging from 10% to 65% despite the latest developments in both surgical and medical management.1 Postoperative AF could lead to prolonged intensive care unit (ICU) and hospital stay, resulting in increased cost. Although its mortality rate is low, it frequently induces hemodynamic disturbance and thromboembolic events.1,2 The hypothesized pathophysiology of postoperative AF is the interaction between acute surgery-related factors, including activated sympathetic nervous system and renin-angiotensin-aldosterone system, inflammation, trauma and oxidative stress, and underlying abnormal atrial substrate which induces electrical instability.3\n\nPharmacological and non-pharmacological measures (e.g. atrial pacing) are used as strategies to prevent postoperative AF. Both beta-blockers and antiarrhythmics such as amiodarone could be used in postoperative AF prevention. Beta-blockers lower myocardial oxygen demand and ischemia events in the postoperative period by lessening the chronotropic and inotropic effects of catecholamine surge.3 Meanwhile, amiodarone prevents AF primarily by blocking potassium channels and through its anti-adrenergic effect, thus decreasing myocyte excitability, and preventing the re-entry mechanism and ectopic foci from causing an arrhythmia.3,4 Both drugs can be administered either orally or intravenously, although the latter route may be more effective.5 However, previous studies on the efficacy of these drugs provide conflicting results.\n\nAs a result, the gold standard regimen of postoperative AF prevention remains uncertain, resulting in varying practices and a high discontinuation rate, which might increase the patient’s risk of developing arrhythmias.1,2 Therefore, this study aims to compare the efficacy of these drugs in preventing postoperative AF.\n\nThe objectives of this research are to compare the efficacy of amiodarone and beta-blockers in preventing postoperative AF after cardiac surgery.\n\n\nMethods\n\nWe explored online medical databases, such as CINAHL, CENTRAL (Cochrane Library), MEDLINE (PubMed), and EMBASE (Science Direct), for a literature search from 11th January to 18th February 2022. The literature search process was performed using medical subject headings (MeSH) terms of (“coronary artery bypass graft”) AND (“amiodarone”) AND (“beta-blocker”). The search process was done according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines (see Reporting guidelines48). The literature searching and selection process were performed by all of the authors unfetteredly.\n\nA study was included if it met the following criteria: a study evaluating amiodarone and beta-blockers in patients who underwent cardiac surgery (coronary artery bypass grafting (CABG), valve repair/replacement, and both), available in full text, and written in English. Our exclusion criteria were studies which full text were not available, non-randomised studies, and studies with irrelevant outcomes. The evaluated effects should include the following parameters: AF number of events and duration, mean ventricular rate, and length of hospital stay.\n\nAll authors were involved in data collection and worked independently. The main author collected the data manually from each author and any disagreement between authors were resolved through discussion. Included studies were examined using the EndNote 20 software for possible study duplication. Alternatively, this process can also be replicated using the Mendeley Reference Manager software. All statistical analysis was performed using STATA 17 software by StataCorp, California, USA, and Review Manager (RevMan) 5.4 software by Cochrane, Oxford, United Kingdom.\n\nAll eight studies investigated AF episodes, which we used as the primary outcome. Secondary outcomes were determined based on comparable outcomes reported among the studies (AF duration, mean ventricular rate, and mean length of hospital stay).\n\nRandomised study quality was assessed using the Cochrane Risk Index of Bias tools. All authors performed bias assessment independently and disagreements were resolved through discussion.\n\nIf the data extracted were binary outcomes, statistical calculation such as risk ratio (RR) or odds ratio (OR) would be selected. Meanwhile, if the data extracted were continuous outcomes, statistical calculation such as mean difference (MD) and standardized mean difference (SMD) would be chosen.\n\nI2 result would determine the heterogeneity test result. If the I2 test result were less than fifty percent, a fixed-effect model would be selected since the heterogeneity was considered to be insignificant. Otherwise, a random-effect model would be chosen. All analyses used 95% of confidence intervals. P-value of less than 0.05 is considered to be statistically significant.\n\nReporting bias of each study was assessed using the assessed using the Cochrane Risk Index of Bias tools. Studies with high risk of reporting bias were not included in this study.\n\nWe used GRADE (grading of recommendations assessment, development and evaluation) approach to assess the certainty in the body of evidence. All authors performed the assessment independently, and disagreements between assessors were resolved through discussion between assessors.\n\n\nResults\n\nThe article selection process was carried out according to PRISMA guidelines. Initial study searching resulted in 186 articles, which all were processed using the EndNote application for study duplication. According to our inclusion criteria, the remaining 155 studies were then assessed manually by all authors. As many as thirteen articles were further analysed for eligibility, resulting in eight studies1,5–11 analysed for final qualitative and quantitative analysis. The assessment of bias in the studies were conducted using Cochrane’s risk-of-bias tool, with the result listed in Table 1.\n\nThis study analysed four outcomes: number of AF episodes, AF duration, mean ventricular rate, and length of hospital stay. The authors, publication year, nation, sample size, mean age, surgery types, outcome, and follow up time were all extracted from the studies and presented in Table 2, while the treatment protocol details (type of drugs, dosage, timing, and duration of the treatment) of the included studies were elaborated in Table 3. AF episodes are presented in risk ratio (RR). AF duration is presented in standardized mean differences (SMD), and the secondary outcomes are presented in mean difference (MD). All analyses used 95% of confidence intervals. P-value of less than 0.05 is considered to be statistically significant.\n\nA total of eight studies including 1370 participants met the inclusion criteria for the comparison of AF episode analysis. Pooled analysis in Figure 1 showed no significant difference in AF episodes between the amiodarone group and beta-blocker group (RR 0.83, 95% CI 0.66, 1.04, p=0.10).\n\nThree studies, including 384 participants, allocated into the amiodarone group (n=189) and beta-blocker group (n=195) compared the duration of AF. In accordance to the comparable risk of AF episode, pooled analysis in Figure 2 also showed no significant difference in terms of AF duration between both groups (SMD 0.46, 95% CI -1.1 to 2.05, p=0.57).\n\nMean ventricular rate comparison in Figure 3 was performed using fixed-effect model (I2=0%), resulting in not significant mean difference in mean ventricular rate comparison between both groups (MD -4.48, 95% CI -14.36 to 5.39, p=0.37).\n\nFour studies with 676 participants reported the difference in mean length of hospital stay. Figure 4 showed that there was no difference in mean length of hospital stay between both groups (MD 0.29, 95% CI -0.06 to 0.63, p=0.11).\n\nAll studies included in this meta-analysis are considered low risk of reporting bias.\n\nAssessment of evidence certainty for all outcomes in this meta-analysis resulted in moderate certainty.\n\n\nDiscussion\n\nPostoperative AF remains the most common complication in cardiac surgery patients. The incidence varies depending on the procedure, occurring after around 30% of coronary artery bypass grafting (CABG) surgery, 40% of valve repair and replacement surgeries, and about 50% in combined cardiac procedures.12 According to the guideline by the American Heart Association/American College of Cardiology and the Heart Rhythm Society in 2014 on the management of AF, preoperative administration of amiodarone is recommended before cardiac surgery on patients with increased risk of developing postoperative AF (Class IIa, Level of Evidence A).13 Risk factors for developing postoperative AF include advanced age, male gender, previous history of AF, diabetes mellitus, and the presence of left atrial enlargement, which are similar to the characteristics of most patients undergoing cardiac surgery. On the other hand, the European Society of Cardiology (ESC), in their most recent guideline on diagnosis and management of AF, recommended routine perioperative administration of amiodarone or beta-blockers regardless of risk factor status (Class I, Level of Evidence A).14 Although the recent guidelines have signified the importance of therapeutic agents administration as a prophylaxis for postoperative AF, there is another issue on whether amiodarone or beta-blockers should be given for better outcomes.\n\nIn our meta-analysis comprising eight studies, there was no difference in postoperative AF episodes between the amiodarone and beta-blockers groups. This result supports the findings from a similar meta-analysis conducted in 2012.15 Furthermore, this study found no difference between both groups in duration of AF, hospital length of stay, and mean ventricular rate. It could be implied that both drugs are equally effective in preventing postoperative AF. Therefore, in clinical practice, it is more appropriate to make an individual decision for each case rather than to follow a prespecified general guideline.\n\nBeta-blockers should be the agent of choice for patients with multiple risk factors who are already receiving long-term beta-blockers, as abrupt discontinuation of beta-blockers before surgery is associated with two- to fivefold increased risk of developing postoperative AF.3,14 On the other hand, it might not be suitable for urgent patients without a history of prior use of the agent as it should be initiated two to seven days before surgery.16–18 Extra caution should also be taken when beta-blockers are administered to patients without a history of previous use, as some patients may develop bronchospasm.13 Another issue is choosing the preferred variant of beta-blocker. Carvedilol has shown an 18 to 20% higher reduction of postoperative AF than metoprolol, although the length of hospital stay was equal.19–22 A more recent type of beta-blocker is sotalol, which exhibits class III antiarrhythmic effects on top of typical beta-blocker features.3 Several studies have demonstrated the superiority of sotalol when compared to conventional beta-blockers to prevent postoperative AF, although the sotalol group developed more side effects such as bradycardia and hypotension.23–26\n\nAmiodarone, which plays a role in both rate control and rhythm control strategies, has been demonstrated to reduce the risk of postoperative AF by 12 to 51% when compared to placebo.27–30 It is equally effective when given in different doses (low dose <3g), medium dose 3 – 5 g, and high dose > 5g), timing (pre/post operative), and through either routes (oral/IV).31,32 However, there is a rising concern regarding safety, as evidenced by a meta-analysis that reported an increased risk of hypotension, prolonged QT interval, and bradycardia in the amiodarone group when compared to placebo. Other extracardiac adverse effects from amiodarone include thyroid, hepatic, and pulmonary toxicities.33\n\nThe emergence of alternative options for preventing postoperative AF, such as corticosteroids, colchicine, and statins may be considered in an individualised manner.34–36 Corticosteroids, for example, were demonstrated to further reduce the incidence of postoperative AF when combined with beta-blockers, although the length of hospital stay was not different.37,38 The overall use of corticosteroids is low due to the popular belief that they are associated with multiple risks.39 Nonetheless, although corticosteroids use is associated with increased risk of hyperglycaemia, several studies reported that administration of corticosteroids did not increase the risk of infection, bleeding, and stroke.40,41\n\nLonger AF duration (>24 h per week) is associated with a higher mortality risk. However, there is no evidence whether this is appropriate for postoperative AF.42 Longer AF duration is also associated with an increased risk of stroke, but there was not enough data in the studies included in this meta-analysis to assess either stroke or mortality as a secondary outcome.43\n\nBoth amiodarone and beta-blockers have been widely utilised in the therapy of postoperative AF, with current evidence reporting comparable outcomes between both agents.30,44,45 Beta-blockers are one of the medications used in rate control strategy, while amiodarone plays a role in both rate control and rhythm control approaches.14 In the RACE (Rate Control Efficacy in Permanent Atrial Fibrillation) II trial, patients set to a stricter limit [heart rate < 80 beats per minute (bpm)] were not associated with lower morbidity, mortality, and hospitalisation when compared to the more lenient group (heart rate <110 bpm).46 In postoperative AF, both rate control and rhythm control approaches have shown similar complication rates and equal days of hospitalisation.47\n\nThere were a few notable limitations in this study. More recent studies investigated the use of less conventional drugs to prevent postoperative AF, resulting in a scarcity of newer trials comparing amiodarone and beta-blockers. It was not possible to examine the risk of bradycardia, hypotension, stroke, and mortality, which are commonly associated with atrial fibrillation, due to a lack of data. It should also be pointed out that in this study, we compared amiodarone with all types of beta-blockers, including sotalol. Each beta-blocker differs in properties, and some patients may benefit more from a specific type of beta-blockers but less from another.\n\nFuture research on specific population (e.g., diabetes, older age, previous history of AF) undergoing cardiac surgeries are needed to understand the efficacy and risk associated with each agent commonly used to prevent postoperative AF. Additionally, more studies investigating the efficacy and safety of emerging unconventional drugs as a first-line prophylaxis is required as existing studies have reported conflicting results.\n\n\nConclusions\n\nOur meta-analysis showed that the use of either amiodarone or beta-blockers for the prevention of postoperative AF after cardiac surgery results in comparable AF episodes, duration, mean ventricular rate and hospital length of stay. The drug of choice for each patient should therefore be personalised based on the pre-existing medical conditions.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nReporting guidelines\n\nOpen Science Framework: PRISMA checklist and flow diagram for ‘Amiodarone versus beta-blockers for the prevention of postoperative atrial fibrillation after cardiac surgery: An updated systematic review and meta-analysis of randomised controlled trials’, https://doi.org/10.17605/OSF.IO/CUYH9.48\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nOnk OA, Erkut B: Is the preoperative administration of amiodarone or metoprolol more effective in reducing atrial fibrillation: after coronary bypass surgery?. Medicine. 2015; 94(41): e1576. PubMed Abstract | Publisher Full Text\n\nPiccini JP, Zhao Y, Steinberg BA, et al.: Comparative effectiveness of pharmacotherapies for prevention of atrial fibrillation following coronary artery bypass surgery. Am. J. Cardiol. 2013; 112(7): 954–960. PubMed Abstract | Publisher Full Text\n\nTuragam MK, Downey FX, Kress DC, et al.: Pharmacological strategies for prevention of postoperative atrial fibrillation. Expert. Rev. Clin. Pharmacol. 2015; 8(2): 233–250. PubMed Abstract | Publisher Full Text\n\nJavot L, Pape E, Yéléhé-Okouma M, et al.: Intravenous single administration of amiodarone and breastfeeding. Fundam. Clin. Pharmacol. 2019; 33(3): 367–372. PubMed Abstract | Publisher Full Text\n\nHalonen J, Loponen P, Järvinen O, et al.: Metoprolol versus amiodarone in the prevention of atrial fibrillation after cardiac surgery: a randomized trial. Ann. Intern. Med. 2010; 153(11): 703–709. PubMed Abstract | Publisher Full Text\n\nBigdelian H, Gharipour M, Behdad GR, et al.: The effect of amiodarone versus propanolol for prophylaxis of atrial fibrillation af-ter cabg in low ef patients.2009.\n\nKojuri J, Mahmoodi Y, Jannati M, et al.: Ability of amiodarone and propranolol alone or in combination to prevent post-coronary bypass atrial fibrillation. Cardiovasc. Ther. 2009; 27(4): 253–258. PubMed Abstract | Publisher Full Text\n\nMooss AN, Wurdeman RL, Sugimoto JT, et al.: Amiodarone versus sotalol for the treatment of atrial fibrillation after open heart surgery: the Reduction in Postoperative Cardiovascular Arrhythmic Events (REDUCE) trial. Am. Heart J. 2004; 148(4): 641–648. PubMed Abstract | Publisher Full Text\n\nNayeem-ul-hassan AMD, Wani ML, Rather HA, et al.: A comparative study on the effect of amiodarone and metaprolol for prevention of arrythmias after open heart surgery. Int. Cardiovasc. Res. J. 2013; 7(1): 1–4. PubMed Abstract\n\nSleilaty G, Madi-Jebara S, Yazigi A, et al.: Postoperative oral amiodarone versus oral bisoprolol as prophylaxis against atrial fibrillation after coronary artery bypass graft surgery: a prospective randomized trial. Int. J. Cardiol. 2009; 137(2): 116–122. PubMed Abstract | Publisher Full Text\n\nSolomon AJ, Greenberg MD, Kilborn MJ, et al.: Amiodarone versus a β-blocker to prevent atrial fibrillation after cardiovascular surgery. Am. Heart J. 2001; 142(5): 811–815. PubMed Abstract | Publisher Full Text\n\nEchahidi N, Pibarot P, O’Hara G, et al.: Mechanisms, prevention, and treatment of atrial fibrillation after cardiac surgery. J. Am. Coll. Cardiol. 2008; 51(8): 793–801. Publisher Full Text\n\nJanuary CT, Wann LS, Alpert JS, et al.: 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2014; 64(21): e1–e76. PubMed Abstract | Publisher Full Text\n\nHindricks G, Potpara T, Dagres N, et al.: 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS) The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur. Heart J. 2021; 42(5): 373–498. PubMed Abstract | Publisher Full Text\n\nZhu J, Wang C, Gao D, et al.: Meta-analysis of amiodarone versus beta-blocker as a prophylactic therapy against atrial fibrillation following cardiac surgery. Intern. Med. J. 2012; 42(10): 1078–1087. PubMed Abstract | Publisher Full Text\n\nFleisher LA, Fleischmann KE, Auerbach AD, et al.: 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J. Am. Coll. Cardiol. 2014; 64(22): e77–e137. PubMed Abstract | Publisher Full Text\n\nKristensen SD, Knuuti J: New ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management. Oxford University Press;2014; 2344–2345.\n\nBouri S, Shun-Shin MJ, Cole GD, et al.: Meta-analysis of secure randomised controlled trials of β-blockade to prevent perioperative death in non-cardiac surgery. Heart. 2014; 100(6): 456–464. PubMed Abstract | Publisher Full Text\n\nAcikel S, Bozbas H, Gultekin B, et al.: Comparison of the efficacy of metoprolol and carvedilol for preventing atrial fibrillation after coronary bypass surgery. Int. J. Cardiol. 2008; 126(1): 108–113. PubMed Abstract | Publisher Full Text\n\nHaghjoo M, Saravi M, Hashemi MJ, et al.: Optimal β-blocker for prevention of atrial fibrillation after on-pump coronary artery bypass graft surgery: carvedilol versus metoprolol. Heart Rhythm. 2007; 4(9): 1170–1174. PubMed Abstract | Publisher Full Text\n\nMerritt JC, Niebauer M, Tarakji K, et al.: Comparison of effectiveness of carvedilol versus metoprolol or atenolol for atrial fibrillation appearing after coronary artery bypass grafting or cardiac valve operation. Am. J. Cardiol. 2003; 92(6): 735–736. Publisher Full Text\n\nWang H-S, Wang Z-W, Yin Z-T: Carvedilol for prevention of atrial fibrillation after cardiac surgery: a meta-analysis. PLoS One. 2014; 9(4): e94005. PubMed Abstract | Publisher Full Text\n\nPatel A, Dunning J: Is Sotalol more effective than standard beta-blockers for the prophylaxis of atrial fibrillation during cardiac surgery. Interact. Cardiovasc. Thorac. Surg. 2005; 4(2): 147–150. PubMed Abstract | Publisher Full Text\n\nBurgess DC, Kilborn MJ, Keech AC: Interventions for prevention of post-operative atrial fibrillation and its complications after cardiac surgery: a meta-analysis. Eur. Heart J. 2006; 27(23): 2846–2857. PubMed Abstract | Publisher Full Text\n\nEvrard P, Gonzalez M, Jamart J, et al.: Prophylaxis of supraventricular and ventricular arrhythmias after coronary artery bypass grafting with low-dose sotalol. Ann. Thorac. Surg. 2000; 70(1): 151–156. PubMed Abstract | Publisher Full Text\n\nWeber UK, Osswald S, Huber M, et al.: Selective versus non-selective antiarrhythmic approach for prevention of atrial fibrillation after coronary surgery: is there a need for pre-operative risk stratification? A prospective placebo-controlled study using low-dose sotalol. Eur. Heart J. 1998; 19(5): 794–800. PubMed Abstract\n\nGuarnieri T, Nolan S, Gottlieb SO, et al.: Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the Amiodarone Reduction in Coronary Heart (ARCH) trial. J. Am. Coll. Cardiol. 1999; 34(2): 343–347. PubMed Abstract | Publisher Full Text\n\nDaoud EG, Strickberger SA, Man KC, et al.: Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N. Engl. J. Med. 1997; 337(25): 1785–1791. PubMed Abstract | Publisher Full Text\n\nBarnes BJ, Kirkland EA, Howard PA, et al.: Risk-stratified evaluation of amiodarone to prevent atrial fibrillation after cardiac surgery. Ann. Thorac. Surg. 2006; 82(4): 1332–1337. PubMed Abstract | Publisher Full Text\n\nAuer J, Weber T, Berent R, et al.: A comparison between oral antiarrhythmic drugs in the prevention of atrial fibrillation after cardiac surgery: the pilot study of prevention of postoperative atrial fibrillation (SPPAF), a randomized, placebo-controlled trial. Am. Heart J. 2004; 147(4): 636–643. PubMed Abstract | Publisher Full Text\n\nBuckley MS, Nolan PE Jr, Slack MK, et al.: Amiodarone Prophylaxis for Atrial Fibrillation After Cardiac Surgery: Meta-Analysis of Dose Response and Timing of Initiation. Pharmacotherapy. 2007; 27(3): 360–368. PubMed Abstract | Publisher Full Text\n\nChatterjee S, Sardar P, Mukherjee D, et al.: Timing and Route of Amiodarone for Prevention of Postoperative Atrial Fibrillation after Cardiac Surgery: A Network Regression Meta-analysis. Pacing Clin. Electrophysiol. 2013; 36(8): 1017–1023. PubMed Abstract | Publisher Full Text\n\nPatel AA, White CM, Gillespie EL, et al.: Safety of amiodarone in the prevention of postoperative atrial fibrillation: a meta-analysis. Am. J. Health Syst. Pharm. 2006; 63(9): 829–837. PubMed Abstract | Publisher Full Text\n\nWang W, Mei YQ, Yuan XH, et al.: Clinical efficacy of epicardial application of drug-releasing hydrogels to prevent postoperative atrial fibrillation. J. Thorac. Cardiovasc. Surg. 2016; 151(1): 80–85. PubMed Abstract | Publisher Full Text\n\nTabbalat RA, Hamad NM, Alhaddad IA, et al.: Effect of colchicine on the incidence of atrial fibrillation in open heart surgery patients: END-AF trial. Am. Heart J. 2016; 178: 102–107. PubMed Abstract | Publisher Full Text\n\nYuan X, Du J, Liu Q, et al.: Defining the role of perioperative statin treatment in patients after cardiac surgery: A meta-analysis and systematic review of 20 randomized controlled trials. Int. J. Cardiol. 2017; 228: 958–966. PubMed Abstract | Publisher Full Text\n\nPrasongsukarn K, Abel JG, Jamieson WE, et al.: The effects of steroids on the occurrence of postoperative atrial fibrillation after coronary artery bypass grafting surgery: a prospective randomized trial. J. Thorac. Cardiovasc. Surg. 2005; 130(1): 93–98. PubMed Abstract | Publisher Full Text\n\nHalonen J, Halonen P, Järvinen O, et al.: Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. JAMA. 2007; 297(14): 1562–1567. Publisher Full Text\n\nPhilip I, Berroëta C, Leblanc I: Perioperative challenges of atrial fibrillation. Curr. Opin. Anaesthesiol. 2014; 27(3): 344–352. PubMed Abstract | Publisher Full Text\n\nDieleman JM, Nierich AP, Rosseel PM, et al.: Intraoperative high-dose dexamethasone for cardiac surgery: a randomized controlled trial. JAMA. 2012; 308(17): 1761–1767. PubMed Abstract | Publisher Full Text\n\nHo KM, Tan JA: Benefits and risks of corticosteroid prophylaxis in adult cardiac surgery: a dose-response meta-analysis. Circulation. 2009; 119(14): 1853–1866. PubMed Abstract | Publisher Full Text\n\nPiccini JP, Passman R, Turakhia M, et al.: Atrial fibrillation burden, progression, and the risk of death: a case-crossover analysis in patients with cardiac implantable electronic devices. EP Europace. 2019; 21(3): 404–413. PubMed Abstract | Publisher Full Text\n\nKaplan RM, Koehler J, Ziegler PD, et al.: Stroke risk as a function of atrial fibrillation duration and CHA2DS2-VASc score. Circulation. 2019; 140(20): 1639–1646. PubMed Abstract | Publisher Full Text\n\nCagli K, Ozeke O, Ergun K, et al.: Effect of low-dose amiodarone and magnesium combination on atrial fibrillation after coronary artery surgery. J. Card. Surg. 2006; 21(5): 458–464. PubMed Abstract | Publisher Full Text\n\nWhite CM, Caron MF, Kalus JS, et al.: Intravenous plus oral amiodarone, atrial septal pacing, or both strategies to prevent post-cardiothoracic surgery atrial fibrillation: the Atrial Fibrillation Suppression Trial II (AFIST II). Circulation. 2003; 108(10_suppl_1): II-200–II-206. Publisher Full Text\n\nVan Gelder IC, Groenveld HF, Crijns HJ, et al.: Lenient versus strict rate control in patients with atrial fibrillation. N. Engl. J. Med. 2010; 362(15): 1363–1373. PubMed Abstract | Publisher Full Text\n\nGillinov AM, Bagiella E, Moskowitz AJ, et al.: Rate control versus rhythm control for atrial fibrillation after cardiac surgery. N. Engl. J. Med. 2016; 374(20): 1911–1921. PubMed Abstract | Publisher Full Text\n\nArdaya R: Extended data for \"Amiodarone versus beta-blockers for the prevention of postoperative atrial fibrillation after cardiac surgery: An updated systematic review and meta-analysis of randomised controlled trials\".2022, May 13. Publisher Full Text"
}
|
[
{
"id": "215995",
"date": "27 Oct 2023",
"name": "Senem Ozgur",
"expertise": [
"Reviewer Expertise Pediatric Arrhythmia and Electrophysiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper's methodology is well expressed, its aims and results are clear and understandable. In this respect, it was able to directly convey the message the author wanted to give to the reader. Of course, as with all studies, it has certain limitations. However, I think it is a compilation that will shed light on the next updates on a subject that is still subject to debate and updates.\n‘’Both beta-blockers and antiarrhythmics such as amiodarone could be used in postoperative AF prevention.’’\nBeta blockers are also used as antiarrhythmics. This sentence implies that beta blockers are not antiarrhythmic. I think this sentence should be rearranged differently.\n\n‘’As a result, the gold standard regimen of postoperative AF prevention remains uncertain, resulting in varying practices and a high discontinuation rate, which might increase the patient’s risk of developing arrhythmias ‘’\nThese two sentences should be separated from each other. An unnecessarily long sentence. Also, there is no cause-effect relationship between the first part of the sentence and the second part.\n\nAs the author already stated in the text, the studies examined and included are relatively old.\n\n‘’A more recent type of beta-blocker is sotalol, which exhibits class III antiarrhythmic effects on top of typical beta-blocker features.3 ‘\nWould it be more appropriate to define sotalol as a Class III (K channel inhibitor) that also has beta blocker activity?\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-569
|
https://f1000research.com/articles/11-567/v1
|
25 May 22
|
{
"type": "Case Report",
"title": "Case Report: A case of Dilated Cardiomyopathy in COVID-19; A case report",
"authors": [
"Bishal Dhakal",
"Neeraj Sharma",
"Bishnu Deep Pathak",
"Nabin Simkhada",
"Binod limbu",
"Neeraj Sharma",
"Bishnu Deep Pathak",
"Nabin Simkhada",
"Binod limbu"
],
"abstract": "As of 2022, myocardial injury associated with COVID-19 has been one of the most discussed topics in literature. Though variety of cardiac manifestations have been reported and described in scientific literature, case of dilated cardiomyopathy (DCM) has not been well reported and described. We present a case of DCM post-COVID-19 without any co-morbidities who was admitted several times for cardiac symptoms post-COVID-19. As it was a new finding associated with COVID-19, it has been worth understanding the variations in which cardiac conditions manifest in COVID-19.",
"keywords": [
"Dilated cardiomyopathy",
"COVID-19"
],
"content": "Introduction\n\nCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), manifests typically with respiratory symptoms but cardiac signs and symptoms have also been common in the process of disease and post-COVID-19. Although the cardiac cases in COVID-19 have been much less as compared to respiratory cases, a review found cardiac injury to be reported in 19.7% to 29.8% of cases.1 The involvement of cardiac myocardium in COVID-19 has been due to various mechanisms and up to 20-30% in hospitalized patients as manifested by elevated troponin levels.2\n\nAlthough lungs have been the primary target of SARS-CoV-2, cardiovascular involvement has been common in hospitalized patients ranging from mild cardiac injury to complications like acute myocardial infarction, myocarditis, arrhythmias, thrombotic complications and heart failure.3 Till date various cases of stress-induced (Takotsubo) cardiomyopathy have been described with a classic case described by a case report where a patient presented with fever for five days and progressive dyspnea on exertion.4\n\nThe cardiac-related conditions like myocarditis, heart failure, thrombotic complications, stress-induced cardiomyopathies associated with COVID-19 have been described in literature. But cases of dilated cardiomyopathy (DCM) in adult have not been described in literature, though a case of DCM has been reported in a child of one year old.5 We hereby present a case of dilated cardiomyopathy (DCM) in a 35 years male post-COVID-19 without any co-morbidities.\n\n\nCase presentation\n\nA 35-year-old Hindu male tested COVID-19 positive (RT-PCR positive) dated six months back presented to our center with cough and shortness of breath. The cough was often associated with hemoptysis and shortness of breath was mostly on lying flat and walking with New York Heart Association (NYHA) grade-II at first. It progressed to NYHA grade III gradually. It was associated with orthopnea and paroxysmal nocturnal dyspnea (PND). It was followed by recurrent hospital admission for the same complaints complemented with dizziness, loss of consciousness and chest pain. For two times he was admitted in high dependency unit and was even treated with nor-adrenaline and dopamine for severe hypotension (SBP/DBP: 80/60). There was not any significant medical, family and psycho-social history related to the case. There were also not relevant past interventions.\n\nOn general examination, he was conscious and oriented to time, place and person. There was bilateral pitting pedal edema but the jugular venous pressure (JVP) was not raised. As for vital parameters, his blood pressure was more of consistent with SBP/DBP of 90/60 mm of Hg and his saturation was maintained at 90% in room air.\n\nOn systemic examination, systolic murmur was heard at the apex beat area which was consistent with carotid pulse and was non-radiating in nature. Bilaterally, crepitations were heard in infra-scapular and infra-axillary regions.\n\nHe was diagnosed as having Covid-19 infection from the real time-polymerase chain reaction (RT-PCR) 6 months back. He was kept on isolation for 14 days and discharged after the RT-PCR test was negative. He started developing shortness of breath after a month of Covid-19 infection. This was followed by recurrent hospital admission and diagnosed was DCM post-Covid-19.\n\nThe baseline laboratory investigations are shown in Table 1.\n\nThe ultrasonography of abdomen and pelvis showed normal scan. The chest x-ray showed cardiomegaly. Similarly, pulmonary function test (PFT) was performed to exclude any respiratory pathology. PFT showed moderate restriction with insignificant post-bronchodilator responsiveness. The 12-lead electrocardiogram showed wide QRS complexes and right bundle branch block (RBBB) pattern. Then, echocardiography was performed to narrow down the diagnosis. The 2D echocardiography findings are given below:\n\n• Left atrium (LA): 4.6 cm; Right atrium (RA): 5.9 cm; Left ventricle (LV): 6.7 cm; Right ventricle (RV): 5.9 cm [Dilated all chambers of heart]\n\n• Global LV hypokinesia\n\n• Severe LV systolic dysfunction [Ejection fraction (EF): 10-15%]\n\n• Severe Mitral regurgitation (MR), mild Pulmonary regurgitation (PR)\n\n• Severe Tricuspid regurgitation (TR)\n\n• Severe Pulmonary artery hypertension (PAH) with elevated Pulmonary artery systolic pressure (ePASP) of 71 mmHg\n\n• RV systolic dysfunction [Tricuspid annular plane systolic excursion (TAPSE): 15 mm and RV systolic prime (RVS′)]\n\n• LV diastolic dysfunction-grade III\n\nThe figure for 2D-echocardiography and 12-lead electrocardiogram are shown in Figures 1 and 2 respectively. The high-resolution computed tomography (HRCT) scan of chest showed cardiomegaly with enlarged pulmonary trunk and diffuse ground glass opacity in basal segment of lungs. He was diagnosed as dilated cardiomyopathy (DCM) secondary to covid-19 infection resulting in heart failure with reduced ejection fraction (HFrEF) of 10-15%. He was kept on following medications Table 2.\n\nLegend: Arrows showing dilated ventricles and atrium.\n\nLegend: White arrow showing wide QRS complex and Black arrows showing right bundle branch block (RBBB) pattern in leads V1 and V6.\n\nThe patient was advised on fluid restriction of less than 1 liter/day and low salt diet. He was then discharged home with plan for follow up in cardiac out-patient department as needed [SOS (Si Opus Sit)].\n\nThe patient was stable on discharge. In previous follow-ups his status was assessed by clinical examination, laboratory investigations like N-terminal pro b-type natriuretic peptide (NT-pro-BNP), troponin I, electrocardiogram and 2D echocardiography. The patient was satisfied under medications and was taking regular medications as described above.\n\n\nDiscussion\n\nCOVID-19 associated myocardial injury has well been described in various literatures throughout the world.2–4 The overall pooled prevalence of acute myocardial injury was found to be 29% in hospitalized COVI-19 patients by 19 studies.6 Various mechanisms have been proposed for myocardial injury. Some of the well described mechanisms are hyperinflammatory reaction, hyperactivation of renin angiotensin aldosterone system pathway and cytokine storm.3 Similarly, abnormal endothelial function and downregulation of angiotensin-converting enzyme-2 (ACE-2) receptor in cardiac myocytes by SARS-CoV-2 have also predominant role in myocardial injury.6\n\nA systematic review found SARS-CoV-2 to cause irreversible changes in heart with right heart dilatation due to pulmonary overload as its main features. Similarly, autopsy microscopic findings suggested necrosis, micro thrombosis and lymphocytic infiltration in myocardium.7 A Systematic review and meta-analysis by Corica et al found prevalence of right ventricular dysfunction (RVD) in COVID-19 patients was almost 1 out of 5 patients.8 As described by Corica et al, the mortality with COVID-19 and RVD was in excess to that with COVID-19 only. In regards to cardiac biomarkers for myocardial injury in COVID-19, a systematic review and metanalysis by Zhu et al found strong association of creatine kinase (CK), CK-MB, lactate dehydrogenase (LDH), troponin I, NT-pro BNP (brain natriuretic peptide) with severity of COVID-19.9\n\nCOVID-19 associated Takotsubo cardiomyopathy has been reported in literature. A classic case of Takotsubo cardiomyopathy in COVID19 was reported by Gomez et al where a 57 year old presented with 5 days of fever (maximum 39.7°Celcius) and progressive dyspnea on exertion and developed rapid deterioration of cardiorespiratory status during hospitalization.4 Similar case of stress-induced (TCM) cardiomyopathy was also reported by Tsao et al in a 59 year old woman who also fulfilled the Mayo clinic criteria for TCM cardiomyopathy.4,10 Our case did not fulfil the criteria as both the ventricles were involved in both systole and diastole.\n\nAlthough cases of dilated cardiomyopathy (DCM) in adult have not been reported till date, a case DCM has been reported in one year old healthy boy without any co-morbidities.5 Among various causes of DCM, viral infection is one of the secondary causes.11 The viral genomes have been detected in myocardial samples of patients with DCM in spite of undetectable infiltrating inflammatory cells.12 Due to the activation of persistent immune mechanism after viral infection, it has been presumed to lead to DCM.13\n\nIn regards to our case, he progressed gradually with cardiac symptoms after COVID-19 infection before he was diagnosed as DCM post-COVID-19. Ultimately, he developed heart failure with reduced ejection fraction of 10-15%. He has been repeatedly visiting our center whenever the cardiac symptoms worsen since the diagnosis was made.\n\n\nConclusions\n\nCOVID-19 has been a burden due to its global impact on livelihood. Apart from respiratory symptoms and complications, myocardial injury and its consequences should also be equally sought out and thoroughly evaluated in COVID-19 patients. It is necessary to keep in mind that COVID-19 can present with wide variances of cardiac symptoms and complications as described above. Among them DCM also stands as a consequence in COVID-19 as evidenced in this case. Therefore, a thorough cardiac evaluation which include cardiac biomarkers, ultrasonogram of abdomen and pelvis, echocardiography and electrocardiogram should be performed in COVID-19 patients. It helps us to guide our management strategies and prevent further cardiac complications in COVID-19 patients.\n\nThe patient was treated on hospital basis with both pharmacological and dietary interventions. According to the patient, he felt relieved after the therapeutic interventions. He was performing daily activities without any hindrance. Similarly, with the intervention his sleep activity was sound and good. He was feeling more comfortable with the treatment and was convinced for the regular follow up.\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.",
"appendix": "References\n\nSingh R, Kashyap R, Hutton A, et al.: A Review of Cardiac Complications in Coronavirus Disease 2019. Cureus. 2020; 12(5): e8034–e8012. PubMed Abstract | Publisher Full Text\n\nMitrani RD, Dabas N, Goldberger JJ: COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Hear Rhythm. 2020; 17(11): 1984–1990. PubMed Abstract | Publisher Full Text\n\nCajanding RJM: Comprehensive Review of Cardiovascular Involvement in COVID-19. AACN Adv. Crit. Care. 2021; 32(2): 169–187. PubMed Abstract | Publisher Full Text\n\nGomez JMD, Nair G, Nanavaty P, et al.: COVID-19-associated takotsubo cardiomyopathy. BMJ Case Rep. 2020; 13(12): e236811–e236815. PubMed Abstract | Publisher Full Text\n\nKishore R, Choudekar A, Xess AB, et al.: Dilated Cardiomyopathy in a Child with COVID-19. Indian J. Pediatr. 2021; 88(3): 278–279. PubMed Abstract | Publisher Full Text\n\nMizera L, Borst O: COVID-19 and the Incidence of Acute Myocardial Injury. Hamostaseologie. 2021; 41(5): 356–364. Publisher Full Text\n\nMaiese A, Frati P, Del Duca F, et al.: Myocardial pathology in covid-19-associated cardiac injury: A systematic review. Diagnostics. 2021; 11(9): 1–14. PubMed Abstract | Publisher Full Text\n\nCorica B, Marra AM, Basili S, et al.: Prevalence of right ventricular dysfunction and impact on all-cause death in hospitalized patients with COVID-19: a systematic review and meta-analysis. Sci. Rep. 2021; 11(1):1–9. Article number: 17774.Publisher Full Text PubMed Abstract |\n\nZhu Z, Wang M, Lin W, et al.: Cardiac biomarkers, cardiac injury, and comorbidities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. Immunity Inflamm. Dis. 2021; 9(4): 1071–1100. PubMed Abstract | Publisher Full Text\n\nTsao CW, Strom JB, Chang JD, et al.: COVID-19-Associated Stress (Takotsubo) Cardiomyopathy. Circ. Cardiovasc. Imaging. 2020; 13(7): e011222–e011224. PubMed Abstract | Publisher Full Text\n\nJefferies JL, Towbin JA: Dilated cardiomyopathy. Lancet. 2010; 375(9716): 752–762. Publisher Full Text\n\nKühl U, Pauschinger M, Noutsias M, et al.: High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation. 2005; 111(7): 887–893. PubMed Abstract | Publisher Full Text\n\nKomiyama M, Hasegawa K, Matsumori A: Dilated cardiomyopathy risk in patients with Coronavirus disease 2019: How to identify and characterise it early? Eur. Cardiol. Rev. 2020; 15: e49–e10. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "141143",
"date": "31 May 2024",
"name": "Dhan Bahadur Shrestha",
"expertise": [
"Reviewer Expertise Internal medicine",
"general cardiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary\nAuthors reported an interesting case of DCM, however, needs some editing in writing and technicalities, those can be sorted out in proofreading.\nMinor comments:\nAbbreviation in first use must be used with full form (eg. COVID-19 in abstract section, and other in the body), and don't need to provide abbreviation with full form in later use eg. RT-PCR.\n\nCase presentation: \"There was not any significant medical, family and psycho-social history related to the case. \" better rephrase it like \"There was no other medical, family, and psycho-social history related to the case.\"\n\nCase presentation: In the fourth paragraph, please maintain a uniform abbreviation here and in other places as well \" Covid-19 \", follow the general rule of scientific writing, check standard guidelines, need to spell out numbers less than 10, eg 6. proper way of writing studies with\"et al\" in discussion\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-567
|
https://f1000research.com/articles/11-563/v1
|
23 May 22
|
{
"type": "Research Article",
"title": "Perceived stress levels in older adults with financial strain are diminished after theater practice",
"authors": [
"Izumi Matsudaira",
"Yasuyuki Taki",
"Yasuyuki Taki"
],
"abstract": "Background: Participating in theater has been shown to be useful for reducing cognitive decline in older adults. This study focused on the social inclusion aspect of the performing arts and aimed to examine whether participation in the theater could help prevent dementia in older adults who are vulnerable to social exclusion. Methods: Our participants were 371 community-dwelling older adults who belonged to the Gold Arts Club organized by the Saitama Arts Theatre. The change in perceived stress levels after a month and a half of theater practice were compared between older adults with and without financial strain. Results: It was revealed that older adults with financial strain had a significantly greater reduction in perceived stress levels than those without financial strain after a month and a half of theater practice. Conclusions: Since stress is one of the risk factors for cognitive decline, the results of this study suggest that participation in theater may be an effective way of reducing cognitive decline associated with dementia in the older people who feel strained financially.",
"keywords": [
"theater",
"financial strain",
"perceived stress",
"dementia",
"social inclusion"
],
"content": "Introduction\n\nActing involves generating emotions and behaviors to characterize a person or thing other than themselves. Higher cognitive functions, such as emotion regulation, memory, verbal skills, empathy, and mentalization, are necessary skills for acting (McDonald et al., 2020). It has been suggested that participation in theater may improve cognitive function in older adults (Banducci et al., 2017; Chung et al., 2018; Noice et al., 2004). In the recent field of preventive medicine, personalized prevention has gained support as an effective strategy for preventing dementia (Sommerlad & Mukadam, 2020). Thus, it is meaningful to detect the population that participating in theater is a more valid choice to maintain cognitive health.\n\nSocial inclusion may be the key concept linking the theater with personalized prevention of dementia. Social inclusion is defined as the process of ensuring that people at risk of being left behind in society have the opportunities and resources they need to participate fully in economic, social, political, and cultural life, and to enjoy a level of well-being that is considered normal in the society in which they live (European Commision, 2004). The World Bank Group has argued the importance of performing arts for the maturation of society in terms of their social inclusion function (Kabanda, 2014). Older adults are likely to be targets of social exclusion (Walsh et al., 2017). Community-engaged art programs for older adults have been reported to promote well-being (Phinney et al., 2014; Poulos et al., 2019) and a sense of connectedness with the community (Moody & Phinney, 2012). However, the effect that participating in the arts has on older people, particularly those at high risk of social exclusion, is unclear.\n\nOne of the significant risk factors for social exclusion is financial strain, which refers to the perception that paying for both daily necessities (e.g., food, clothing, housing, and medical care) and other things, such as furniture, automobiles, and recreation (Pearlin et al., 1981), is difficult. A validation study of the social exclusion index for older adults found a significant positive association between self-perceived poverty and a sense of social exclusion (Chou, 2018). Recent findings have also suggested that financial strain increases the risk of developing dementia (Samuel et al., 2020). A putative mechanism underlying the relationship between financial strain and dementia may be an impairment in the stress response system because a significant association between financial strain and physiological markers of stress has been reported (Grossi et al., 2001; Palta et al., 2015; Steptoe et al., 2020). Also, it has been confirmed that psychological stress is associated with the increased risk of dementia (Franks et al., 2021).\n\nThis study, therefore, aimed to determine whether participating in the theater could be an effective way of preventing dementia in older adults with financial strain. To achieve this goal, we adopted a cohort design to investigate the effect of participating in the theater on perceived stress levels in older adults according to the presence or absence of financial strain.\n\n\nMethods\n\nOur participants were community-dwelling older adults who belonged to the Gold Arts Club organized by the Saitama Arts Theatre (https://www.saf.or.jp/arthall/). The Gold Arts Club is a large theatre company with almost 1,600 members and features large crowd plays with hundreds of performers. Members of the Gold Arts Club were recruited in 2016 through an open call for applications, provided that they were ≥ 60 years old at the time. The members include both experienced and inexperienced theatre performers, but no professional actors. The Gold Arts Club performed one play each year between 2016 and 2018 after a month or two of rehearsals. Each member had participated in at least one performance at the time of this study. Our survey was distributed in November 2019, when the Gold Arts Club was preparing for its fourth performance. The eligibility criteria was males and females aged 65 over, because in Japan, the definition of an elderly is being 65 years and older (Cabinet Office Japan, 2018). The pre-survey was carried out on the day of orientation before the start of rehearsals, and the post-survey was carried out during the final rehearsal about a month and a half later. Participants took part in up to six rehearsals of approximately two and a half hours each between the pre-and post-surveys. A total of 786 people participated in this production, of which 639 took part in the pre-survey. Of these, 456 also completed the post-survey. After excluding 62 participants with missing answers and 23 participants who were under 64 years, 371 participants were included in the final analysis. The purpose of this study was explained to the participants during the pre-survey. Written informed consent was obtained from each participant. This study was approved by the Institutional Review Board of Tohoku University.\n\nParticipants chose one of the following options to describe their financial situation: 1 = difficult, 2 = slightly difficult, 3 = somewhat secure, and 4 = secure. Those who chose 1 or 2 were categorized into the group with financial strain, while those who chose 3 or 4 were categorized into the group without financial strain. This question was asked only during the pre-survey.\n\nThe perceived stress levels were assessed using the Comprehensive Stress Response Inventory for the elderly (http://labo-wakashima.c.ooco.jp/CSI_elder.pdf), a scale that assesses stress levels through the extent of psychological stress response experienced in the preceding month (Asai et al., 2013). The answers to the 17 questions were summed to calculate a perceived stress score. A Likert scale ranging from 1 to 4 (1 = “never” to 4 = “very often”) was used. These questions were asked both in the pre-and post-surveys. We subtracted the pre-survey score from the post-survey score to measure the change in perceived stress levels before and after participating in the theater practice.\n\nMann-Whitney’s U test was conducted to compare the extent of the change in perceived stress levels between the groups with and without financial strain. The significance level was set at P < 0.05. This analysis was performed using R studio (Version 1.2.5042).\n\n\nResults\n\nThe participants’ characteristics are presented in Table 1. No significant differences in age, sex, the number of previous performances, and the perceived stress levels at the post-survey were found between the groups. The perceived stress levels on the pre-survey were significantly higher in those with financial strain than in those without financial strain (Table 1).\n\na The number of productions at the Gold Arts Club the participant had participated in before the survey.\n\nb Score of perceived stress levels at the pre-survey.\n\nc Score of perceived stress levels at the post-survey. As all continuous variables in this data did not distribute normally, the differences between groups were analyzed using Mann-Whitney’s U test.\n\nAs shown in Figure 1 and Table 2, participants with financial strain showed a significantly greater decrease in perceived stress levels after participating in the theater practice than those without financial strain.\n\nWith_pre, score at the pre-survey in older adults with financial strain. With_post, score at the post-survey in older adults with financial strain. Without_pre, score at the pre-survey in older adults without financial strain. Without_post, score at the post-survey in older adults without financial strain.\n\na Subtracted value of perceived stress levels at the pre-survey from the post-survey.\n\n\nDiscussion\n\nOur results are consistent with the idea that economically disadvantaged older adults are likely to experience depressive symptoms (Mojtabai & Olfson, 2004). The findings of neuroimaging studies may explain why the perceived stress levels declined before and after theatre practice. Recent pioneering work about neural substrates of acting revealed that when actors respond to several questions as fictional characters, the ventromedial prefrontal cortex (vmPFC) is deactivated compared to when they responded as themselves (Brown et al., 2019). The vmPFC activation has been associated with stress resilience and recovery (Sinha et al., 2016; Meine et al., 2021; Yang et al., 2018). Consequently, although the subjects of these previous neuroimaging studies were younger than our participants, it is speculated that the reduction in perceived stress levels may have been due to the flexibility of vmPFC activation through repeated experiences of leaving from one’s own perspective through theater practice.\n\nThis study has limitations. First, due to that we have no control group, it should be noted that this study is preliminary to examine the effect of theatre participation on the reduction in perceived stress levels among economically disadvantaged older people. Further study designed with the randomized controlled trial is necessary. Second, the participants in this study were not complete beginners in theater. This may have reduced the impact of theater practice on their perceived stress levels in this study. Third, since this study only involved participants in theater practice, it is not possible to make any definite claims about whether the present results are specific to the theater. Further studies designed to compare theater and other artistic activities are needed.\n\nTo the best of our knowledge, this is the first study to reveal that participating in the theater improves mental health particularly in older people with financial strain. Since higher psychological stress increases the risk of dementia, participation in theater may be an effective way to prevent dementia in older adults who are experiencing financial difficulties.\n\n\nConsent\n\nWritten informed consent for publication of their answers for questionnaire was obtained from the participants.\n\n\nData availability\n\nFigshare. Perceived_stress_levels_in_older_adults _with_financial_strain_are_diminished_after _theater_practice.xlsx. DOI: https://doi.org/10.6084/m9.figshare.19657143.v3\n\nThis project contains the following underlying data:\n\n- Our participants were community-dwelling older adults who belonged to the Gold Arts Club organized by the Saitama Arts Theatre (https://www.saf.or.jp/arthall/). The Gold Arts Club performed one play each year between 2016 and 2018 after a month or two of rehearsals. Each member had participated in at least one performance at the time of this study.\n\n- Financial Strain: Participants chose one of the following options to describe their financial situation: 1 = difficult, 2 = slightly difficult, 3 = somewhat secure, and 4 = secure. Those who chose 1 or 2 were categorized into the group with financial strain, while those who chose 3 or 4 were categorized into the group without financial strain. This question was asked only during the pre-survey.\n\n- Stress Levels: The stress levels were assessed using the Comprehensive Stress Response Inventory for the elderly (http://labo-wakashima.c.ooco.jp/CSI_elder.pdf), a scale that assesses stress levels through the extent of psychological stress response experienced in the preceding month. The answers to the 17 questions were summed to calculate a perceived stress score. A Likert scale ranging from 1 to 4 (1 = “never” to 4 = “very often”) was used. These questions were asked both in the pre-and post-surveys. We subtracted the pre-survey score from the post-survey score to measure the change in stress levels before and after participating in the theater practice.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgement\n\nWe appreciate Mr. Hiroshi Watanabe, Mr. Fumiaki Taniguchi, Ms. Sachiko Ukegawa, Mr. Tatsuya Takagi, and Ms. Takako Maeda for collaborating with us as research partners. We also thank all the members of the Saitama Gold Arts Club, the Saitama Gold Theatre, and the Saitama Arts Theatre. We thank Editage (www.editage.com) for English language editing.\n\n\nReferences\n\nAsai K, Morikawa N, Hiraizumi T, et al.: Development of Comprehensive Stress Response Inventory. Annual Report Graduate School of Education, Tohoku University; 2013; 62(1): 283–302.\n\nBanducci SE, Daugherty AM, Biggan JR, et al.: Active Experiencing Training Improves Episodic Memory Recall in Older Adults. Front. Aging Neurosci. 2017; 9: 133. Publisher Full Text\n\nBrown S, Cockett P, Yuan Y: The neuroscience of Romeo and Juliet: an fMRI study of acting. R. Soc. Open Sci. 2019; 6(3): 181908. PubMed Abstract | Publisher Full Text\n\nCabinet Office Japan: Annual Report on the Ageing Society. Tokyo: Cabinet Office Japan; 2018.\n\nChou K-L: Social exclusion in old age: a validation study in Hong Kong. Aging Ment. Health. 2018; 22(8): 1078–1085. PubMed Abstract | Publisher Full Text\n\nChung KSY, Lee ESL, Tan JQ, et al.: Effects of Playback Theatre on cognitive function and quality of life in older adults in Singapore: A preliminary study. Australas. J. Ageing. 2018; 37(1): E33–E36. PubMed Abstract | Publisher Full Text\n\nEuropean Commision: Joint Report on Social Inclusion (Report 7101/04). Brussels: European Commission; 2004.\n\nFranks KH, Bransby L, Saling MM, et al.: Association of Stress with Risk of Dementia and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. J. Alzheimers Dis. 2021; 82(4): 1573–1590. PubMed Abstract | Publisher Full Text\n\nGrossi G, Perski A, Lundberg U, et al.: Associations between financial strain and the diurnal salivary cortisol secretion of long-term unemployed individuals. Integrative Physiological and Behavioral Science: The Official Journal of the Pavlovian Society. 2001; 36(3): 205–219. PubMed Abstract | Publisher Full Text\n\nKabanda P: The creative wealth of nations: How the performing arts can advance development and human progress. The World Bank; 2014. Publisher Full Text\n\nMcDonald B, Goldstein TR, Kanske P: Could Acting Training Improve Social Cognition and Emotional Control?. Front. Hum. Neurosci. 2020; 14: 348. PubMed Abstract | Publisher Full Text\n\nMeine LE, Meier J, Meyer B, et al.: Don’t stress, it's under control: Neural correlates of stressor controllability in humans. NeuroImage. 2021; 245: 118701. PubMed Abstract | Publisher Full Text\n\nMojtabai R, Olfson M: Major depression in community-dwelling middle-aged and older adults: prevalence and 2- and 4-year follow-up symptoms. Psychol. Med. 2004; 34(4): 623–634. PubMed Abstract | Publisher Full Text\n\nMoody E, Phinney A: A community-engaged art program for older people: fostering social inclusion. Can. J. Aging (La Revue Canadienne Du Vieillissement). 2012; 31(1): 55–64. PubMed Abstract | Publisher Full Text\n\nNoice H, Noice T, Staines G: A short-term intervention to enhance cognitive and affective functioning in older adults. J. Aging Health. 2004; 16(4): 562–585. PubMed Abstract | Publisher Full Text\n\nPalta P, Szanton SL, Semba RD, et al.: Financial strain is associated with increased oxidative stress levels: the Women’s Health and Aging Studies. Geriatr. Nurs. 2015; 36(2 Suppl): S33–S37. PubMed Abstract | Publisher Full Text\n\nPearlin LI, Lieberman MA, Menaghan EG, et al.: The stress process. J. Health Soc. Behav. 1981; 22(4): 337–356. Publisher Full Text Reference Source\n\nPhinney A, Moody EM, Small JA: The Effect of a Community-Engaged Arts Program on Older Adults’ Well-being. Can. J. Aging (La Revue Canadienne Du Vieillissement). 2014; 33(3): 336–345. Publisher Full Text\n\nPoulos RG, Marwood S, Harkin D, et al.: Arts on prescription for community-dwelling older people with a range of health and wellness needs. Health Soc. Care Community. 2019; 27(2): 483–492. Publisher Full Text\n\nSamuel LJ, Szanton SL, Wolff JL, et al.: Socioeconomic disparities in six-year incident dementia in a nationally representative cohort of U.S. older adults: an examination of financial resources. BMC Geriatr. 2020; 20(1): 156. PubMed Abstract | Publisher Full Text\n\nSinha R, Lacadie CM, Constable RT, et al.: Dynamic neural activity during stress signals resilient coping. Proc. Natl. Acad. Sci. U. S. A. 2016; 113(31): 8837–8842. Publisher Full Text\n\nSommerlad A, Mukadam N: Evaluating risk of dementia in older people: a pathway to personalized prevention?. Eur. Heart J. 2020; 41(41): 4034–4036. Publisher Full Text\n\nSteptoe A, Emch S, Hamer M: Associations Between Financial Strain and Emotional Well-Being With Physiological Responses to Acute Mental Stress. Psychosom. Med. 2020; 82(9): 830–837. Publisher Full Text\n\nWalsh K, Scharf T, Keating N: Social exclusion of older persons: a scoping review and conceptual framework. Eur. J. Ageing. 2017; 14(1): 81–98. PubMed Abstract | Publisher Full Text\n\nYang X, Garcia KM, Jung Y, et al.: vmPFC activation during a stressor predicts positive emotions during stress recovery. Soc. Cogn. Affect. Neurosci. 2018; 13(3): 256–268. Publisher Full Text"
}
|
[
{
"id": "225856",
"date": "10 Oct 2024",
"name": "Vaitsa Giannouli",
"expertise": [
"Reviewer Expertise Psychology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article investigates if theater can be used as an intervention for older adults who are vulnerable to social exclusion. Some points to revise can be found below:\nIn the Abstract, please provide basic statistics in the Results section. In the Introduction authors need to support their hypotheses with relevant literature. Please justify the over 60 years of age as an inclusion critierion. Usually over 65 is used in most published studies. How was the sample size estimated? Please explain the figures in the main text. Please provide a more detailed discussion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-563
|
https://f1000research.com/articles/9-1365/v1
|
24 Nov 20
|
{
"type": "Research Article",
"title": "Factors associated with producing a scientific publication during medical training: evidence from a cross-sectional study of 40 medical schools surveyed in Latin America",
"authors": [
"Mario J. Valladares-Garrido",
"Christian R. Mejia",
"Annel B. Rojas-Alvarado",
"Mary M. Araujo-Chumacero",
"Jhacksson S. Córdova-Agurto",
"Jessica Fiestas",
"Feeder J. Rojas-Vilar",
"Carlos Culquichicón",
"Mario J. Valladares-Garrido",
"Christian R. Mejia",
"Annel B. Rojas-Alvarado",
"Mary M. Araujo-Chumacero",
"Jhacksson S. Córdova-Agurto",
"Jessica Fiestas",
"Feeder J. Rojas-Vilar"
],
"abstract": "Background: Scientific publication during medical training is key to promote enduring cutting-edge knowledge. The promotion of science among medical students in Latin America is a multi-sphere issue hampered by the unawareness of governments to invest in national research, as well as a lack of support from local universities. This study aims to determine the factors associated with producing a scientific publication during medical training among Latin American medical students of local scientific societies. Methods: This is a secondary data analysis of a cross-sectional study initially conducted in 2016 to evaluate the use of information and communications technologies (TICs) among medical students of 40 local scientific societies of medical students affiliated to the Latin American Federation of Medical Students Scientific Societies (FELSOCEM, in Spanish). Teams in each local scientific society surveyed self-reported scientific publications and explored its association with socioeconomic, academic, and research training conditions. We included medical students enrolled in the 2016-I term and excluded medical interns. We implemented nested models to identify covariates associated with self-reported scientific publication until reaching a parsimonious mixed-effect multilevel model clustered by medical scientific society. Results: We surveyed 11,587 medical students. The prevalence of scientific publications increased in 36% among medical students affiliated to a Scientific Society of Medical Students [parsimonious prevalence ratio (PRp)=1.36, 95%CI=1.16–1.59], 51% among medical students with advanced English proficiency [PRp=1.51, 95%CI=1.21 – 1.87], 85% among medical students who attended a scientific writing skills course [PRp=1.85, 95%CI=1.59–2.15], 81% among medical students who use Sci-Hub [PRp=1.81, 95%CI=1.50–2.20], and 108% among medical students who have access to a pirated academic account [PRp=2.08, 95%CI=1.83–2.36]. Conclusions: Producing a scientific publication among medical students is associated with being affiliated to a Scientific Society of Medical Students, English proficiency, training in scientific writing, use of Sci-Hub, and pirated academic accounts.",
"keywords": [
"Medical Education",
"Undergraduate",
"Scientific Societies",
"Latin America",
"Medical Students"
],
"content": "Introduction\n\nProducing a scientific publication during medical training is key to promote the constant medical training and to encourage students to create cutting-edge knowledge; in this way, students will build-up research skills and critical thinking, and conduct evidence-based practice and patient-centered care with an endured vision to follow a scientific career1–3. Latin American universities are progressively recognizing the critical importance of foster science in the early onset of undergraduate, and are implementing research-oriented courses such as research design methods, biostatistics, epidemiology, and a final research-centered thesis4. However, there are still gaps in Latin America when comparing to research university systems from developed countries in terms of the number of publications, the quality of articles published, the outreach of the studies, and funding opportunities5. Studies in Colombia and Brazil show that medical students consider scientific research as an important issue of their training and the low scientific production is influenced by the lack of inspirational and committed mentors as role models for the beginning of a scientific career6,7. Between 1997 and 2010, there was an increase of 8.4% in student participation in manuscripts published on journals indexed in Scielo-Peru, of whom 42% reported being affiliated to a scientific society of medical students4,8.\n\nIn Peru, the progress of research in medical undergraduate has been strongly promoted by the Peruvian Scientific Society of Medical Students (SOCIMEP, by its acronym in Spanish), an organization that has been improving the research training of medical students for 27 years9. SOCIMEP stands scientific and academic committees in their central and 38 local scientific societies throughout local medical schools of Peru, and held international, national, and local scientific conferences9. The SOCIMEP also foster societies to actively participate and integrate them into a nation-wide research network, and provide connections with experienced research mentors. Being affiliated to the SOCIMEP's local scientific society is associated with increased scientific production (PR: 2.41; 95% CI: 1.55-3.74)10. However, only 10% of the projects conducted in local scientific societies are published in indexed journals due to deficient methods implemented in the studies, lack of knowledge about editorial processes, few local mentors and a lack of financial support from public agencies and institutions11. The funding opportunities for medical students are poor in the local medical schools of Peru and in much of Latin America; overall government investment is disproportionately granted to attend local public health priorities with well-implemented laboratories, and full-time research-centered faculties12. In Peru, less than 30% of universities have research funding programs for students to implement their thesis research operations, or research student program awards13.\n\nThe promotion of science among medical students in Latin America is a multi-sphere issue hampered by the unawareness of governments on the investment in nation research and innovation well-structured systems, as well as a lack of local universities support, their lack of investment in research facilities, and a lack of international-research experienced mentors3. In this scenario, our study aims to determine the factors associated with scientific publication during medical training, in order to identify the needs of Latin American local scientific societies for the implementation of their continuing education programs in research. Our hypothesis is that there are factors from medical training associated with producing a scientific publication during undergraduate.\n\n\nMethods\n\nThis is a secondary data analysis of a cross-sectional study initially conducted in 2016 to evaluate the use of information and communications technologies (TICs) in medical students along Latin America14,15. This study evaluated 40 scientific societies of medical students from Latin America. We primarily evaluated the self-report of scientific publications and used the following variables to explore its associated factors: gender, age, university, current year of career, affiliated to a scientific medical student society, English proficiency, studied previous career, courses in scientific databases including PubMed, Scopus and Scielo, courses in scientific writing skills, courses in scientific browsing, courses in Zotero, use of Sci-Hub, access and provider of pirated academic accounts.\n\nThe primary study surveyed 11,587 students from 40 medical schools, including two from Ecuador, two from Panama, four from Paraguay, three from Bolivia, 18 from Peru, two from Mexico, two from Venezuela, one from Honduras, three from Colombia, one from Chile, and two from Argentina. This study included medical students enrolled in the term 2016-I and excluded who were doing the internship.\n\nWe made a stratified sampling using the academic year in the medical school as a stratum. The estimated sample size for each investigation site was 289 medical students, we also added 10% to anticipate withdraws. Thus, we aimed to survey 318 medical students in each university. We consider a sample size calculation with an 80% of power, and 5% of significance for an infinite sample size. Regarding participant selection, the interviewer team entered the course with greatest credits in each academic year and picked the students who were sat in an odd numbered location per row. In three universities, the sample size was not enough large to reach the minimum required, so we conducted a census-type sampling.\n\nIn 2015, the ICTs project was awarded on the category of multi-center projects by the XXX International Congress of the Latin American Federation of Medical Students Scientific Societies (FELSOCEM, by its acronym in Spanish). This award let connect the researchers within the FELSOCEM’s international collaboration network and carry out the study. We could enroll teams from 40 out of 69 Scientific Medical Students Society (SOCEMs, by its acronym in Spanish) along Latin American. Each scientific society had at least one team with three medical students who were trained on scientific integrity16, standardized methods for survey participants, data entry procedures, and quality control of datasets.\n\nIn each medical school, every team of interviewers surveyed at the beginning or the end of the lectures, prioritizing that the students had long time enough for their convenience. The surveys were self-reported and last approximately 15 minutes per participant. An English translation of the survey is available as Extended data17.\n\nWe analysed the self-reported manuscript publication as a binary outcome. Multinomial variables included gender, age, current year of career, English proficiency, courses in PubMed, courses in Scopus, courses in Scielo and provider of pirated academic accounts. Binary variables included university, affiliation to a Scientific Medical Student Society, studied previous career, courses in scientific data bases, courses in scientific writing, courses in scientific browsing, courses in Zotero, use of Sci-hub, use of pirated academic accounts. All of these variables were assessed with a self-administered survey.\n\nWe evaluated the association between self-reported manuscript publication and its covariates using chi-squared tests for categorical variables and Mann-Whitney U-test for numerical variables. Poisson family regressions were performed using a log link function and mixed effects multilevel models. We estimated nested models following a manual forward selection method to identify covariates associated with self-reported manuscript publication until reaching a parsimonious multivariable model. These covariates were selected using likelihood ratio tests. Crude and adjusted prevalence ratios (PR) were estimated with 95% confidence intervals (CI 95%). All hypotheses were contrasted using 5% significance. The analysis was performed using Stata 15.1, and the analysis code is openly available on GitHub and Zenodo18.\n\nThis study was classified as minimal risk for participants by the San Bartolome Hospital’s Institutional Review Board (CIE15325-15) and issued its approval. Trained interviewers verbally consent participants, provided them an anonymized self-administered survey. Also, each survey was assigned a numeric ID to protect the privacy of the participants.\n\n\nResults\n\nWe interviewed 11,587 medical students, of whom the mean age was 21±2.9 years and 53% were female. In total, 22.2% (n=2,575) of medical students were in the first year of career. There were 12.5% (n=1,449) affiliated to a Scientific Medical Student Society and 14.1% (n=1,618) reported advanced English skills. The individual-level responses are available as Underlying data19.\n\nA total of 65.1% (n=3,989) had attended a scientific writing course, and 7.9% (n=893) published at least one scientific article during his medical training. There were 22.6% (n=2,514) with a pirated academic account, and from a total of 6,632 medical students, 19.2% (n=1,273) used Sci-Hub at a certain point of their careers (Table 1).\n\n* Mean ± standard deviation.\n\nThere were differences on the prevalence of scientific publications among first-year and last-year medical students (13% vs 4.3%, respectively), being affiliated to a Scientific Medical Student Society (12.43% vs 7.24%), the advanced and elementary proficiency of English (11.2% vs 6.4%), took a scientific writing course (14.6% vs 4.3%), use Sci-Hub (19.3% vs 4.7%) and having pirated academic accounts (15.3% vs 5.5%) (Table 2).\n\n* Simple logistic regression. Beta and p-value.\n\nThe nested models progressively selected the following covariates: courses in scientific writing, pirated academic accounts, universities, courses in Zotero, courses in scientific databases, year of study, previous career, English proficiency, and affiliation to a scientific medical student society. The prevalence of having a scientific publication were 36% (PRp=1.36, 95%CI=1.16–1.59, p<0.001) higher if a medical student was affiliated to a Scientific Medical Student Society, 51% (PRp=1.51, 95%CI=1.21–1.87, p<0.001) higher among the medical students with advanced English proficiency, 85% (PRp=1.85, 95%CI=1.59–2.15, p<0.001) higher in medical students who took a scientific writing course, 81% (PRp=1.81, 95%CI=1.50–2.20, p<0.001) higher in medical students who used Sci-Hub, and 108% (PRp=2.08, 95%CI=1.83–2.36, p<0.001) higher among medical students who have a pirated academic account (Table 3). The information about medical schools in Latin America is available as Extended data20.\n\n(1) Poisson´s regression model with robust variance.\n\n(2) Poisson´s regression model with robust variance and multilevel analysis.\n\n* Multiple regression parsimonious model was indepently adjusted by each variable below\n\nAbbreviations: PRc, Crude prevalence ratio; PRp, Parsimonious model's prevalence ratio; PRa, adjusted parsimonious' prevalence ratio.\n\n\nDiscussion\n\nThe use of Sci-Hub was reported by 19.2% (n= 1273) of the students surveyed, of whom 19.3% (n=243) published a manuscript during their medical training. The awareness and use of Sci-Hub may be due to the high need to access top-level scientific evidence behind a paywall. However, medical students have reported difficulties to access Sci-Hub because it is considered an illegal service in many regions, meaning the web domain is often blocked21–24.\n\nThe use of Sci-Hub was associated with higher prevalence of scientific publications among medical students (PR: 1.81; CI95%: 1.50-2.20). Students feel the great need to obtain access to payed articles, leading them to seek free access throughout Sci-Hub23,25. However, even those students who do not face a paywall, found using Sci-Hub reduced the time and increased simplicity of browsing26. In addition, many researchers and students identify Sci-Hub as a faster option that is not limited to their institution's catalogue24. This is likely homogeneous between high- and low-income countries worldwide27. More than 56,000 article downloads via Sci-Hub came from different east coast cities of the United States, especially from cities where large universities have subscriptions to different publishers26.\n\nThe use of pirated academic accounts was associated with higher prevalence of scientific publications (PR: 2.08; CI95%: 1.83–2.36). The institutional licenses let access to journals, books, or specialized databases such as Scopus or Web of Science. These paid services are funded by government institutions in low- or middle-income countries (LMIC); however, these are not widely distributed or have not been implemented in LMIC28. Alternatives such as HINARI allow access to paid articles in LMIC, and is available to the academic and research community only from certified institutions who achieved certain milestones defined by local science systems29. All this complex context leads users to exchange, loan or acquire access accounts or proxy links to journal catalogs of institutions by non-legal terms27.\n\nA total of 34.9% of students who had produced a scientific publication attended a course in scientific writing skills. Attending a scientific writing skills course increased the prevalence of scientific publications by 85% (PRp=1.85, CI95%=1.59–2.15, p<0.001). This is likely because of the great need of medical students to improve their skills to effectively communicate scientific findings, make a relevant academic reflection, and enhance the chances of acceptance into a scientific journal30. New medical students in research training are eager to be trained in scientific writing skills and seek an experienced mentor to train them31. In addition, medical students actively seek for courses of scientific writing and communication, for instance, the Brazilian DivulgaMicro initiative was a course funded by the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, by its acronym in Portuguese) to train early career researchers to translate complex scientific messages to understandable pieces of information to community members32. At 30 days after launch, the website registered 1,026 users from different regions worldwide, including Latin American, United Kingdom, Pakistan, Germany and Canada. This was one of the most visited free and open scientific communication workshops, which trained over 600 novel medical student researchers32.\n\nAn advanced English proficiency was reported in 14.1% of the students, of whom 11.2% published a scientific manuscript during medical training. In addition, the prevalence of scientific publications increased by 51% among students with advanced English proficiency (PRp=1.51, 95%CI=1.21–1.87, p<0.001). Students are encouraged to understand a scientific evidence written in English33. The TOEFL score is correlated with publishing in a medical journal (correlation coefficient: 0.63)34. Scientific journals preferably accept articles from English natives versus non-English natives (acceptance rate 7% vs 3.6%, respectively)35. Likewise, Americans are 49% more likely to reach an article peer-review or acceptance in an American journal comparing to non-English natives35. Medical students from second to sixth year who attended an English scientific writing skills training reported 53% of them perceived that they were not proficient enough at English to publish a manuscript in English-language journals36.\n\nThe association between scientific publications and advanced English proficiency could be likely because of students’ desire to pursue an academic training abroad offered by institutions requiring academic excellence and a great potential. In 2016, the Peruvian Program of Educational Grants and Credits (PRONABEC, by its acronym in Spanish) jointly funded the Fulbright, FONDECYT, and Chevening scholarships in Peru which benefited 14, 6, and 15 Peruvian graduate applicants, respectively37. In this way, the scholars could be trained by outstanding foreign universities producing a generation of researchers with masters and doctoral degrees who upon returning to their home countries seek to improve the science and technology system38–40. During 2004–2012, the Fogarty International Clinical Research Fellows Program funded promising initiatives of highly competitive English-dominant students from LMIC whose scientific discoveries can address long-term global health needs41,42. This approach has become Fogarty's hallmark: bringing great science to solve local problem of global outreach and building local research capacities42. During 2014–2015, Fogarty has contributed substantially to the training of more than 6,100 global health leaders, 140 of whom have earned doctorates in epidemiology and 96 in public health43.\n\nThe Fogarty International Center builds a bridge between the US National Institutes of Health and the global health research community; 85–90% of trained fellows return to LMICs and obtain research positions into academia, government agencies, and institutes42. However, young Latin American scholars and postdoctoral researchers trained abroad find it difficult because of an unfavourable science system29. For instance, the investment of the Peruvian administration to progress in science and research is still insufficient, it is only 0.12% of the gross domestic product compared to 0.36% in Chile, 1.3% in Brazil and 2.8% in the United States44,45.\n\nOur findings showed that being affiliated to a medical student scientific society increased the prevalence of scientific publication in 36% (PRp:1.36, CI95%=1.16-1.59, p<0.01). Student scientific societies, such as the Peruvian Medical Student Scientific Society (SOCIMEP, by its acronym in Spanish) tries to fill the gaps of research training and provide students the mentors, courses, and scientific opportunities to pursue a research career9,46. With over 30 years of operations with local-level scientific societies across Peru, SOCIMEP promotes research events at a regional, national, and local level multidisciplinary university research and service camps (CUMIS, by its acronym in Spanish), the annual scientific conferences, and foundation courses in epidemiology, research design, and biostatistics47. The outreach the SOCIMEP achieved overall was reflected in the 242 published articles by scientific societies, of which 11% (n=67) were published in Q1 journals, under the mentorship of highly experienced national researchers48.\n\nWe must understand our findings have limitations, described in the following statements. First, several parameters of the questionnaire were self-reported which may cause an undifferentiated classification of the outcome, and may increase the residual confusion of confounding parameters, indicating potential information bias. However, we tried to control this situation by motivating the students to answer the questionnaire truthfully and not to rush their answers; in this sense, our outcome is consistent with reality. Second, all 40 medical schools were affiliated with FELSOCEM, indicating potential selection bias, so our findings are useful for these schools and similar studies should be extended to understand local and regional scientific realities from different countries.\n\n\nConclusion\n\nFactors associated with producing a publication among medical students during their medical training in Latin America include being affiliated to a local Scientific Society of Medical Students, having an advanced English proficiency, attended a course of scientific writing skills, the use of Sci-Hub, and having pirated accounts. The promotion of science among medical students in Latin America is a multi-sphere issue which needs to be addressed as part of multilevel strategies coming from high government authorities, to empower universities and build-up a committed science system in each nation.\n\n\nData availability\n\nFigshare: Scientific article. https://doi.org/10.6084/m9.figshare.13061699.v219.\n\nThis project contains the underlying data in DTA and CSV formats.\n\nFigshare: Technological and educational factors associated with the use of information sources in medical students from Latin America. https://doi.org/10.6084/m9.figshare.13070603.v117.\n\nThis project contains an English-language copy of the questionnaire used for data collection.\n\nFigshare: Latin American medical students surveyed in 2016 - Supplementary materials from a cross-sectional study of 40 medical schools surveyed in Latin America. https://doi.org/10.6084/m9.figshare.13070693.v120.\n\nThis project contains a list of the medical schools surveyed for this study.\n\nAnalysis code used in this study is available at: https://github.com/culquichicon/Scientific_writing.\n\nArchived code at time of publication: https://doi.org/10.5281/zenodo.373035918.\n\nAnalysis code license: GNU General Public License v3.0.\n\nUnless otherwise indicated, data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nRiggs KR, Reitman ZJ, Mielenz TJ, et al.: Relationship Between Time of First Publication and Subsequent Publication Success Among Non-PhD Physician-Scientists. J Grad Med Educ. 2012; 4(2): 196–201. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGouda MA, Zidan HS, Marey AA, et al.: Medical undergraduates’ contributions to publication output of world’s top universities in 2013. QJM. 2016; 109(9): 605–11. PubMed Abstract | Publisher Full Text\n\nCorrales-Reyes IE, Dorta-Contreras AJ: Students scientific production: a proposal to encourage it. Medwave. 2018; 18(1): e7166. PubMed Abstract | Publisher Full Text\n\nTaype-Rondán Á, Lajo-Aurazo Y, Gutiérrez-Brown R, et al.: Aporte de las sociedades estudiantiles en la publicación científica en Scielo-Perú, 2009 - 2010. Rev Peru Med Exp Salud Publica. 2011; 28(4): 691–2. Publisher Full Text\n\nMachado-Alba J, Machado-Duque M: The Role of Research Incubators in Encouraging Research and Publication Among Medical Students. Acad Med. 2014; 89(7): 961–2. PubMed Abstract | Publisher Full Text\n\nBonilla-Escobar FJ, Bonilla-Velez J, Tobón-García D, et al.: Medical student researchers in Colombia and associated factors with publication: a cross-sectional study. BMC Med Educ. 2017; 17(1): 254. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoraes DW, Jotz M, Menegazzo WR, et al.: Interest in research among medical students: Challenges for the undergraduate education. Rev Assoc Med Bras (1992). 2016; 62(7): 652–8. PubMed Abstract | Publisher Full Text\n\nHuamaní C, Chávez-Solis P, Mayta-Tristán P: Aporte estudiantil en la publicación de artículos científicos en revistas médicas indizadas en Scielo-Perú, 1997 - 2005. An Fac Med. 2008; 69(1): 42–5. Publisher Full Text\n\nCvetkovic-Vega A, Inga-Berrospi F, Abel Mestas C: Organizaciones científicas estudiantiles como semilleros de líderes y gestores de la investigación científica en el Perú: SOCIMEP. Acta Méd Peru. 2017; 34: 70–71. Publisher Full Text\n\nToro-Huamanchumo CJ, Failoc-Rojas VE, Díaz-Vélez C: Participación en sociedades científicas estudiantiles y en cursos extracurriculares de investigación, asociados a la producción científica de estudiantes de medicina humana: estudio preliminar. FEM Rev Fund Educ Médica. 2015; 18(4): 293–8. Publisher Full Text\n\nToro-Polo M, Pereyra-Elías R, Nizama-Vía A, et al.: Publicación de los trabajos presentados a los congresos científicos de estudiantes de medicina, Perú 2002-2009: características y factores asociados. Rev Peru Med Exp Salud Publica. 2012; 29(4): 461–8. PubMed Abstract | Publisher Full Text\n\nMoses H 3rd, Matheson DHM, Cairns-Smith S, et al.: The anatomy of medical research: US and international comparisons. JAMA. 2015; 313(2): 174–89. PubMed Abstract | Publisher Full Text\n\nToro-Huamanchumo CJ, Arce-Villalobos LR, Gonzales-Martínez J, et al.: Financiamiento de la investigación en pregrado en las facultades de medicina peruanas. Gac Sanit. 2017; 31(6): 541–2. Publisher Full Text\n\nMejia CR, Valladares-Garrido MJ, Quintana-Gomez S, et al.: Carrera previa como factor asociado al uso de buscadores científicos entre estudiantes de medicina latinoamericanos: cuando la experiencia no cuenta. Educ Médica. 2019; 20: 131–5. Publisher Full Text\n\nMejia CR, Valladares-Garrido MJ, Almanza-Mio C, et al.: Participación en una sociedad científica de estudiantes de Medicina asociada a la producción científica extracurricular en Latinoamérica. Educ Médica. 2019; 20(Supplement 1): 99–103. Publisher Full Text\n\nQUIPU- Centro Andino de Investigación y Entrenamiento en Informática para la Salud Global de la Universidad Peruana Cayetano Heredia: Conducta Responsable en Investigación. 2018; [accessed 17 january 2020]. Reference Source\n\nCulquichicón C: Technological and educational factors associated with the use of information sources in medical students from Latin America..figshare. Journal contribution. 2020. http://www.doi.org/10.6084/m9.figshare.13070603.v1\n\nCulquichicón C: culquichicon/Scientific_writing: Associated factors with reaching a scientific publication during medical training: evidence from 40 medical schools surveyed in Latin America. (Version sw_v1). Zenodo. 2020. http://www.doi.org/10.5281/zenodo.3730359\n\nCulquichicón C, Valladares-Garrido MJ: Scientific article. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.13061699.v2\n\nCulquichicón C: Latin American medical students surveyed in 2016 - Supplementary materials from a cross-sectional study of 40 medical schools surveyed in Latin America.. figshare. Journal contribution. 2020. http://www.doi.org/10.6084/m9.figshare.13070693.v1\n\nMejia CR, Valladares-Garrido MJ, Miñan-Tapia A, et al.: Use, knowledge, and perception of the scientific contribution of Sci-Hub in medical students: Study in six countries in Latin America. PLoS One. 2017; 12(10): e0185673. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchiermeier Q: Pirate research-paper sites play hide-and-seek with publishers. Nature. 2015. Publisher Full Text\n\nHimmelstein DS, Romero AR, Levernier JG, et al.: Sci-Hub provides access to nearly all scholarly literature. eLife. 2018; 7: e32822. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHoy MB: Sci-Hub: What Librarians Should Know and Do about Article Piracy. Med Ref Serv Q. 2017; 36(1): 73–8. PubMed Abstract | Publisher Full Text\n\nGreshake B: Looking into Pandora's Box: The Content of Sci-Hub and its Usage [version 1; peer review: 2 approved, 2 approved with reservations]. F1000Res. 2017; 6: 541. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBohannon J: Who's downloading pirated papers? Everyone. Science. 2016; 352(6285): 508–12. PubMed Abstract | Publisher Full Text\n\nTill BM, Rudolfson N, Saluja S, et al.: Who is pirating medical literature? A bibliometric review of 28 million Sci-Hub downloads. Lancet Glob Health. 2019; 7(1): e30–1. PubMed Abstract | Publisher Full Text\n\nDanda D: Cost of publication - who pays for it? Int J Rheum Dis. 2014; 17(4): 358. PubMed Abstract | Publisher Full Text\n\nCiocca DR, Delgado G: The reality of scientific research in Latin America; an insider's perspective. Cell Stress Chaperones. 2017; 22(6): 847–52. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBhardwaj P, Sinha S, Yadav RK: Medical and scientific writing: Time to go lean and mean. Perspect Clin Res. 2017; 8(3): 113–117. PubMed Abstract | Free Full Text\n\nKennedy AB: Journal Aspirations: Improving Scientific Writing and Publication Through a Writing Mentorship Program. Int J Ther Massage Bodyw. 2017; 10(2): 1–2. PubMed Abstract | Free Full Text\n\nOliveira LMA, Bonatelli ML, Pinto TCA: DivulgaMicro: A Brazilian Initiative To Empower Early-Career Scientists with Science Communication Skills. J Microbiol Biol Educ. 2019; 20(1): 7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRezaeian M: The pitfalls of writing and publishing a scientific health manuscript in English for non-English language scholars. Epidemiol Health. 2015; 37: e2015021. Reference Source\n\nMan JP, Weinkauf JG, Tsang M, et al.: Why do some countries publish more than others? An international comparison of research funding, English proficiency and publication output in highly ranked general medical journals. Eur J Epidemiol. 2004; 19(8): 811–7. PubMed Abstract | Publisher Full Text\n\nLink AM: US and Non-US Submissions: An Analysis of Reviewer Bias. JAMA. 1998; 280(3): 246–7. PubMed Abstract | Publisher Full Text\n\nMolina-Ordóñez J, Huamaní C, Mayta-Tristán P: Apreciación estudiantil sobre la capacitación universitaria en investigación: Estudio preliminar. Rev Peru Med Exp Salud Publica. 2008; 25(3): 325–329. Reference Source\n\nPRONABEC: Memoria Anual 2016. 2018. [accessed 10 january 2020]. Reference Source\n\nFulbright Perú: Beca de Posgrado Fulbright. 2019. [accessed 10 january 2020]. Reference Source\n\nFondecyt: Becas y Co-financiamiento de Concytec. 2020. [accessed 10 january 2020]. Reference Source\n\nChevening: English language. 2019. [accessed 10 january 2020]. Reference Source\n\nHeimburger DC, Carothers CL, Blevins M, et al.: Impact of Global Health Research Training on Career Trajectories: The Fogarty International Clinical Research Scholars and Fellows Program. Am J Trop Med Hyg. 2015; 93(3): 655–61. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBridbord K, Weymouth KH, Puderbaugh A, et al.: Fifty Years of Supporting Global Health Research at the NIH Fogarty International Center. Ann Glob Health. 2019; 85(1): 43. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNational Institutes of Health: Report of the Director National Institutes of Health Fiscal Years 2014 and 2015. 2018. Reference Source\n\nCáceres CF, Mendoza W: Globalized Research and “National Science”: The Case of Peru. Am J Public Health. 2009; 99(10): 1792–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBajak A: What should Peru do to improve its science? Nature. 2019; 576(7787): S65–S67. PubMed Abstract | Publisher Full Text\n\nCvetkovic-Vega A: Propuesta de una sociedad científica de estudiantes de medicina afiliada a SOCIMEP e IFMSA-Perú: SOCEMURP y su modelo de estructura mixta. FEM. 2017; 20(2): 89–89. Reference Source\n\nChalco-Huamán J, Zavala-Portugal J, Andonaire-Munaico C: Responsabilidad social en estudiantes de medicina: experiencia de una sociedad científica estudiantil peruana. An Fac Med. 2016; 77: 69–70. Publisher Full Text\n\nTaype-Rondán A, Bazán-Ruiz S, Valladares-Garrido D: Producción científica de las sociedades científicas de estudiantes de medicina del Perú, 2002-2012. CIMEL. 2013; 18(1): 23–29. Reference Source"
}
|
[
{
"id": "75348",
"date": "14 Dec 2020",
"name": "Virgilio Efrain Failoc Rojas",
"expertise": [
"Reviewer Expertise Infectious diseases",
"Health interventions",
"Systematic Reviews and meta-analysis",
"Medical education."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study brings a broad view of the current efforts of local Scientific Societies of Medical Students on promoting research among medical students. The authors found relevant factors associated with producing a scientific manuscript during medical school including the use of pirated academic accounts, training in basic research skills, English proficiency, and ultimately being affiliated to a scientific medical student society. All of these conditions are validated by the faculties of medical schools across Latin America, and are linked between them. The outreach of this study is to give us a sight of factors to continue promoting research capacities among medical students and take advantage of the Medical Students Scientific Society as an ally in this mission.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "128598",
"date": "14 Apr 2022",
"name": "Megan Anakin",
"expertise": [
"Reviewer Expertise My research area encompasses teaching",
"learning",
"curriculum",
"and faculty development in health professions education."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview of Factors associated with producing a scientific publication during medical training: evidence from a cross-sectional study of 40 medical schools surveyed in Latin America. DOI: 10.12688/f1000research.26596.1\nGeneral comments\nThe authors provide a report that addresses the aim of a secondary data analysis to better understand the factors from medical training associated with producing a scientific publication during undergraduate study. One major recommendation is to enhance the focus of the article to emphasise the relevance, importance, and implications of study and its findings to education more generally, and to students, teachers, and medical programme curriculum and resourcing, specifically.\nNote: I appreciate that English might not be the authors' first language. I have made suggestions to improve the grammar of the manuscript. For example, in first sentence of the abstract, the verb 'promote' should be 'promoting'. I have not identified all instances of where subject-verb agreement needs checking. I recommend that a copy of the manuscript is shared with a colleague who can edit the manuscript for grammar or the authors access a professional editing service. Other grammar suggestion examples are:\nIntroduction section, first paragraph, first sentence: The verb 'promote' makes more sense as 'promoting' and the verb 'endure' makes more sense as 'enduring'\n\nIntroduction section, first paragraph, second sentence: The verb 'foster' makes more sense as 'fostering'\n\nIntroduction section, first paragraph, third sentence: The verb 'comparing' makes more sense as 'compared'\n\nIntroduction section, second paragraph, second sentence: Subject-verb agreement. Since the SOCIMEP is singular, then the verbs should be 'fosters' and 'provides'.\nSpecific feedback with constructive comments\nAbstract\nThe authors succinctly outline the topic, a problem that is addressed by the methods, and present the main results. Missing from the abstract is a few sentences outlining the discussion section. Please consider outlining the key discussion points related to the significance and implications of the results for clinical educators who will be reading this article.\nIntroduction\nSecond paragraph, awkward word choice: I'm not certain what 'stands' means in this sentence. Please consider revising this long sentence into two shorter ones. The second sentence could begin: \"SOCIMEP holds international,...\"\nThe introduction provides a well-argued warrant for the study by established the local need for the study. As a reader from outside Latin America, I am wondering how this situation might be similar and different to other regions. Please consider relating this problem to the locations of readers beyond Latin America.\nMethods\nThe aim is clearly stated at the beginning of this section and the methods presented are appropriate to address it.\nPopulation and sampling section. Please explain the educational outcome-related evidence that was used to determine the power calculation, or if not, state the reason for why you considered a sample size calculation with an 80% of power and 5% of significance. Please describe the census-type sampling procedure or support the terminology with a reference that describes it to the reader.\nOperational procedures section. First paragraph, first sentence: Please consider replacing XXX with number or word because it looks like information has been omitted to the reader, or please further explain this reference. Please specify what the ICT project was awarded or to whom the project was awarded. Please consider revising the second to last sentence of the second paragraph to explain how participants completed the surveys to provide responses selected or written by themselves and participants took about 15 minutes to complete it.\nMeasures section. Please clarify the term, ‘self-administered survey’ by providing more information or revising the sentence so it better matches the description of the survey in the operational procedures section.\n\nData analysis section. The analyses performed by the authors looks appropriate, however, the explanations are dense and may not be easily understood by readers of this journal. Please revise this section so that it is suitable for clinical educators who are not necessarily biomedical scientists or statisticians. Please clarify in the text below on what statistical basis the covariates were selected so the reader does not need to make inferences about the procedures. Please explain if the forward addition assessed using a LRT and if so, explain if a chi-squared distribution or something else was used. Please also describe the criterion used to include or exclude the covariate. Otherwise, the reader has to make the assumption that this information is encompassed in the ‘all hypotheses…’ statement. Please consider stating the following information more thoroughly and with descriptions meaningful to a clinical educator reader: “We estimated nested models following a manual forward selection method to identify covariates associated with self-reported manuscript publication until reaching a parsimonious multivariable model. These covariates were selected using likelihood ratio tests. Crude and adjusted prevalence ratios (PR) were estimated with 95% confidence intervals (CI 95%). All hypotheses were contrasted using 5% significance”\nResults\nFirst paragraph, first sentence: Please resolve the following contradiction: The methods state that participants completed surveys, however, the first sentence of the results states that interviews were conducted. Both cannot be true.\nPlease consider revising the first, second, third, and fourth paragraphs of the results section so the information presented in them is not repeated in the tables of results as well. Instead, please draw the reader’s attention to important or relevant proportions, relationships, differences, and similarities among the results. In the third paragraph, the percentage stated for the prevalence of scientific publications among first-year and last-year medical students (13% vs 4.3%, respectively) is backwards from the Table 2. The remaining differences need to have the two categories identified. For example, the reader does not know by reading the sentence what being affiliated to a Scientific Medical Student Society (12.43% vs 7.24%) means unless you state (12.43% yes vs 7.24% no).\nDiscussion\nPirated academic accounts and use of Sci-Hub section. To appreciate the similarities and differences between Sci-hub and pirated accounts, please define and explain these two factors in the methods section for the reader. To help the reader understand the significance of the results presented in the first and second paragraphs, please explain how the use Sci-Hub might contrast with access to relevant literature provided by the participating medical schools. In the second paragraph, the fifth sentence begins with ‘This’. Please specify the subject at the beginning of this sentence so the reader can appreciate what might be homogeneous and better understand the point made in the final sentence in the paragraph. In the last paragraph of this section, please make links between the finding about pirated academic accounts in the first sentence and the statements that follow it. Please help the reader to understand how the statements help the reader to understand the significance and implications of this finding.\nThe discussion in the sections about courses in writing, English proficiency, and affiliated to a scientific medical student society do a good job of relating the findings to the local context and the literature. Please consider how the discussion can be broadened to address how your findings might be used by others to generate insights into their own local context or make suggestions about how the findings might offer insights to educators and other educational researchers about the factors from medical training associated with producing a scientific publication during undergraduate study. Since this is a medical and health professions education journal, our readers are interested in the implications for students, teachers, and medical programme curriculum and resourcing.\nLimitations section. Please give an example to explain to the reader what an undifferentiated classification of the outcome and an increase in residual confusion. Please remember the readers are clinical educators who are not necessarily biomedical scientists or statisticians. Please explain the possible influence of FELSOCEM on the results and how it may bias the results. What factors might be missing in these results that might give readers further insights into the problem of producing scientific publications during medical training. Please outline a few future directions that you or other researchers might take with the findings or the study design to extend our understanding of this problem and topic\nConclusion\nPlease revise the very long final sentence into at least three shorter ones to help the reader appreciate the important concluding points.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8185",
"date": "23 May 2022",
"name": "Annel Rojas Alvarado",
"role": "Author Response",
"response": "\"Abstract The authors succinctly outline the topic, a problem that is addressed by the methods, and present the main results. Missing from the abstract is a few sentences outlining the discussion section. Please consider outlining the key discussion points related to the significance and implications of the results for clinical educators who will be reading this article.\" Response: Thank you. A sentence on the significance and implications of the results has been added to the end of the conclusion section. \"Introduction Second paragraph, awkward word choice: I'm not certain what 'stands' means in this sentence. Please consider revising this long sentence into two shorter ones. The second sentence could begin: \"SOCIMEP holds international,...\"\" Response: Thank you. The overall sentence was revised. \"The introduction provides a well-argued warrant for the study by established the local need for the study. As a reader from outside Latin America, I am wondering how this situation might be similar and different to other regions. Please consider relating this problem to the locations of readers beyond Latin America.\" Response: Thank you. A sentence about the problem related to other contexts was added in the last paragraph (second sentence). \"Methods The aim is clearly stated at the beginning of this section and the methods presented are appropriate to address it.\" Response: Thank you \"Population and sampling section. Please explain the educational outcome-related evidence that was used to determine the power calculation, or if not, state the reason for why you considered a sample size calculation with an 80% of power and 5% of significance. Please describe the censustype sampling procedure or support the terminology with a reference that describes it to the reader.\" Response: Thank you. The reason for the sample size calculation with the referred parameters were explained. Census-type sampling was revised to a simpler phrase. \"Operational procedures section. First paragraph, first sentence: Please consider replacing XXX with number or word because it looks like information has been omitted to the reader, or please further explain this reference. Please specify what the ICT project was awarded or to whom the project was awarded. Please consider revising the second to last sentence of the second paragraph to explain how participants completed the surveys to provide responses selected or written by themselves and participants took about 15 minutes to complete it.\" Response: Thank you. \"XXX\" was revised to 30th. The ICTs project was awarded an amount of money for publication (details in first & second sentence). The second to last sentence of the second paragraph was revised (please refer to this part). \"Measures section. Please clarify the term, ‘self-administered survey’ by providing more information or revising the sentence so it better matches the description of the survey in the operational procedures section.\" Response: Thank you. The term “self-administered survey” was revised \"Data analysis section. The analyses performed by the authors looks appropriate, however, the explanations are dense and may not be easily understood by readers of this journal. Please revise this section so that it is suitable for clinical educators who are not necessarily biomedical scientists or statisticians. Please clarify in the text below on what statistical basis the covariates were selected so the reader does not need to make inferences about the procedures. Please explain if the forward addition assessed using a LRT and if so, explain if a chi-squared distribution or something else was used. Please also describe the criterion used to include or exclude the covariate. Otherwise, the reader has to make the assumption that this information is encompassed in the ‘all hypotheses…’ statement. Please consider stating the following information more thoroughly and with descriptions meaningful to a clinical educator reader: “We estimated nested models following a manual forward selection method to identify covariates associated with self-reported manuscript publication until reaching a parsimonious multivariable model. These covariates were selected using likelihood ratio tests. Crude and adjusted prevalence ratios (PR) were estimated with 95% confidence intervals (CI 95%). All hypotheses were contrasted using 5% significance”\" Response: Thank you. We clarified the statistical basis for the forward selection method and other procedure details so that the information is meaningful to clinical educator readers. \"Results First paragraph, first sentence: Please resolve the following contradiction: The methods state that participants completed surveys, however, the first sentence of the results states that interviews were conducted. Both cannot be true.\" Response: Thank you. The term “were interviewed” was clarified to “completed the survey” to avoid the contradiction. \"Please consider revising the first, second, third, and fourth paragraphs of the results section so the information presented in them is not repeated in the tables of results as well. Instead, please draw the reader’s attention to important or relevant proportions, relationships, differences, and similarities among the results. In the third paragraph, the percentage stated for the prevalence of scientific publications among first-year and last-year medical students (13% vs 4.3%, respectively) is backwards from the Table 2. The remaining differences need to have the two categories identified. For example, the reader does not know by reading the sentence what being affiliated to a Scientific Medical Student Society (12.43% vs 7.24%) means unless you state (12.43% yes vs 7.24% no).\" Response: Thank you. Relevant results were highlighted in the text. In addition, the results in Table 2 were revised and categories were included with their corresponding percentages. Discussion \"Pirated academic accounts and use of Sci-Hub section. To appreciate the similarities and differences between Sci-hub and pirated accounts, please define and explain these two factors in the methods section for the reader. To help the reader understand the significance of the results presented in the first and second paragraphs, please explain how the use Sci-Hub might contrast with access to relevant literature provided by the participating medical schools. In the second paragraph, the fifth sentence begins with ‘This’. Please specify the subject at the beginning of this sentence so the reader can appreciate what might be homogeneous and better understand the point made in the final sentence in the paragraph. In the last paragraph of this section, please make links between the finding about pirated academic accounts in the first sentence and the statements that follow it. Please help the reader to understand how the statements help the reader to understand the significance and implications of this finding.\" Response: Thank you. Use of Sci-Hub and use of pirated accounts were defined and explained in the methods section. The contrast between Sci-Hub usage and access provided by medical schools is detailed in paragraph 1 of the referred section. The subject was specified in the fifth sentence of the second paragraph. Sentences in the last paragraph have been revised to better link them to the first sentence of this part. \"The discussion in the sections about courses in writing, English proficiency, and affiliated to a scientific medical student society do a good job of relating the findings to the local context and the literature. Please consider how the discussion can be broadened to address how your findings might be used by others to generate insights into their own local context or make suggestions about how the findings might offer insights to educators and other educational researchers about the factors from medical training associated with producing a scientific publication during undergraduate study. Since this is a medical and health professions education journal, our readers are interested in the implications for students, teachers, and medical programme curriculum and resourcing.\" Response: Thank you. Suggestions were added at the end of each paragraph in the referred sections. \"Limitations section. Please give an example to explain to the reader what an undifferentiated classification of the outcome and an increase in residual confusion. Please remember the readers are clinical educators who are not necessarily biomedical scientists or statisticians. Please explain the possible influence of FELSOCEM on the results and how it may bias the results. What factors might be missing in these results that might give readers further insights into the problem of producing scientific publications during medical training. Please outline a few future directions that you or other researchers might take with the findings or the study design to extend our understanding of this problem and topic\" Response: Thank you. Undifferentiated classification of the outcome and residual confounding were detailed. The influence of FELSOCEM was also explained. A brief list of relevant factors were added. Future directions were outlined. \"Conclusion Please revise the very long final sentence into at least three shorter ones to help the reader appreciate the important concluding points.\" Response: Thank you. The final sentence was revised to three shorter ones."
}
]
}
] | 1
|
https://f1000research.com/articles/9-1365
|
https://f1000research.com/articles/11-562/v1
|
23 May 22
|
{
"type": "Systematic Review",
"title": "Post-industrial context of cassava bagasse and trend of studies towards a sustainable industry: A scoping review – Part I",
"authors": [
"José Gabriel Serpa-Fajardo",
"Elvis Judith Hernández-Ramos",
"Gregorio Fernández-Lambert",
"Luis Carlos Sandoval-Herazo",
"Ricardo David Andrade-Pizarro",
"José Gabriel Serpa-Fajardo",
"Elvis Judith Hernández-Ramos",
"Luis Carlos Sandoval-Herazo",
"Ricardo David Andrade-Pizarro"
],
"abstract": "Background: The cassava starch industry is recognized as a source of negative externalities caused by the agroindustrial waste ‘cassava bagasse’. Even though options for bioconversion of cassava bagasse have been introduced, it is also true that hundreds of tons of this waste are produced annually with the consequent negative environmental impact. This agroindustrial context highlights the need for further research in technological proposals aimed at lowering the water contained in cassava bagasse.\nMethods: We report a scoping review of studies from 2010–2021 that mention the uses of cassava bagasse, as well as the technological options that have become effective for drying fruits and vegetables. The method used for selecting articles was based on the Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) method. Articles selected were taken from the databases of ScienceDirect, Google Scholar, Scopus and Springer.\nResults: This review highlights fruit and vegetable osmotic dehydration and drying studies assisted by the combination of emerging technologies of osmotic pressure, ultrasound, and electrical pulses. Studies that take advantage of cassava bagasse have focused on biotechnological products, animal and human food industry, and development of biofilms and biomaterials.\nConclusions: In this review, we found 60 studies out of 124 that show the advantages of the residual components of cassava bagasse for the development of new products. These studies do not mention any potential use of bagasse fiber for post-industrial purposes, leaving this end products’ final use/disposal unaddressed. A viable solution is osmotic dehydration and drying assisted with electrical pulse and ultrasound that have been shown to improve the drying efficiency of fruits, vegetables and tubers. This greatly improves the drying efficiency of agro-industrial residues such as husks and bagasse, which in turn, directly impacts its post-industrial use.",
"keywords": [
"waste bioconversion",
"emerging technologies",
"biomass",
"industrial drying"
],
"content": "Introduction\n\nCassava crop (Manihot esculenta Crantz) has had significant growth in agriculture worldwide, particularly in the tropical countries of Latin America, the Caribbean, Asia, Africa, and Oceania. Because of its tolerance to drought, the ability to thrive in marginal soils, and flexibility for planting and harvesting, cassava is currently considered a multipurpose crop responding to food and commercial expectations of emerging countries (Howeler et al., 2013 cited in Zainuddin et al., 2017).\n\nAnnual world production of cassava is approximately 303.5 million tons (FAO, 2019) which, once harvested, shows the great constraint of being a highly perishable product. For this reason, besides being part of the food diet, the harvest surplus is processed into chips, pellets, flour, bioethanol, cookies, balanced feed for animals, as well as for producing native starch and modified starches.\n\nStarch production from cassava is one of the industrial processes of recent global importance, especially in the textile, chemical, pharmaceutical, food, and beverage industries, even in gastronomy, powdered beverages, and others. The FAO (2019) reported that the world market for cassava starch reached an approximate production of eight million tons in 2018, with a compound annual rate of 4.73% between 2011 and 2018. Thus, for 2024 it is expected to exceed 10 million tons, with a compound annual rate of 3.76% from 2019 to 2024.\n\nObtaining industrial starch from cassava generates a high organic load of cassava bagasse, with environmental impact on the soil, water, and air, requiring an alternative treatment for its reincorporation into the environment. Processing 250–300 tons of cassava tubers results in approximately 1.6 tons of solid peel and approximately 280 tons of cassava bagasse with high moisture content (Escaramboni et al., 2018; Florencia et al., 2019). Zhang et al. (2016) report that for every ton of processed cassava, between 0.93 and 1.12 tons of bagasse and cassava peel are produced, which is later discarded, and in the best of cases disposed of in sanitary landfills technically in the open without any treatment, negatively impacting the environment (John, 2009; Grande Tovar, 2016; Morales et al., 2018; Oyewole and Eforuoku, 2019; Grasso, 2020).\n\nCassava bagasse is a fibrous material with a humidity percentage higher than 85%, difficult to efficiently remove by conventional drying. This by-product contains relatively low content of proteins, ashes, and fats, and approximately 16% dry matter, mainly made up of carbohydrates with up to 82.85% with a content greater than 50% starch (Polachini et al., 2016; De Souza et al., 2018; Travalini et al., 2019), and fiber between 15–50% (Chen et al., 2015). With all this, cassava bagasse is not being used by the cassava starch production industry, generating daily large volumes, fermenting in an uncontrolled way, and producing unpleasant odors. This waste has become an issue of environmental pollution for the same factories and neighboring regions (Grasso, 2020).\n\nEfforts to use alternative low-cost and renewable materials as raw materials to generate new products at an efficient cost and environmentally friendly, have led to implementation of innovative technologies to use agroindustrial waste to obtain valuable, useful, and beneficial products in other industrial processes (Sharmila et al., 2020). Nonetheless, generation of agroindustrial waste in the varied industrialization stages is currently a problem with negative environmental impacts worldwide because in most cases they are not properly processed or handled (Vargas & Pérez, 2018). The main problem found during waste management with high humidity content such as cassava bagasse, is the low use by other industrial sectors due to issues in handling, storage, transport, and conservation. This requires them to be subjected to a drying process (Polachini et al., 2016) or to humidity elimination to lower their volume or mass to favor handling and subsequent use in different industrial processes.\n\nDifferent alternatives for drying have been abundantly used in the agroindustrial sector, among which, solar drying, hot air drying, spray drying, or osmosis dehydration stand out (Vargas & Pérez, 2018) among other emerging technological options such as electric pulses, high hydrostatic pressure, ultrasound, centrifugal force, vacuum, gamma irradiation, and traditional technologies. All of which have been shown to improve the efficiency of osmotic dehydration and drying operations to reduce drying time with lower energy cost (Ahmed et al., 2016).\n\nThese combined techniques of emerging and conventional technologies have been efficiently applied in the osmotic dehydration and drying processes of various products, such as fruits, vegetables, fillets, and tubers (yams, cassava, potatoes, and sweet potatoes), as well as in some polymeric matrices. These results make it interesting to study its impact on the efficiency of the osmotic dehydration process and subsequent drying of the cassava bagasse, as well as other agroindustrial waste, especially using emerging technologies that are attractive due to their simplicity and economy for these processes. The lack of studies on efficient techniques for drying agroindustrial waste opens up the need to advance in technological innovation processes to identify opportunities for the economic revaluation of the agroindustry and its wastes. There is a growing interest in finding technological alternatives to provide added value to these agroindustrial waste with high moisture content (Florencia et al., 2019).\n\nIn order to guide the cassava starch industry towards a sustainable agribusiness, this article synthesizes the technological advances reported in scientific literature from 2010–2021 for the use of cassava bagasse, as well as the technological options that have become good solutions in the dehydration of fruits, tubers, and vegetables; thus, proposing the hypothesis that they can be adapted to cassava bagasse drying. Derived from this technological synthesis, this article contributes to the knowledge of the industrial and scientific community. Recommendations of technological alternatives for the industrial scaling of options for the use of cassava bagasse are proposed. These include implementation of efficient drying processes, particularly through application of combined techniques of emerging and traditional technologies in the field of post-agroindustrial drying of cassava bagasse and other similar agroindustrial residues.\n\nTo this end, the following sections of this article describe the methodological approach of this research, order of cassava world production, its industrialization and studies on the use of cassava bagasse. Emerging technologies are also described, which apply good results in the field of fruit, vegetable, and tuber waste. These can be replicated as options to the drying of cassava bagasse to minimize the negative externality of this waste and manage its efficient handling in post-industrial processes as a by-product of high industrial value.\n\n\nMethods\n\nFor the systematic review of the scientific literature, according to the objectives of study, the following databases were used: ScienceDirect, Google Scholar, Scopus and Springer. The Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) methodology was used for identification, selection, eligibility and inclusion, results synthesis, and discussion (Tricco et al., 2018), and a PRISMA 2020 flow diagram was created (Neal et al., 2021). This study is reported in line with the PRISMA guidelines for scoping reviews (Serpa-Fajardo et al., 2022).\n\nThe annual world production of cassava bagasse was estimated based on the statistics from the Food and Agriculture Organization (FAO, 2019), while the conversion factors for the generation of this residue were taken from what was reported in the scientific literature.\n\nOnly records corresponding to the publication period between 2010 and 2021 were considered, and only reviews articles and research articles were examined. Furthermore, only reviews and research articles addressing the current cassava bagasse issue and its different use options were considered, excluding articles on cassava, use of other cassava residues, cassava flour and cassava starch.\n\nReviews and research articles that addressed the combined techniques of osmotic dehydration as pretreatment to improve the efficiency of the convective air-drying process of agro-industrial products were also considered, and those that employ the support of emerging ultrasound or electrical pulse technologies in the osmotic dehydration and drying processes to further improve their efficiency. Articles that address other types of emerging technologies different to ultrasound and electrical pulses, in addition to articles that address these technologies individually and not as combined techniques were excluded, e.g., articles addressing only osmotic dehydration operation or only the drying operation.\n\nThe most recent search date was November 2021. The keywords used in the search were: ‘cassava bagasse’; ‘cassava waste assessment’; ‘use of cassava bagasse’. The title, abstract and keywords of the articles were searched, chained as follows: ‘cassava bagasse’ OR bran OR cassava residues AND valuation OR utilization AND NOT starch. Similarly, for the purposes of reviewing the application of combined techniques of emerging ultrasound and electrical pulse technologies with osmotic dehydration operations and conventional drying of various products, the following keywords were used: ‘drying’; ‘osmotic dehydration’, ‘emerging technology’, ‘ultrasound’ and ‘electrical pulses’. The title, abstract and keywords of the articleswere searched as follows: osmotic dehydration AND drying; ultrasound AND dehydration AND drying; Electrical pulses AND osmotic dehydration AND drying.\n\nRecord selection was carried out by two authors: J.G. Serpa-Fajardo and E.J. Hernández-Ramos, independently, based on the predetermined inclusion and exclusion criteria previously mentioned. Discrepancies were resolved through discussion.\n\nGiven the particular features of the records selected in this scoping review, such as the heterogeneous evidence base, data management was performed using thematic and content analysis according to the objectives of this study, grouping results in common applications as follows: studies related to the use of cassava bagasse were grouped by publication year, country conducting the study and according to the addressed application field. Consistently, research work related to the application of the combined techniques were grouped according to the publication year, countries that carried out the study and according to the combination of techniques used. Processing, illustration and synthesis of results were developed in a narrative format, table and figure, through the use of Microsoft Excel (version 16.0) spreadsheet software (RRID:SCR_016137).\n\n\nResults\n\nIn this review carried out to establish the current problems of cassava bagasse and its different use options according to the adopted search strategy, an initial record of 5,215 results was obtained: ScienceDirect (1,260), Google Scholar (3,020), Scopus (128), and Springer (807). Meanwhile to establish the current application state of combined techniques of emerging technologies of ultrasound and electrical pulses with the operation of osmotic dehydration and conventional drying of various products, based on the mentioned search strategy, a record of initial results obtained was of 15,973 documents: ScienceDirect (8,534), Google Scholar (5,180), Scopus (2,019), and Springer (240).\n\nStarting from the total number of records (21,188 total documents), the screening process was conducted according to the study objectives. First, of the records were restricted by publication year (2010–2021) and only reviews and research articles were selected. A total of 20,793 documents were discarded including repeated articles and articles regarding other areas not included in this review (Figure 1). Out of the 395 articles that remained an additional 83 articles were excluded, namely: 21 articles on cassava use, use of other cassava residues, cassava flour, cassava starch and 62 articles that addressed other types of emerging technologies other than ultrasound and electrical pulses, as well as articles that address these technologies individually and not as combined techniques, e.g., articles that addressed only osmotic dehydration or the drying operation. Only articles that addressed the combined techniques of osmotic dehydration as a pretreatment to improve the efficiency of the convective air-drying process of agro-industrial products, and those that employ emerging ultrasound or electrical pulse technologies in osmotic dehydration and drying processes to improve efficiency were selected. Moreover, we excluded one publication that was not retrievable, 13 articles corresponding to studies related to cassava but with other types of bagasse, 34 articles that were discarded for applying said technologies combined with other purposes, and 140 articles addressed in Part II of this study. Part II reports the current status of osmotic dehydration technology, used alone or assisted by emerging ultrasound technologies or electrical pulse technology, which today are used to improve drying efficiency in various agro-industrial products; potentially useful findings so that these combined drying techniques are addressed through new research aimed at achieving an efficient process of water removal in cassava bagasse and other agroindustrial residues.\n\nFinally, a total of 124 articles were selected: seven review articles and 117 research articles, of which 60 corresponded to studies on the use of cassava bagasse, 44 were about the use of the combined techniques of ultrasound, electrical pulses, osmotic dehydration, and drying, and 20 about the generalities of the cassava industry related to the assessment of cassava bagasse. Futhermore, two FAO reports from 2019 and 2020 were considered.\n\nIt was established that the cultivation of cassava (Manihot esculenta, crantz) has had significant growth in world agriculture (Lobell et al., 2008 and Howeler et al., 2013, cited in Zainuddin et al., 2017), and today it is considered the sixth most important crop in the world after wheat, rice, corn, potato, and barley (Otekunrin & Sawicka, 2019; Adepoju & Oyewole, 2013, cited in Dada, 2018). Cassava is ranked as the fifth most used starch source in the world and the third among the food sources consumed in tropical regions (Florencia et al., 2019), which has contributed to the global expansion of rapid commercialization of this crop and large-scale investments in order to expand product processing (OECD y FAO, 2020). Table 1 highlights that ten countries hold 74.4% of the world production of cassava, where Nigeria, the Democratic Republic of Congo, Thailand, Ghana, and Brazil contribute 56.1% to world production.\n\nIn addition to its fresh consumption, cassava bagasse has an agroindustrial use with the highest demand for ethanol production and other biofuels since 2000. Cassava bagasse is also used in the food sector as a raw material to produce traditional foods, to obtain native and modified starches, and in balanced animal feed (Edhirej et al., 2017). Nonetheless, industrialization of cassava generates large amounts of waste rich in organic matter and suspended solids with serious environmental implications in the absence of post-harvest treatments. On the other hand, the complex biochemical composition with high organic content of cassava industrial waste provides great potential for bioconversion into value-added products, thus, providing economic sustainability to the cassava industry (Zhang et al., 2016; Li et al., 2017).\n\nThe most important postharvest constraint in cassava cultivation is its short shelf life. Therefore, one of the best options to increase the value of harvested cassava to benefit rural economies is to process excess cassava for starch production (Teixeira et al., 2009, cited in Travalini et al., 2019). Approximately 60 million tons of starch are extracted annually worldwide from different sources for use in a large number of products. Out of this quantity, eight million tons, equal to 13.3% of the starch produced worldwide, is produced from cassava (FAO, 2019). Furthermore, cassava and its waste generated by its industrialization have attracted researchers to explore its capacity as a reinforcement material in biodegradable compounds and as a raw material to improve animal and human food safety (Edhirej et al., 2017).\n\nNonetheless, the high humidity content of some waste from the cassava industry makes it a perishable product in which all kinds of microorganisms proliferate. Decomposition is generated through uncontrolled fermentation causing bad odors and affecting both processing plants as well as the surrounding regions. This has become an environmental problem that must be properly managed.\n\nIn this industrial system, Ubalua (2007) highlights that not applying the zero waste principle in this agribusiness can have a negative impact on vegetation and soil, making soils unproductive and devastated due to the biological and chemical reactions taking place among waste, soil and surrounding vegetation. In this sense, the search for applications for cassava waste should contribute to reducing environmental problems (Leite et al., 2017).\n\nGrande Tovar (2016) agree with Escaramboni et al. (2018) and Florencia et al. (2019) in that processing of 250–300 tons of cassava root produces around 1.16 tons of husk and 280 tons of bagasse. Zhang et al. (2016) report that for each ton of cassava processed to obtain 0.25 tons of cassava starch, between 0.93 and 1.12 tons of bagasse and cassava husk are generated, due to imbibition of water. Consequently, considering these conversion factors and the reported annual world production of cassava starch of eight million tons approximately, it is estimated that the approximate annual world generation of cassava bagasse is between 29.76 and 35.84 million tons/year approximately.\n\nThis cassava bagasse agroindustrial waste can contain up to 60% by weight of starch on a dry basis, and humidity of about 85%, complicating its short-term storage (Araujo-Silva et al., 2018; María, Martha, & Juan, 2012). The costs associated with handling and disposal of this waste constitutes an undesirable financial burden on the cassava processing industries. As a result of this challenge, cassava processors generally choose to dispose of waste in the open air, which becomes a major environmental issue (Barros et al., 2012; Olukanni et al., 2013; Omilani et al., 2015; Cited in Olukanni & Olatunji, 2018).\n\nTable 2 specifically presents the studies on the use of cassava bagasse, classified by author, application field and specific use. Other types of studies are excluded, such as those aimed at use of cassava, cassava leaves and stems, cassava flour, and cassava starch. Cassava studies related to other types of bagasse from other raw materials are also excluded.\n\nIn this context, the diverse studies aimed at seeking a viable use for cassava bagasse can be ranked into three large areas: 1) Use in the food industry, 2) Biotechnological applications to generate products with greater added value, and 3) Use as a reinforcement material in biomaterials. However, use alternatives reported in these studies leave the results of this research on the use of cassava bagasse at an experimental level, without having the scope of a cost-effective industrial scaling of the said process. In effect, the enduring problem for the industrial scaling of cassava bagasse in these studies is the need to implement innovative and efficient drying processes for this residue, which reduces its mass and volume and eases handling, transport, storage, and conservation.\n\nThe studies reported in the scientific literature relate to use of cassava bagasse from 2012–2021 (Figure 2a). They show a clear interest in this research topic by the scientific community, who tend to seek alternatives for the use of cassava bagasse, particularly in three study fields (Figure 2b). Fifty percent of the studies correspond to the use of cassava bagasse in the biotechnological processes field: fungi production, organic acids, xanthan gum, bio-pigments, and production of biofuels (bioethanol, biomethane, hydrogen, and butanol); 23% of the studies are oriented to cassava bagasse use in the animal and human food industry: balanced feed, gastronomic diets, cookie making, ice cream, and others; and 27% of the studies are oriented towards use of cassava bagasse in the production of biofilms and other biomaterials as biodegradable reinforcement material, foam production, and nanofibers, and others. This study trend from 2012–2021 is marked by Brazil as the country contributing more than 39% of the research in this field of study, followed by China with 13%, and Argentina, Colombia, India, Indonesia and Nigeria with percentages between 6 and 7% (Figure 2c). Figure 3 illustrates the interest field of countries leading the studies on the use of cassava bagasse. In these illustrations it can be seen that South America and Asia show the greatest interest in biotechnological processes and development of biomaterials.\n\nAdvances in the different options for the use of cassava bagasse highlight the need to simultaneously advance in efficient technologies for the drying of this waste. For effective use of post-harvest cassava bagasse, prior drying is essential (Rodríguez et al., 2016). Drying is widely used in the food industry to extend shelf life of products by inhibiting growth of microorganisms and enzyme activity. Traditional drying techniques such as convective drying have drawbacks, mainly because they require a long processing time and generate changes in products’ properties (Prosapio & Norton, 2017). Some pre-drying treatments have been proposed with good results for the drying of fruits and vegetables. For example, Table 3 describes some of the studies that examine the emerging technologies of ultrasound and electrical pulses in combination with osmotic dehydration and convective drying operations of various agroindustrial products. These technologies are useful for agribusiness that is always looking for innovative technologies to improve the efficiency of its processes and reduce energy consumption.\n\nIn this context, more studies are required that examine the use of environmentally friendly techniques to lower energy use and the environmental footprint induced by food processing and waste generation throughout the supply chain. This will allow the replacement of traditional techniques with more efficient and sustainable processes (López-Pedrouso et al., 2019). In this regard, osmotic dehydration has received considerable attention in recent years as it is one of the simplest and cheapest dehydration treatments that reduces energy consumption and accelerates drying time (Feng et al., 2018). This has led to the evaluation of different osmotic agents for the dehydration of fruits and tubers as a pretreatment to convective drying in order to improve energy efficiency and process costs (Abbasi et al., cited by Sharma and Dash, 2019). When osmotic dehydration is assisted by the emerging technologies of electric pulses, high hydrostatic pressure, ultrasound, centrifugal force, vacuum, and gamma irradiation, it has been shown to improve the dehydration process by increasing cell membrane permeability and generating a greater diffusion and mass transfer rate. These combined operations have been shown to reduce drying time, and energy costs associated with this operation (Ahmed et al., 2016; Dehnad et al., 2016).\n\nThese novel or emerging technologies arose to meet the need to improve conventional drying technologies. Today, they are the subject of study alone or in combination with conventional techniques to improve product safety, shelf life and processing time (Moreno-Vilet et al., 2018). Table 3 shows articles that apply these technologies individually or in combination, but with other purposes rather than improving the efficiency of the osmotic dehydration and convective drying processes that use air as a drying agent. Studies excluded are those that apply these combined techniques in operations of lyophilization, freezing, frying, homogenization, extraction of bioactive compounds, extraction of essential oils, extraction of phenolic compounds, protein extraction, crystallization operations, recovery extraction of intracellular compounds, inactivation of microorganisms, and enzyme inactivation.\n\nOther alternative technologies, not object of this study, that have been shown to improve food processing and preservation conditions are supercritical fluids, subcritical water extraction, microwave-assisted treatments, and infrared radiation (Gamboa-Santos et al., 2016).\n\nEmerging technologies can be generally used as drivers of osmotic dehydration efficiency and convective drying in various agroindustrial products. Use of emerging technologies of ultrasound and electrical pulses has been successfully applied to improve the efficiency of osmotic dehydration and drying processes of fruits, vegetables, meat, and tubers such as yams, sweet potatoes, cassava, and potatoes, as well as in some polymeric matrices This generates changes in their structure and makes them more permeable with the consequent reduction in drying time of up to 50% and 70% in some cases depending on their structure, degree of hardness and porosity (Bozkir et al., 2019; Prithani & Dash, 2020; Rahaman et al., 2019; Sakooei-Vayghan et al., 2019; Sharma & Dash, 2019; Li et al., 2020; Allahdad et al., 2018; Feng et al., 2018; Goula et al., 2017; Yu et al., 2018; Dermesonlouoglou et al., 2018; Barman & Badwaik, 2017; Traffano-Schiffo et al., 2016; Yildiz et al., 2016).\n\nFigure 4 presents the statistics of the application of combined ultrasound techniques, electrical pulses, dehydration, and drying of different products from 2008–2021. Use of emerging technologies in the agro-food industry for the dehydration and drying of fruits, vegetables, and tubers, shows a trend in studies, especially since 2016 (Figure 4a). Figure 4b shows that the major investigations have focused on studying the combined use of ultrasound technologies with convective drying and osmotic dehydration. In other studies, use of electrical pulses with osmotic dehydration has been reported. For countries such as China, Poland, Brazil, India, Iran, and Greece (Figure 4c). This demonstrates an open research agenda for studies using emerging technologies alone or in combination in food dehydration and drying processes.\n\nThe study of dehydration and drying of fruits and vegetables, among other products, in the period between 2010–2021 has been framed by the use of techniques combined with the assistance of emerging technologies, resulting in improved energy efficiency and lower the operating cost of the drying process. These findings, added to the volume of research related to drying of fruits and vegetables in recent years, highlight the trend of studies on dehydration prior to conventional drying of various products, mainly fruits and vegetables, supported in turn by emerging technologies.\n\n\nDiscussion\n\nThe high humidity of cassava bagasse makes it a perishable product in which all kinds of microorganisms proliferate, generating decomposition by uncontrolled fermentation, causing bad odors, affecting both, processing plants and surrounding regions, and becoming an environmental problem that must be properly managed. The aforementioned, together with the large volumes of generated waste, have drawn the attention of the scientific community, especially in the last five years. Studies have aimed at finding alternatives for the use of cassava bagasse, which have been orientated towards three main areas: 1) Use in the food industry, 2) Biotechnological applications to generate higher value-added products, and 3) Use as reinforcement material in biomaterials. Nevertheless, the main problem encountered during the management of high-humidity waste such as cassava bagasse is related to handling, storage, transportation, and conservation, a problem further increased due to the daily generation of high production volumes of this residue. So, it is essential that this waste goes through a pre-treatment to eliminate moisture thus reducing its mass and volume to favor handling and preserve the product. In this sense, it is necessary to look for new dehydration or drying alternatives, opening a research agenda aimed at evaluating the application of new technologies or emerging technologies or combinations of these with traditional technologies, which lead to an efficient drying process of cassava bagasse, for exploitation purposes, and promote the cassava starch industry towards a sustainable agroindustry.\n\nThe vast range of alternatives reported in the scientific literature on the use of cassava bagasse and its specific use options in different applications, justify the need to advance in technological innovation research in efficient dehydration and/or drying processes of this agro-industrial by-product. In this regard, it was found that use of emerging ultrasound and electrical pulse technologies in the agrifood industry favor mass and heat transfer processes in osmotic dehydration and drying operations, being a trend of studies especially as of 2016. Despite the fact that these combined techniques have been efficiently applied in osmotic dehydration and drying processes of various products, such as fruits, vegetables, fillets, and tubers including yams, sweet potatoes and potatoes, as well as in some polymer matrices, there is no scientific literature that reports how these technologies sways the efficiency of the osmotic dehydration process and subsequent drying of cassava bagasse and other agro-industrial residues. In this sense, one of the limitations of the scoping review process in this article was to consolidate the search strategy for cassava bagasse, due to the different names that cassava (Manihot esculenta) can have. It is known in different countries with different local names including cassava, aipim, lumu, tapioca, guacamota, casabe or mandioca. In addition, various names are adopted in each country for the residue: cassava bagasse, cassava bran, typyraty or cassava starch bagasse. Therefore, we may not have been able to retrieve all relevant articles on cassava bagasse. Furthermore, by restricting our search to journal articles in English, we may have also excluded relevant research in languages other than English.\n\n\nConclusions\n\nEfficient management of agroindustrial waste to lower its negative environmental externality is among the important challenges for a sustainable industry. Negative externalities generated by the cassava bagasse waste in starch-producing plants have attracted the attention of the scientific community to seek alternative solutions aimed at the sustainable use of this waste in three large areas: biotechnological, food, and biomaterials. Nonetheless, internationally today, the strategies implemented by the cassava starch industry have not been able to relieve the negative externality largely generated by the humidity held in this agroindustrial waste, making it unmanageable and unaffordable for post-industrial purposes. In this sense, technological alternatives are necessary for the efficient drying of cassava bagasse.\n\nEven though studies have been reported that provide alternatives for the use of cassava bagasse, these studies leave unsolved the daily accumulation of large volumes of this residue in the cassava starch plants with the consequent problems of management and environmental pollution. As a result, it is not only important to continue advancing in studies on the use of this residue, but it is also necessary to advance in studies aimed at achieving an efficient drying of this residue that allows its handling and subsequent use and drives the cassava starch industry towards a sustainable agribusiness. In this sense, in recent years, the application of combined techniques of emerging and traditional technologies have been used successfully to achieve efficient dehydration of various products, also becoming an alternative for its application in the efficient drying of cassava bagasse and other agro-industrial residues, especially using those technologies that, due to their simplicity and economy, make their evaluation interesting in these processes.\n\nWith this regard, we have found that osmotic dehydration with the assistance of ultrasound technologies and electrical pulses as a pretreatment for drying fruits, vegetables, and tubers, marks a trend in studies with excellent results in terms of reducing drying time and energy expenditure. This has become an interesting option to be evaluated in the efficiency of drying agro-industrial residues of husks and bagasse among other residues from the extractive food industry that carry a high-water content. Accordingly, it is paramount to review the use of these technologies in supporting the drying of cassava bagasse.\n\nThe follow-up to this article presents a review of the current state of osmotic dehydration technology, alone or assisted by the emerging technologies of ultrasound or electric pulses, applied as a pretreatment to improve the efficiency of the drying operation in various agroindustrial products. The aspects addressed are the effects on the drying process, the related factors or parameters and the operating conditions, the main results, the equipment used, and the products to which this type of combined technology has been applied. The information in Part II of this article provides elements for future research, which may lead to the application of these combined technologies to improve the efficiency of the osmotic dehydration process and drying of new products, by-products, and agroindustrial waste. The findings in Part II will be useful as parameters for the design of the drying process for agroindustrial waste with high moisture content.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nOpen Science Framework: PRISMA checklist and flow chart for ‘Post-industrial context of cassava bagasse and trend of studies towards a sustainable industry: A scoping review – Part I’. https://doi.org/10.17605/OSF.IO/RQTGC (Serpa-Fajardo et al., 2022).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nAbral H, Putra G, Asrofi M, et al.: Effect of Vibration Duration of High Ultrasound Applied to Bio-composite While Gelatinized on its Properties. Ultrason. Sonochem. 2017; 40: 697–702. PubMed Abstract | Publisher Full Text\n\nAdepoju A, Oyewole O: Households’ Perception and Willingness to pay for Bread with Cassava Flour Inclusion in Osogbo Metropolis, Osun State, Nigeria. Invited paper presented at the 4th International Conference of the African Association of Agricultural Economists, September 22-25.2013.\n\nAhmed I, Qazi IM, Jamal S: Developments in osmotic dehydration technique for the preservation of fruits and vegetables. Innov. Food Sci. Emerg. Technol. 2016; 34: 29–43. Publisher Full Text\n\nAjala E, Ajala M, Tijani I, et al.: Kinetics modelling of acid hydrolysis of cassava (Manihot esculanta Cranz) peel and its hydrolysate chemical characterisation. J. King Saud Univ. Sci. 2020; 32: 2284–2292. Publisher Full Text\n\nAlbis Arrieta AR, Ortiz Muñoz E, Piñerez Ariza I, et al.: Análisis de gases desprendidos de residuos industriales de yuca (Manihot esculenta). Inge Cuc. 2018; 14: 113–121. Publisher Full Text\n\nAllahdad Z, Nasiri M, Varidi M, et al.: Effect of sonication on osmotic dehydration and subsequent air-drying of pomegranate arils. J. Food Eng. 2018; 244: 202–211. Publisher Full Text\n\nAraujo-Silva R, Mafra ACO, Rojas MJ, et al.: Maltose Production Using Starch from Cassava Bagasse Catalyzed by Cross-Linked β-Amylase Aggregates. Catalysts. 2018; 8(4): 170. Publisher Full Text\n\nAsrofi M, Abral H, Putra Y, et al.: Effect of duration of sonication during gelatinization on properties of tapioca starch water hyacinth fiber biocomposite. Int. J. Biol. Macromol. 2018; 108: 167–176. PubMed Abstract | Publisher Full Text\n\nBarman N, Badwaik L: Effect of ultrasound and centrifugal force on carambola (Averrhoa carambola L.) slices during osmotic dehydration. Ultrason. Sonochem. 2017; 34: 37–44. PubMed Abstract | Publisher Full Text\n\nBarros F, Ana P, Júnio C, et al.: Potential Uses of Cassava Wastewater in Biotechnological Processes. Agriculture Issues and Policies: Cassava Farming, Uses and Economic Impact. Pace CM, editor. New York, NY, USA: NOVA Science Publishers Inc.; 2012; pp. 33–54. Chapter 2. 978-1-61209655-1\n\nBayata A: Review on Nutritional Value of Cassava for Use as a Staple Food. Sci. J. Anal. Chem. 2019; 7(4): 83–91. Publisher Full Text\n\nBizzuti BE, Faria LD, Da Costa WS, et al.: Potential use of cassava by-product as ruminant feed. Trop. Anim. Health Prod. 2021; 53: 108. Publisher Full Text\n\nBozkir H, Ergünb A, Serdarb E, et al.: Influence of ultrasound and osmotic dehydration pretreatments on drying and quality properties of persimmon fruit. Ultrason. Sonochem. 2019; 54: 135–141. Publisher Full Text\n\nChavadej S, Wangmor T, Maitriwong K, et al.: Separe la producción de hidrógeno y metano de las aguas residuales de yuca con adición de residuo de yuca bajo una temperatura termofílica en relación con la digestibilidad. Revista de Biotecnología. 2019; 291: 61–71.\n\nChen H, Chen B, Su Z, et al.: Efficient lactic acid production from cassava bagasse by mixed culture of Bacillus coagulans and lactobacillus rhamnosus using stepwise pH controlled simultaneous saccharification and co-fermentation. Ind. Crop. Prod. 2020; 146: 112175. Publisher Full Text\n\nChen J, Liu X, Wei D, et al.: High yields of fatty acid and neutral lipid production from cassava bagasse hydrolysate (CBH) by heterotrophic Chlorella protothecoides. Bioresour. Technol. 2015; 191: 281–290. PubMed Abstract | Publisher Full Text\n\nChen Y, Wei X, Chang G, et al.: Study of bagasse/tapioca starch film preparation and characterization. Conf. Series: Earth and Environmental Science. 2017; 69: 012053. Publisher Full Text\n\nChiquito J, Jorge M, Dorini J, et al.: Desarrollo y aceptación de cookies formuladas a partir de envases de Yuca. Archivos de Ciencias de la Salud de Unipar. 2017; 21(3): 193–199. Publisher Full Text\n\nCiurzynska A, Kowalska H, Czajkowska K, et al.: Review Osmotic dehydration in production of sustainable and healthy food. Trends Food Sci. Technol. 2016; 50: 186–192. Publisher Full Text\n\nCoelho B, Mazzarino L, Pitz H, et al.: Development of nanoparticles coated with cassava bagasse pectin (Manihot esculenta Crantz) containing β-carotene for mucoadhesive applications. An. Acad. Bras. Cienc. 2020; 92(4) Publisher Full Text\n\nCorrea J, Rasia M, Mulet A, et al.: Influence of ultrasound application on both the osmotic pretreatment and subsequent convective drying of pineapple (Ananas comosus). Innov. Food Sci. Emerg. Technol. 2017; 41: 284–291. Publisher Full Text\n\nDada A: Taking Local Business to Global Market: The Case for Nigerian Cassava Processing Industry. European Journal of Business and Management. 2018; Vol.10, No.15. ISSN 2222-1905 (Paper) ISSN 2222-2839 (Online)\n\nDe Carvalho J, Borghetti I, Carrilo L, et al.: Biorefinery integration of microalgae production into cassava processing industry: potential and perspectives integración de biorefinería de la producción de microalgas en la industria de procesamiento de yuca: potencial y perspectivas. Bioresour. Technol. 2018; 247: 1165–1172. PubMed Abstract | Publisher Full Text\n\nDe Souza C, Jonathan M, Isay S, et al.: Characterization and in vitro digestibility of by-products from Brazilian food industry: Cassava bagasse, orange bagasse and passion fruit peel. Bioact. Carbohydr. Diet. Fibre. 2018; 16: 90–99. Publisher Full Text\n\nDe Souza P, Garcia P, De Souza S, et al.: Changes in biochemical composition of cassava and beet residues during solid state bioprocess with Pleurotus ostreatus. Biocatal. Agric. Biotechnol. 2020; 26: 101641. Publisher Full Text\n\nDehnad D, Jafari S, Afrasiabi M: Influence of drying on functional properties of food biopolymers: from traditional to novel dehydration techniques. Trends Food Sci. Technol. 2016; 57: 116–131. Publisher Full Text\n\nDermesonlouoglou E, Chalkia A, Dimopoulos G, et al.: Combined effect of pulsed electric field and osmotic dehydration pre-treatments on mass transfer and quality of air-dried goji berry. Innfoo. 2018; 49: 106–115. Publisher Full Text\n\nDiabor E, Paul F, Elsie E: Characterization of Cassava Fiber of Different Genotypes as a Potential Reinforcement Biomaterial for Possible Tissue Engineering Composite Scaffold Application. Fibers Polym. 2019; 20(2): 217–228. Publisher Full Text\n\nDien LQ, Anh K: Nanocellulose Preparation from Cassava Bagasse via Hydrolysis by Sulfuric Acid and Hydrogen Peroxide Medium. J. Jpn. Inst. Energy. 2021; 100: 135–143. Publisher Full Text\n\nEdhirej A, Sapuan S, Jawaid M, et al.: Preparation and Characterization of Cassava Bagasse Reinforced Thermoplastic Cassava Starch. Fibers Polym. 2017; 18(1): 162–171. Publisher Full Text\n\nEkop I, Simonyan K, Evwierhoma E: Utilization of Cassava Wastes for Value Added Products: An Overview. International Journal of Scientific Engineering and Science. 2019; 3(1): 31–39.\n\nEscaramboni B, Fernández E, Azevedo A, et al.: Ethanol biosynthesis by fast hydrolysis of cassava bagasse using fungal amylases produced in optimized conditions. Ind. Crop. Prod. 2018; 112: 368–377. Publisher Full Text\n\nFan K, Zhang M, Mujumdar A: Application of airborne ultrasound in the convective drying of fruits and vegetables: A review. Ultrason. Sonochem. 2017; 39: 47–57. PubMed Abstract | Publisher Full Text\n\nFAO: Food Outlook- Biannual Report on Global Food Markets.2019.\n\nFeng Y, Yu X, Yagoub A, et al.: Vacuum pretreatment coupled to ultrasound assisted osmotic dehydration as a novel method for garlic slices dehydration. Ultrason. Sonochem. 2018; 50: 363–372. PubMed Abstract | Publisher Full Text\n\nFernandes F, Linhares F, Rodrigues S: Ultrasound as pre-treatment for drying of pineapple. Ultrason. Sonochem. 2008; 15: 1049–1054. PubMed Abstract | Publisher Full Text\n\nFerreira D, Molina G, Pelissari F: Biodegradable trays based on cassava starch blended with agroindustrial residues. Composites Part B. 2019; 183: 107682. Publisher Full Text\n\nFiorda F, Soares M, Da Silva F, et al.: Physical quality of snacks and technological properties of pre-gelatinized flours formulated with cassava starch and dehydrated cassava bagasse as a function of extrusion variables. LWT Food Sci. Technol. 2015; 62: 1112–1119. Publisher Full Text\n\nFlorencia V, López O, García M: Exploitation of by-products from cassava and ahipa starch extraction as filler of thermoplastic corn starch. Composites Part B. 2019; 182: 107653. Publisher Full Text\n\nGamboa-Santos J, Rodríguez J, Carvajal G, et al.: Aplicación de tecnologías emergentes al procesamiento de frutas con elevada calidad nutricional. – Una revisión. Revista Colombiana de Investigaciones Agroindustriales. 2016; 3: 57–75. Publisher Full Text\n\nGodoy M, Amorim G, Barreto M, et al.: Chapter 12, Agricultural Residues as Animal Feed: Protein Enrichment and Detoxificatio Using Solid-State Fermentation. Biotechnol. Bioeng. 2018; 235–256. Publisher Full Text\n\nGois IM, Santos AM, Silva CF: Amylase from Bacillus sp. Produced by Solid State Fermentation Using Cassava Bagasse as Starch Source. Braz. Arch. Biol. Technol. 2020; 63: 20170521. Publisher Full Text\n\nGoula A, Kokolaki M, Daftsiou E: Use of ultrasound for osmotic dehydration. The case of potatoes. Food Bioprod. Process. 2017; 105: 157–170. Publisher Full Text\n\nGrande Tovar CD: Valoración Biotecnológica de residuos Agrícolas y Agroindustriales. Universidad de San Buenaventura-Colombia. Editorial Bonaventuriana; 2016. 978-958-8785-81-3.\n\nGrasso S: Extruded snacks from industrial by-products: A review. Trends Food Sci. Technol. 2020; 99: 284–294. Publisher Full Text\n\nHernández H, Moreno L, Villanueva S: Estado actual de las tecnologías emergentes de procesamiento de alimentos en América Latina: novedoso procesamiento no térmico. Innov. Food Sci. Emerg. Technol. 2019; 58: 102233. Publisher Full Text\n\nHidayat B, Hasanudin U, Nurjanah S, et al.: Improvement of Cassava Bagasse flour characteristics to increase their potential use as food. Series: Earth and Environmental. Science. 2018; 209: 012006. Publisher Full Text\n\nHoweler RL, Thomas N, Holst Sanjuán K, et al.: Save and Grow Cassava: A Guide to Sustainable Production Intensification. Roma (Italia): FAO; 2013. Reference Source\n\nHuang J, Du Y, Bao T, et al.: Producción de n-butanol a partir de hidrolizado de bagazo de mandioca mediante ingeniería genética de Clostridium tyrobutyricum que sobreexpresa adhE2: cinética y análisis de costos. Tecnología de fuentes biológicas. 2019; 292: 121969. Publisher Full Text\n\nInguillay S, Jadán F, Maldonado-Alvarado P: Fermentation study of Cassava bagasse starch hydrolyzed's using INIAP 650 and INIAP 651 varieties and a strain of Lactobacillus leichmannii for the lactic acid production. Bionatura Latin American Journal of Biotechnology and Life Sciences. 2021; 6(2): 1803–1811. Publisher Full Text\n\nJohn RP: Biotechnological Potentials of Cassava Bagasse.” Biotechnology for Agro-Industrial Residues Utilisation. Poonam Singh nee’ Nigam, Ashok Pandey Editors.2009; p.225. Publisher Full Text\n\nKaur K, Ahluwalia P: La yuca como cultivo potencial para la industria alimentaria y de fermentación: una revisión. Revista internacional de tecnología de alimentos y fermentación. 2017; 7 (1): 1–12. Publisher Full Text\n\nKeller M, Ambrosio E, De Oliveira V: Polyurethane foams synthesis with cassava waste for biodiesel removal from water bodies. Bioresource Technology Reports. 2020; 10: 100396. Publisher Full Text\n\nKiani H, Karimi F, Labbafi M, et al.: A novel inverse numerical modeling method for the of estimation of water and salt mass transfer coefficients during ultrasonic assisted-osmotic dehydration cucumber cubes. Ultrason. Sonochem. 2018; 44: 171–176. PubMed Abstract | Publisher Full Text\n\nKowalski S, Rybicki A: Ultrasound in wet biological materials subjected to drying. J. Food Eng. 2017; 212: 271–282. Publisher Full Text\n\nKowalski S: Ultrasound in wet materials subjected to drying: A modeling study. Int. J. Heat Mass Transf. 2015; 84: 998–1007. Publisher Full Text\n\nLa Fuente C, Zabalagaa R, Tadinia C: Combined effects of ultrasound and pulsed-vacuum on air-drying to obtainunripe banana flour. Innov. Food Sci. Emerg. Technol. 2017; 44: 123–130. Publisher Full Text\n\nLeite AL, Zanon CD, Menegalli FC: Aislamiento y caracterización de nanofibras de celulosa a partir de bagazo y cáscaras de raíz de yuca. Carbohydr. Polym. 2017; 157: 962–970. PubMed Abstract | Publisher Full Text\n\nLi L, Zhang M, Wang W: Ultrasound-assisted osmotic dehydration pretreatment before pulsed fluidized bed microwave freeze-drying (PFBMFD) of Chinese yam. Food Biosci. 2020; 35: 100548. Publisher Full Text\n\nLi P, Chen Z, Sheng L: Determination of optimum operation conditions in an ultrasound assisted fibrous porous media drying process. Appl. Therm. Eng. 2018; 138: 394–402. Publisher Full Text\n\nLi S, Cui Y, Zhou Y, et al.: The industrial applications of cassava: current status, opportunities and prospects. J. Sci. Food Agric. 2017; 97(8): 2282–2290. PubMed Abstract | Publisher Full Text\n\nLiu L, Chen J, Lim P, et al.: Enhanced single cell oil production by mixed culture of Chlorella pyrenoidosa and Rhodotorula glutinis using cassava bagasse hydrolysate as carbon source. Bioresour. Technol. 2018; 255: 140–148. PubMed Abstract | Publisher Full Text\n\nLobell D, Buerke M, Tebaldi C, et al.: Prioritizing climate change adaptation needs for food security in 2030. Science. 2008; 319(5863): 607–610. PubMed Abstract | Publisher Full Text\n\nLópez O, Versino F, Villar M, et al.: Agroindustrial residues from Pachyrhizus ahipa starch extraction as filler for thermoplastic corn starch films. Carbohydr. Polym. 2015; 134: 324–332. PubMed Abstract | Publisher Full Text\n\nLópez-Pedrouso M, Díaz-Reinoso B, Lorenzo J, et al.: Green technologies for food processing: Principal considerations. Innovative Thermal and Non-Thermal Processing. 2019; 55–103. Publisher Full Text\n\nLuchese C, Garrido T, Spada J, et al.: Development and characterization of cassava starch films incorporated with blueberry pomace. Int. J. Biol. Macromol. 2018; 106: 834–839. PubMed Abstract | Publisher Full Text\n\nManimala M, Murugesan R: Studies on physiochemical analysis and applicability of carotenoid pigment production from rhodotorula mucilaginosa as food colourant. Int. J. Agricult. Stat. Sci. 2017; 13(2): 507–511.\n\nMaría M, Martha L, Juan E: Use of Cassava (Manihot Esculenta Crantz) and Other Starchy. Revista Colombiana de Ciencias Pecuarias. 2012; 25(3): 488–499.\n\nMartinez D, Feiden A, Bariccatti R, et al.: Ethanol Production from Waste of Cassava Processing. Appl. Sci. 2018; 8: 2158. Publisher Full Text\n\nMorales E, Zajul M, Goldman M, et al.: Effects of Solid-State Fermentation and the Potential Use of Cassava By-products as Fermented Food. Waste and Biomass Valorization. 2018; 11: 1289–1299. Publisher Full Text\n\nMoreno-Vilet L, Hernández-Hernández H, Villanueva-Rodríguez S: Current status of emerging food processing technologies in Latin America: Novel thermal processing. Innfoo. 2018; 50: 196–206. Publisher Full Text\n\nMusielak G, Mierzwa D, Kroehnke J: Food drying enhancement by ultrasound - A review. Trends Food Sci. Technol. 2016; 56: 126–141. Publisher Full Text\n\nNeal RH, Pritchard CC, McGuinness LA: PRISMA2020: R package and ShinyApp for producing PRISMA 2020 compliant flow diagrams. Zenodo. 2021. Publisher Full Text\n\nNowacka M, Fijalkowska A, Wiktor A, et al.: Influence of power ultrasound on the main quality properties and cell viability of osmotic dehydrated cranberries. Ultrasonics. 2018; 83: 33–41. PubMed Abstract | Publisher Full Text\n\nOECD y FAO: La Perspectiva Agrícola 2020-2029.2020. 1999-1142\n\nOlukanni D, Agunwamba J, Abalogu R: Interaction between suspended and settled solid particles in cassava wastewater. Sci. Res. Essay. 2013; 8: 414–424. Publisher Full Text\n\nOlukanni DO, Olatunji TO: Cassava Waste Management and Biogas Generation Potential in Selected Local Government Areas in Ogun State, Nigeria. Recycling. 2018; 3(4): 58. Publisher Full Text\n\nOmilani O, Abass A, Okoruwa V: Willingness to Pay for Value-Added Solid Waste Management System among Cassava Processors in Nigeria.2015. Reference Source\n\nOrtuño C, Pérez-Munuera I, Puig A, et al.: Influence of power ultrasound application on mass transport and microstructure of orange peel during hot air drying. Phys. Procedia. 2010; 3: 153–159. Publisher Full Text\n\nOtekunrin OA, Sawicka B: Cassava, a 21st Century Staple Crop: How Can Nigeria Harness Its Enormous Trade Potentials. Acta Scientific Agriculture. 2019; 3(8): 194–202. Publisher Full Text\n\nOyewole M, Eforuoku F: Value Addition on Cassava Wastes among Processors in Oyo State Nigeria. J. Agric. Ext. 2019; 23(3): 135–146. Publisher Full Text\n\nOzoegwu CG, Eze C, Onwosi CO, et al.: Biomass and bioenergy potential of cassava waste in Nigeria: Estimations based partly on rural-level garri processing case studies. Renew. Sust. Energ. Rev. 2017; 72: 625–638. Publisher Full Text\n\nPayá J, Monzó J, Borrachero MV, et al.: Bagasse ash. Woodhead Publishing; 2018; 559–598. Publisher Full Text\n\nPereira L, Mattos C, Ferreira F, et al.: Milk production and economic assessment of cassava bagasse in the feed of dairy cows. Anim. Sci. 2015; 37(3): 307–313. Publisher Full Text\n\nPinheiro K, Watanabeb L, Nixdorf S, et al.: Cassava bagasse as a substrate to produce cyclodextrins. Starch-Journals. 2018; 70: 11–12. Publisher Full Text\n\nPolachini T, Leonardo L, Lopes-Filho J, et al.: Water adsorption isotherms and thermodynamic properties of cassava bagasse. Thermochim. Acta. 2016; 632: 79–85. Publisher Full Text\n\nPrithani R, Dash K: Mass transfer modelling in ultrasound assisted osmotic dehydration of kiwi fruit. Innov. Food Sci. Emerg. Technol. 2020; 64: 102407. Publisher Full Text\n\nProsapio V, Norton I: Influence of osmotic dehydration pre-treatment on oven drying and freeze-drying performance. LWT Food Sci. Technol. 2017; 80: 401–408. Publisher Full Text\n\nRahaman A, Zeng X, Kumari A, et al.: Influence of ultrasound-assisted osmotic dehydration on texture, bioactive compounds and metabolites analysis of plum. Ultrason. Sonochem. 2019; 58: 104643. PubMed Abstract | Publisher Full Text\n\nRamya V, Jain N: A review on osmotic dehydration of fruits and vegetables: An integrated approach. J. Food Process Eng. 2017; 40(3): 12440. Publisher Full Text\n\nRibeiro G, Silva G, De Matos Jorge L, et al.: Cassava bagasse as a reinforcement agent in the polymeric blend of biodegradable films. J. Appl. Polym. Sci. 2018; 136: 12. Publisher Full Text\n\nRicce C, Rojas M, Miano A, et al.: Ultrasound pre-treatment enhances the carrot drying and rehydration. Food Res. Int. 2016; 89: 701–708. PubMed Abstract | Publisher Full Text\n\nRodríguez E, Polania L, Lorenzo G: Efecto del bagazo seco de yuca sobre las propiedades de cocción del pan de trigo compuesto. J. Texture Stud. 2016; 48(1): 76–84. Publisher Full Text\n\nRodriguez J, Torregroza A, Salgado R: Kinetics of mass transfer during osmotic dehydration of auyama (Caribbean pumpkin) in ternary solutions. DYNA. 2019; 86(209): 120–125. Publisher Full Text\n\nRomero R, Alcívar E, Alpizar J: Afrecho de yuca como sustituto parcial del maíz en la alimentación de cerdos de engorde. La Técnica: Revista de Las Agrociencias. 2017; 54–61. 2477-8982 54–61. Edición especial. Publisher Full Text\n\nSakooei-Vayghan R, Hadi Peighambardoust S, Hesari J, et al.: Effects of osmotic dehydration (with and without sonication) and pectin-based coating pretreatments on functional properties and color of hot-air dried apricot cubes. Food Chem. 2019; 311: 125978. PubMed Abstract | Publisher Full Text\n\nSalcedo J, Contreras K, Garcia A, et al.: Modeling of drying kinetics of cassava baggase (Manihot esculenta Crantz). Revista Mexicana de Ingeniería Química. 2016; 15(3): 883–891. Publisher Full Text Reference Source\n\nSemenoglou I, Dimopoulos G, Tsironi T, et al.: Mathematical modelling of the effect of solution concentration and the combined application of pulsed electric fields on mass transfer during osmotic dehydration of sea bass fillets. Food Bioprod. Process. 2020; 121: 186–192. Publisher Full Text\n\nSerpa-Fajardo J, Hernández-Ramos E, Fernández-Lambert G, et al.: Post-industrial context of cassava bagasse and trend of studies towards a sustainable industry. Open Science Framework. 2022. Publisher Full Text\n\nSharma M, Dash K: Effect of ultrasonic vacuum pretreatment on mass transfer kinetics during osmotic dehydration of black jamun fruit. Ultrason. Sonochem. 2019; 58: 104693. PubMed Abstract | Publisher Full Text\n\nSharmila G, Muthukumaran C, Manoj N, et al.: Current Developments in Biotechnology and Bioengineering. Chapter 12, Food waste valorization for biopolymer production.2020; 233–249. Publisher Full Text\n\nSiddhartha GVAO, Costa Marcia N, Jonas C; Biotechnological Potential of Cassava Residues: Peel, Bagasse and Wastewater. Pace CM, editor. Agriculture Issues and Policies: Cassava Farming, Uses and Economic Impact. New York: Nova Science publishers Inc.; 2012; 4. : 79–98. 978-1-62081-698-19\n\nSilviana S, Brandon P, Silawanda B: Preparación de película biodegradable a base de almidón de bagazo de yuca reforzada con gelatina de pollo, ácido cítrico como reticulante y glicerol como plastificante. Indonesian J. Chem. 2018; 18(4): 688–695. Publisher Full Text\n\nSivamani S, Chandrasekaran A, Balajii M, et al.: Evaluation of the potential of cassava-based residues for biofuels production. Rev. Environ. Sci. Biotechnol. 2018; 17: 553–570. Publisher Full Text\n\nSouza E, Rupert S, Lopes A, et al.: Ultrasound-assisted vacuum drying of nectarine. J. Food Eng. 2019; 246: 119–124. Publisher Full Text\n\nSugiharto S: A review on fungal fermented cassava pulp as a cheap alternative feedstuff in poultry ration. Journal of World’s Poultry Research. 2019; 9: 01–06. Publisher Full Text\n\nSujithra B, Deepika S, Akshaya K, et al.: Production and optimization of xanthan gum from three-step sequential enzyme treated cassava bagasse hydrolysate. Biocatal. Agric. Biotechnol. 2019; 21: 101294. Publisher Full Text\n\nTraffano-Schiffo M, Tylewicz U, Castro-Giraldez M, et al.: Effect of pulsed electric fields pre-treatment on mass transport during the osmotic dehydration of organic kiwifruit. Innov. Food Sci. Emerg. Technol. 2016; 38: 243–251. Publisher Full Text\n\nTeixeira ED, Pasquini D, Curvelo A, et al.: Cassava bagasse cellulose nanofibrils reinforced thermoplastic cassava starch. Carbohydr. Polym. 2009; 78: 422–431. Publisher Full Text\n\nTrakarnpaiboon S, Srisuk N, Piyachomkwan K, et al.: Enhanced production of raw starch degrading enzyme using agro-industrial waste mixtures by thermotolerant Rhizopus microsporus for raw cassava chip saccharification in ethanol production. Prep. Biochem. Biotechnol. 2017; 47 (8): 813–823. PubMed Abstract | Publisher Full Text\n\nTravalini A, Lamsal B, Esteves W, et al.: Cassava starch films reinforced with lignocellulose nanofibers from cassava bagasse. Int. J. Biol. Macromol. 2019; 139: 1151–1161. PubMed Abstract | Publisher Full Text\n\nTricco AC, Lillie E, Zarin W, et al.: PRISMA Extension for Scoping Reviews (PRISMAScR): Checklist and Explanation. Ann. Intern. Med. 2018; 169: 467–473. PubMed Abstract | Publisher Full Text\n\nTroy D, Ojha K, Kerry J, et al.: Sustainable and consumer-friendly emerging technologies for application within the meat industry: Anoverview. Meat Sci. 2016; 120: 2–9. PubMed Abstract | Publisher Full Text\n\nUbalua AO: Residuos de Yuca: Opciones de Tratamiento y Valor Añadido Alternativas. Revista Africana de Biotecnología. 2007; 6(18): 2065–2073.\n\nVargas Y, Pérez L: Aprovechamiento de residuos agroindustriales para el mejoramiento de la calidad del ambiente. Revista Facultad de Ciencias Básicas. 2018; 14(1): 59–72. Publisher Full Text\n\nVera Y, Ordoñes V, Aponte A: Ultrasonido en el procesamiento (homogenización, extracción y secado) de alimentos. Biotecnología en el Sector Agropecuario y Agroindustrial: BSAA. 2018; 16(1): 102–113. Publisher Full Text\n\nVersino F, García M: Efecto de distribución del tamaño de partícula sobre los biocompuestos de almidón de yuca y bagazo de yuca. ACS Sustain. Chem. Eng. 2019; 7: 1052–1060. Publisher Full Text\n\nVieira E, Lins L, Batista R, et al.: Influence of ultrasound and vacuum assisted drying on papaya quality parameters. LWT Food Sci. Technol. 2018; 97: 317–322. Publisher Full Text\n\nWali Y, Sriherwanto C, Yunita E, et al.: Growth of nile tilapia (oreochormis niloticus) fry fed with coconut testa-cassava bagasse mixed substrate fermented using rhizopus oryzae. J. Bioteknol. Biosains. Indones. 2017; 4(1): 1–9.\n\nWiktor A, Dadan M, Nowacka M, et al.: The impact of combination of pulsed electric field and ultrasound treatment on air drying kinetics and quality of carrot tissue. LWT Food Sci. Technol. 2019; 110(2019): 71–79. Publisher Full Text\n\nXue C, Zhao J, Chen L, et al.: Recent advances and state-of-the-art strategies in strain and process engineering for biobutanol production by Clostridium acetobutylicum. Biotechnol. Adv. 2017; 35(2): 310–322. PubMed Abstract | Publisher Full Text\n\nYildiz H, Icier F, Eroglu S, et al.: Effects of electrical pretreatment conditions on osmotic dehydration of apple slices: Experimental investigation and simulation. Innov. Food Sci. Emerg. Technol. 2016; 35: 149–159. Publisher Full Text\n\nYu Y, Jin T, Fan X, et al.: Biochemical degradation and physical migration of polyphenolic compounds in osmotic dehydrated blueberries with pulsed electric field and thermal pretreatments. Food Chem. 2018; 239: 1219–1225. PubMed Abstract | Publisher Full Text\n\nZainuddin IM, Fathoni A, Sudarmonowati E, et al.: Cassava Post-Harvest Physiological Deterioration: From Triggers to Symptoms. Postharvest Biol. Technol. 2017; 142: 115–123. Publisher Full Text\n\nZakariyah RF, Ojo MO, Ajijolakewu KA, et al.: Optimisation of Lactic Acid Fermentation from Cassava Peel by Lactobacillus casei (ATCC334). Microbiol. Res. J. Int. 2021; 31(6): 29–42. Publisher Full Text\n\nZanatta ER, Reinehr TO, Awadallak JA, et al.: Kinetic studies of thermal decomposition of sugarcane bagasse and cassava bagasse. J. Therm. Anal. Calorim. 2016; 125(1): 437–445. Publisher Full Text\n\nZhang M, Xie L, Xin Z, et al.: Biorefinery approach for cassava-based industrial wastes: current status and opportunities. Bioresour. Technol. 2016; 215: 50–62. PubMed Abstract | Publisher Full Text\n\nZhang Y, Abatzoglou N: Review: fundamentals, applications and potentials of ultrasound-assisted drying. Chem. Eng. Res. Des. 2019; 154: 21–46. Publisher Full Text\n\nZheng Y, Xue S, Zhao Y, et al.: Effect of Cassava Residue Substituting for Crushed Maize on in vitro Ruminal Fermentation Characteristics of Dairy Cows at Mid-Lactation. Effect of Cassava Residue Substituting for Crushed Maize on in vitro Ruminal Fermentation Characteristics of Dairy Cows at Mid-Lactation. Animals. 2020; 10(5): 893. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "139181",
"date": "16 Sep 2022",
"name": "Eduardo Martínez-Mendoza",
"expertise": [
"Reviewer Expertise Sustainable development",
"Complex Systems"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis work is important because studied an actual problem, and the authors have justified it within the work. The relevance of this work is that identifies technologies that could be applied to improve waste cassava bagasse management. PRISMA method is appropriate for this work. The research contributes to proposing using current technological solutions on vegetables or fruit to reduce cassava bagasse externalities.\nThe paper developed correctly the PRISMA methodology and has reviewed vast and recent decade literature from important databases, that they have classified and categorized adequately.\nThe results are relevant and systematically presented according to the research method.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "152452",
"date": "21 Dec 2022",
"name": "Fernando Salazar Arrieta",
"expertise": [
"Reviewer Expertise Humanitarian logistics",
"agrifood security",
"strategic planning logistics",
"financial logistics",
"reverse logistics."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIt is an interesting and current topic in the post-pandemic reality. It represents an interesting analysis for companies and the new way in which they are called to operate in the business and business context, given the current circumstances of uncertainty and more so in the field of agribusiness and by-products.\nThe methodological development of the article complies with the theme, from the approach to the problem, the approach to the solution, the analysis of the results and the conclusions.\nThe topic is topical, which guarantees an additional contribution or analysis that particularly contributes to the productive sector once the Pandemic has been overcome, which has led to a global crisis and local repercussions. For these reasons I have given the final concept that it be indexed with minor adjustments in the part indicated in the evaluation.\nFrom here it is important to consider that new studies arise based on strengthening the productive sector of small and medium enterprises that suffer most of the impacts.\nAs additional comments, I wish to expand the reasons why I consider that the article represents a topic of interest to be indexed. Both the topic addressed and the object of study, which are small and medium-sized companies, make this article work as a basis or source of analysis for these companies. Also, it presents interesting elements to be considered by companies and incorporated into their management or administration plans in the current post-pandemic circumstances, where high levels of uncertainty flood the reality of most or all of the world's countries and economies, which suggests elements so that companies see them as tools that allow them to operate in the markets, trying not to be affected to a greater extent, assigns to the article that I have reviewed the conditions and characteristics of a work of interest to the academic community and to the productive sector, even more supportive.\nFrom the methodological point of view, the article meets the standards of the Journal and scientific rigor for its indexing, evidenced from the problem, materials and methods, conclusions and references for the investigation.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-562
|
https://f1000research.com/articles/11-27/v1
|
11 Jan 22
|
{
"type": "Research Article",
"title": "An empirical examination of customer advocacy influenced by engagement behaviour and predispositions of FinTech customers in India",
"authors": [
"Archana Nayak Kini",
"Savitha Basri",
"Archana Nayak Kini"
],
"abstract": "Background: The extensive adoption and usage of emerging technologies furthered by the global coronavirus disease 2019 (COVID-19) pandemic, has reduced direct face to face communications. New FinTech (financial technology) apps and technologies are flooding the Indian digital payments market and competitors are striving hard to attract and retain their customers. Especially when customer engagement behaviours (CEBs) are digital in nature, it is essential to gauge the intrinsically driven customer motivations which drive a positive CEB. The objective of this paper was to empirically test the influence of customer-based antecedents such as emotions, moral identity, self-concept, communal focus, perceived cost and perceived benefits on non-transactional experiential customer engagement behaviours (CEBs) and CEB’s effect on customer advocacy in the FinTech industry. Methods: Data from 380 financial app users in south India were gathered by administering a survey that captured customer predispositions, CEBs, and customer advocacy. Structural equation modelling (SEM) using smart PLS (partial least squares) 3.0 was applied to test the theoretical model. Results: Results indicate that CEB fully mediates the relationship between self-concept and customer advocacy. The positive CEBs get formed through customer predispositions leading to referral/advocacy behaviours. Conclusions: This paper provides directions for FinTech practitioners, marketers, technologists, and academicians to devise marketing strategies customized to customer needs and factors. This is one of the first research studies to demonstrate and empirically validate the CEB model for the FinTech industry during the COVID-19 pandemic.",
"keywords": [
"customer engagement behaviour",
"customer advocacy",
"e-word-of-mouth",
"emotions",
"perceived benefits",
"self-concept",
"FinTech",
"technology enabled services"
],
"content": "Introduction\n\nSince the liberalization of the financial services industry in India in the 1990s and the global financial crisis in 2008, the financial sector has undergone a series of changes and reforms. In India, the passage of the information technology (IT) Act of 2000 provided much-needed momentum to financial technology (FinTech) operations by establishing legal validity. With increased internet usage, the reduction of entry hurdles, and the easing of regulations, the post-crisis period from 2010 saw a tremendous rise in the use of financial technology (Feyen et al., 2021). FinTech firms provide financial services on digital platforms by combining innovative business models and advanced technologies such as artificial intelligence (AI), social media, data analytics and robotics acting as enablers. FinTech is setting a new paradigm in the design and delivery of financial products and services through alternative channels (Lee & Shin, 2018). The key service offerings emerging on digital platforms in India include peer-to-peer (P2P) lending services such as Lendbox, Shiksha Financial, payment services such as Google pay, PhonePe, Paytm, BHIM, personal advisory services such as FundsIndia.com, Scripbox, PolicyBazaar, and BankBazaar, among others (Cyrill, 2018). India's digital payment is predicted to comprise 2.2% of the world's payments which is poised to reach $12.4 trillion in another 3 to 5 years (Payments Council of India and PWC Report, 2020). The coronavirus disease 2019 (COVID-19) pandemic has ushered in a new era of contactless mobile banking. Retail payments in India through various digital channels rose from $37.7 billion in financial year (FY) 2018-19 to $48.35 billion in FY 2020-21 (1 US$ = Rs 74.25, 03 August 2021) and mobile phone usage for banking operations in India grew from 61% in 2017 to 87% in 2021 (RBI, 2021). India along with China accounts for the highest FinTech adoption rate of 87% compared to the global adoption rate which is at 64% (Ernst & Young, 2017). An increase in the adoption of FinTech solutions was due to the COVID-19 pandemic. In emerging and developing markets such as India, FinTech has helped expand access to affordable financial services to the common masses in times of lockdown and social distancing (RBI, 2021).\n\nFinTech is prompting drastic changes in the way financial transactions - especially payments and advisory services - are perceived, marketed and consumed (Mention, 2021). The most significant result of FinTech is that it has shifted the focus on customer's convenience and needs with anytime, anywhere banking, breaking down the time and distance barriers that traditional banking imposes. Consumers are also finding it easier to browse around and switch service providers in search of more product options, greater features, lower prices, or discounts. Customers, on the other hand, are perplexed because the market is swamped with services and products from a variety of providers. Additionally, unlike traditional banking techniques, FinTech is perceived as sophisticated and thus difficult to use by older cohorts who are not tech-savvy. As a result, it has become incredibly challenging for FinTech firms to manage consumer demands, establish or retain a customer base, and hence obtain a competitive advantage.\n\nCan gaining a certain level of customer advocacy help FinTech firms beat the competition in this emerging and dynamic market? Can customers be motivated to interact positively with other customers by nurturing their self-concept, emotional states of mind and pre-dispositions? Also, can achieving a certain level of engagement with the FinTech brand ensure customers endorse the products and services and become its advocates? It has been observed over the years that a services firm can gain a competitive advantage by retaining, sustaining and nurturing its customer base (Anderson et al., 2004) by looking beyond the repurchase behaviour. Digital and social media with their richer media not only help firms to connect but also communicate information and emotions to their immediate customers and also between customers (Sashi, 2012). Hence customer-to-customer (C2C) interactions help companies promote brand advocacy by listening and learning about customers’ needs, influencing them through social media ‘thought leaders’ and also considering customer opinions (Constantinides & Fountain, 2008).\n\nCustomization, personalization efforts, and systems that engage with customers are known to affect favourable e-WOM(e-word of mouth), reviews and testimonials. To personalise, it is useful to know consumers' channel preferences, breadth of engagement, time, effort, and money spent, as well as the kind of activities they engage in. These can then predict the intensity of their referrals and product reuse (van Doorn et al., 2010). In a COVID-19 world, where all these engagement behaviours are digital, interactive, brand centred and non-transactional, it becomes essential to gauge the intrinsically driven customer motivations. Customers’ helping behaviour where they guide other customers with useful suggestions or solve a problem, or customers’ sense of community could aid them in engaging with the brand. The emotions of happiness, anger, contentment, or disgust can motivate a desirable or an undesirable customer engagement behaviour (CEB) or a referral, working as a differentiator amidst competition. Establishing emotional connections with customers can build trust and in turn assist these firms to face several challenges and intense competition in the FinTech industry.\n\nThe goal of this quantitative study is to empirically test the conceptual model on the influence of customer-based predispositions on non-transactional CEBs, and its strength in predicting the resultant advocacy behaviours in the emerging FinTech industry especially in covid pandemic times. The study sample were FinTech app customers who use Google Pay, PhonePe and so on for payment services and BankBazaar, PolicyBazaar for advisory services. The results of this study may guide marketing managers to formulate robust segmentation, positional strategies in line with the emotional, self-concept and individual needs so that they engage positively with the brand. Customer engagement and advocacy behaviours gained from these campaigns can help the companies to build and retain the competitive edge in the market.\n\n\nLiterature review\n\nService-Dominant (SD) logic in the light of relationship marketing theory attempts to know the significance of customer-to-customer (C2C) relational and referral behaviours in developing and maintaining loyalty and advocacy. The customer engagement framework in this study endorses Oliver's (1999) theory elaborating the belief-attitude-behaviour formation. In addition, social exchange theory (SET) proposes that customers display positive thoughts, feelings or behaviours towards a product or brand in reciprocation to specific benefits from the brand (Blau, 1964). CEBs arising through these processes help in spreading positive word-of-mouth (Oliver, 1999), thus advancing the underlying theories and also inspiring a future research agenda in this direction.\n\nIn a technology-intensive financial services sector, the use of new information and technologies has led to a reduction in direct physical contact with the customer. The online customer communities facilitate customers to have an open dialogue to understand and solve their problems mutually, thus effectively engaging with the brand community. This has changed the traditional roles of a buyer and a seller in such exchange relationships. Thus, customers create and share content and thus intangibly advocate the product and service value to other customers, influencing their purchase decisions. Customer advocacy is a natural side-effect of the forces that create a strong service provider-customer relationship and is a dominant pointer of repeat buying (Fullerton, 2011). An investment in the brand from an experiential approach consisting of CEBs determines customer advocacy (van Doorn et al., 2010; Moliner et al., 2018).\n\nCEB denotes firm or brand centred behaviours that go beyond transactions but have positive or negative manifestations depending on the motivational drivers of the customer and are measured by valence (positive or negative), form/modality, scope (temporal and geographic), choice of channel and customer goals (van Doorn et al., 2010). The form/modality component depicts ways in which customers express their engagement based on time and money resources available at their disposal. The scope encompasses customers’ extra-role behaviours such as providing product-related feedback helping the company improve the product or develop new products (van Doorn et al., 2010; Kumar & Pansari, 2016). Customers' social media influence (CSMI) embodies C2C conversations over social media channels sharing their views on product benefits, thus influencing other customers of the brand community positively (Kumar & Pansari, 2016). Customers' choice of the channel such as communication via phone, in-person, in a retail setting or via the internet (email/website) can impact the CEB in terms of immediacy, intensity, length and breadth of CEB (van Doorn et al., 2010). CEBs are those non-purchase C2C behaviours where the customers influence the development of the firm's offering, brand identity through knowledge, skills, opinions, recommendations, online reviews and referrals on their own accord making it a part of experiential marketing (Jaakkola & Alexander, 2014). Studies show that customer dialogue and engagement mediates the relation between emotionally connected satisfied customers and advocacy behaviours (Moliner-Tina et al., 2019). As per Figure 1, CEB is a mediator and it is primarily motivated by customers’ pre-dispositions and which can predict customer behaviour defined by referrals and advocacy.\n\nThere is a relationship between customer engagement behaviour (CEB) and customer advocacy.\n\nCustomer predispositions are the customer-based factors, mainly the individual traits and predispositions of customers which influence the product, brand decisions and CEBs (van Doorn et al., 2010). Levy and Hino (2016) and Bhat and Darzi (2016) substantiated that emotional and relational elements influence a bank's relation with customers rather than a purely transactional approach leading to bank advocacy. It was discovered that emotional states such as anger, regret, disgust towards the company or the brand can result in CEBs and customers' accumulated emotional experiences turning into actions and behaviours (Bagozzi et al., 1999; Martin et al., 2008) and positive emotions generate positive CEBs and vice versa. Emotional connections with customers help in exhibiting the desirable CEB working as a differentiator amidst competition (Garg et al., 2005; Levy & Hino, 2016). A quantitative study observed that the emotional dimension of engagement has a positive effect on advocacy intention as well as the intention to reuse mobile payment services compared to the cognitive dimension of engagement which only influences advocacy intention (Glavee-Geo et al., 2019).\n\nThere is a relationship between emotions and CEB.\n\nThere is a relationship between emotions and customer advocacy.\n\nSelf-concept is defined as a “desire for positive recognition by others”. Moral identity is similar to self-identity and manifests in helping behaviour. The greater the moral identity of a customer, the more is the engagement behaviour with the brand and more likely is the helping behaviour. Customers who displayed a higher value for self-concept tend to warn other customers from negative product experiences or recommend installing the right application thus exhibiting a high degree of CEBs (Hennig-Thurau et al. 2004). Similarly, customers with helping behaviour tend to participate in blogging or co-promote the brand with which they are involved (Sundaram et al. 1998). Customers who are emotionally linked to brands symbolizing their self-concept are more inclined to champion the brand and disseminate favourable information about the product. They are thus less likely to be lured by competitors, are less difficult to persuade to stay, and are more eager to recommend the product (Grisaffe & Nguyen, 2011; Jayasimha & Billore, 2016).\n\nThere is a relationship between self-concept and CEB.\n\nThere is a relationship between self-concept and customer advocacy.\n\nThere is a relationship between moral identity and CEB.\n\nThere is a relationship between moral identity and customer advocacy.\n\nCommunal focus is the behaviour where the people belonging to a particular community are likely to voice their support for their community during difficult times (He et al., 2008). It was revealed that a strong agentic focus is likely to be displayed by the female gender while they voice their negative WOM or advocacy. The motivations for involving in positive e-WOM may vary from the impulses which drive a negative e-WOM as evident in communal focus (van Doorn et al., 2010).\n\nThere is a relationship between communal focus and CEB.\n\nThere is a relationship between communal focus and customer advocacy.\n\nPerceived cost and benefits are the perception by the customer related to the time, effort and money involved in buying and recommending the brand or product vis-à-vis the returns sought. Based on the perceived benefits and cost of engagement, the customer may engage in specific behaviours such as blogging or participation in online discussion forums or making donations to brand-related charity which has been defined as the form and modality of engagement (van Doorn et al., 2010).\n\nThere is a relationship between perceived cost and CEB.\n\nThere is a relationship between perceived benefits and CEB.\n\n\nMethods\n\nWritten informed consent was obtained from all survey participants before administering the survey questionnaire. The content of the form started with the information sheet introducing the research objectives, its outcomes and implications before getting respondents’ informed written consent. It contains statements on confirming that the data collected would be used for research and publication purposes keeping any personal details confidential (see Extended data, (Nayak Kini & Basri, 2021c)). In addition, approval from the Manipal Institute of Management ethics committee was received for this empirical study in the Indian Fintech industry.\n\nPositivism philosophy was adopted for this study which helps to inquire the customers' emotions, attitudes and actions related to their app engagement scientifically and objectively. A cross-section of app users were initially chosen for the survey using a convenience sampling method and later this initial sample of app users helped to snowball their contacts who became the next set of respondents. The prevailing theories of engagement and exchange acted as a basis to understand the different phenomenon assisting in deductively formulating the various hypotheses to be tested for the theoretical model.\n\nThe survey questionnaire used a 5-point Likert scale adapted from several researchers such as Levy and Hino (2016) to capture customers’ overall perceptions about self-concept, van Doorn et al. (2010) for communal focus, Hennig-Thurau et al. (2004) for moral identity, Hayashi and Bradford (2014) for perceived cost and Moliner et al. (2018), Kumar and Pansari (2016), for CEBs, and Moliner et al. (2018) and Han et al. (2008) for advocacy concerning the specific apps they were using. For emotions, a 7-point Likert scale was used which was adapted from Wong (2004). The survey can be found as Extended data (Nayak Kini & Basri, 2021b).\n\nThe universe for the study sample comprised of the customers of major FinTech payment and advisory applications such as Google Pay, PhonePe, Amazon Pay, BHIM, PayTM, BankBazaar, Policy Bazaar, and others in Karnataka located in southern region of South India. A pilot pretest with 38 respondents was conducted before administering the survey to a larger sample size during November 2020 and March 2021. A pilot pre-test is a trial run conducted before the final run for administering the survey. The pilot pretest conducted helps to identify any problems which might be encountered during the administration of the survey for data collection and find possible solutions before proceeding for the final study. The pre-test tried to gauge certain research design issues such as whether the respondents clearly understood the wording of the questions and also the time taken by the respondent to answer the whole questionnaire. The size of the sample for the pilot study was taken to be 10% of the sample size for the final study with sample size calculated to be 380 (formula below). The participants of the pilot test were chosen based on convenience sampling strategy but the initial criteria were that they had to belong to a city in Karnataka and also be using any of the above financial apps. We found out from the study that few questions and wording were hard for the respondents to understand, hence this helped to simplify the wording of few questions for the final study.\n\nWe had an initial contact list of participants chosen in the same way as that of the pilot study. These respondents were sent an unsolicited email introducing them to the survey and asking for their written consent. Once they provided the consent, the online survey link was shared with them and at the end of the survey, they were also asked to refer their contacts who used any of the FinTech apps. Thus, they helped refer their contacts’ email ids as well as the phone numbers. This new group of people referred more people from their network with a snowball effect. This process was iterated until the final targeted sample size of 420 was reached. Response bias occurs when individuals respond to a survey leading to misrepresentation of their true value due to reasons such as social desirability and a set pattern of questions while filling. Response bias can also develop when the researcher's intent and the respondent's comprehension are not in sync. By using reversely coded, neutrally phrased, and brief questions, as well as avoiding leading questions, response bias was avoided.\n\nBecause the data was collected using a single survey instrument, there was a chance that common method variance (CMV) would occur (Podsakoff and Organ, 1986). Harmon’s single-factor test was carried out in the software IBM SPSS 26.0 to assess CMV. From the exploratory factor analysis of the data related to CEB, four components such as form/modality, scope, customers’ social media influence (CSMI) and the choice of channel, emerged which together define the CEB. Thus CEB became the formative second-order construct formed by the four reflective first-order constructs which were validated by literature review.\n\nIn terms of digital payments, Karnataka had the greatest adoption rate (26.64%), followed by Maharashtra (15.92%), and Delhi NCR (13%). Hence, Karnataka was picked as the geographical area based on this information. The tentative final sample size was calculated to be 382 customers using the formula:\n\nAfter adding 10% to the calculated sample size to accommodate non-response errors, the target sample size was 420.\n\nThe sample was measured for sample adequacy using the KMO test and Bartlett’s Test of Sphericity using IBM SPSS 26.0. A principal component analysis was conducted to ascertain patterns in data and to condense the variables to a more manageable level. Based on the criterion of Kaiser (1960), all factors with eigenvalues 1 or greater than 1 were retained. It was observed that KMO values for all constructs involved in this model were ≥ 0.5 (Cerny & Kaizer, 1977) indicating that factor analysis is an appropriate method for further data analysis. Structural equation modelling (SEM) stating the path model and estimation of various quality parameters was analysed and reported using the Smart PLS 3.00 software, abiding by the latest guiding principles on Partial Least Squares (Hair et al., 2013; Henseler et al., 2012). First, the measurement model was evaluated to check the reliability and validity of various constructs. Smart PLS 3.0 software was used to validate and analyze this hierarchical reflective-formative model of CEB through the disjoint two-stage approach. The relevance of the hypothesised associations between the constructs was then determined using the structural model. Alternatively, JASP which is an open-source PLS 3 software can be used to undertake SEM using lavaan R package based on a covariance-based approach.\n\n\nResults\n\nOut of the 420 responses, it was found that 25 responses had incomplete responses and 15 other responses had a straight-lining pattern, hence 40 responses were discarded and 380 responses remained to be analysed (Nayak Kini & Basri, 2021a). Almost 46% of respondents were found to use Google Pay, 17% each were found to use Phonepe and PayTM followed by Yono (SBI), Imobile (ICICI), BHIM and the others (fig 2). Almost 55% were males and 45% females and half of this sample population were in the age group of 25-40 years (millennials) earning anywhere between $1-$13,468 per year (1 US$ = Rs 74.25, 03 August 2021). The educational background of more than half of the sample (57%) was found to be postgraduates (Table 1).\n\nFirst, the lower-order constructs were taken into consideration and reliability and validity of the constructs were calculated for the reflective measurement models (refer to Table 2) For reliability, Cronbach’s alpha and composite reliability were checked and for validity, convergent validity and discriminant validity were assessed. Cronbach's α value for each construct is well above the threshold limit of α ≥ 0.70 (Henson, 2001). Convergent validity was found to be acceptable as the average variance extracted (AVE) was greater than 0.5. Indicator reliability for each indicator was observed to be 0.70 or higher and was found acceptable (Hulland, 1999). Discriminant validity was assessed by heterotrait-monotrait (HTMT) ratio of correlation (Henseler et al., 2015), with values below the threshold of 0.9 acceptable. Multi-collinearity of each construct was checked where variance inflation factor (VIF) values were found to be below 5 hence they are moderately correlated and are not evidenced to create any issue. The assessment of the measurement model substantiated that all the construct measures are reliable and valid.\n\nThe latent scores of the four lower-order constructs of CEB were added to the data set before running stage two. Here the four latent variable constructs acted as the indicators of the higher-order construct CEB. The measurement model of the formative higher-order construct (HOC) CEB was validated by running the bootstrapping procedure with 5000 samples. The outer weights were checked for significance, here the outer weight of FM (form/modality) was < 0.5 and that of scope, CSMI and channel were below 0.5, hence the outer loading was then checked which was > 0.5 and was thus found to be significant.\n\nThe structural model was assessed using the principal measure of assessment which is the coefficient of determination R2 (Henseler et al., 2012). The high R2 value of 0.465 for customer engagement behaviour and 0.495 for customer advocacy signifies that almost 46.5% of the variance in CEB is explained by its antecedents which are emotions, self-concept, communal focus, perceived cost and benefits. Also, half of the variance in customer advocacy is explained by CEB. The high R2 values thus substantiate the model's predictive validity. The model fit indices were checked. SRMR value is 0.068 which is < 0.10 or 0.08 (Hu and Bentler, 1999) and NFI (normed fit index) of 0.668 represents an acceptable fit. RMS_theta is 0.104 which is well below the threshold value of 0.12.\n\nThe direct and indirect effects of various constructs were analyzed. The path-coefficient ‘β’ of a path, its t statistics, p-value, effect size f2 and whether hypotheses on direct paths are supported or not are outlined in Table 3. In terms of variables having the highest influence on CEB suggested by path-coefficient, self-concept has the highest influence on CEB (β = 0.366) followed by communal focus (β = 0.184), perceived benefits (β = 0.118) and emotions (β = 0.110). The f2 values signify the effect sizes of the path. The path self-concept> CEB has the highest f2 value 0.145 followed by communal focus (f2 = 0.095), perceived benefits (f2 = 0.023), suggesting a small effect and emotions with an f2 value of 0.019 suggesting that there is no effect of emotions on CEB’s R2.\n\nCEB, communal focus and emotions are found to have a significant effect on customer advocacy as suggested by path coefficients 0.303, 0.279 and 0.198 respectively and the effect sizes f2 values of 0.098, 0.095 and 0.065 respectively. Again, based on the t and p-value, moral identity has an insignificant effect both on CEB and customer advocacy whereas perceived cost has an insignificant effect on CEB.\n\nThe mediator CEB necessitates the need for checking the significance of indirect effects for the model. The indirect effect of self-concept on customer advocacy is the highest, followed by the communal focus and perceived benefits as suggested by the t and the p values as well as the path coefficients in Table 4. However, there is no significant indirect influence of perceived cost, moral identity or emotions on customer advocacy.\n\nCustomer engagement behaviour fully mediates the relationship between self-concept and customer advocacy (CA) as the direct relation between them is insignificant whereas the indirect relation is significant. CEB partially mediates the path between perceived benefits and CA with a VAF (variance accounted for) = 0.306 (30.6%), the path communal focus and CA with a VAF = 0.166 (16.6%). CEB does not mediate the other paths such as emotions -> CA, perceived cost -> CA or moral identity -> customer advocacy.\n\n\nDiscussion\n\nIn the FinTech industry, the extensive usage of innovative technology has drastically reduced the direct face-to-face customer communications requiring experiential elements to be cherished. Our study result empirically suggests that CEBs displayed by e-WOM (e-word of mouth) behaviour are predominantly experiential and result in non-transactional outcomes such as advocacy. Study results show self-concept has a direct effect on CEB supporting the Levy and Hino (2016) study which encourages social media conversations based on a sense of brand belongingness. Self-concept also shows an indirect effect on advocacy that is fully mediated by CEB. This means that customers with a positive self-concept associated with the product tend to advocate the product only if they are engaged positively. Thus, managers need to focus on identifying and nurturing the self-concept of their customers where customers identify themselves with the brand, for them to engage. This can be achieved by having individual 'thought leaders' whose opinions on products are followed by the customers to make buying or usage decisions. Customers' product benefit perceptions can engage customers positively but cost perceptions of the FinTech transaction do not inspire them to propagate any e-WOM to their brand community.\n\nThe study results show that the emotional dimension of engagement has a direct positive effect on both engagement and advocacy (e-WOM). If emotions are positive, customers tend to experience a positive CEB or recommend the product to other customers in their social media community thus being favourable to the company, validating the previous studies by Garg (2005) and Levy and Hino (2016). If emotions are negative customers end up with negatively valenced CEB making customers less likely to recommend products. This also confirms previous studies on negative emotions linked to disengagement (van Doorn et al., 2010). Study results suggest customers' propensity to help others does not result in e-WOM or a referral campaign refuting previous studies by Sundaram (1998) and van Doorn et al. (2010).\n\nOur study propositions companies to design and build the products and applications to address customer needs. Companies now need to invest in creating unique engaging experiences accommodating customers' perceptions on product benefits, their inherent communal focus, self-concept and emotional needs in mind for them to engage and promote the brand to others turning them into advocates. FinTech firms need to primarily have platforms and social media channels that nurtures C2C interactions, reviews, and testimonials favourable for the FinTech brands and companies. The companies can inspire improved perceptions on product benefits by implementing necessary mechanisms that make the transactions safer, faster, smoother, and more convenient. In addition, FinTech companies should incorporate innovative features, deals and offers customised to the past app user behaviour and the market needs. Moreover, it becomes essential not to hurt the communal feelings of the product community giving way to any unfavourable CEB such as a negative WOM. This implies that brands need to be focused and sensitive to the needs of community groups, which otherwise can turn into a negative engagement affecting a larger customer base.\n\nThis empirical study authenticates the role of CEB as a mediator fully mediating the relationship path self-concept -> customer advocacy and partially mediating the relationship paths perceived benefits -> customer advocacy and communal focus -> customer advocacy. Correspondingly, it assists practitioners to devise suitable and personalised segmentation or promotional strategies for various marketing campaigns.\n\nThis paper provides directions for marketing managers, e-marketers, technologists, academicians, and practitioners of engagement marketing in the FinTech industry. It guides the managers on how best to engage customers through self-concept, emotional connect and by suitably managing customer predispositions so that they display positive advocacy behaviours (reviews/testimonials). These insights may help the firms to enhance personalization and digital engagement in real-time and improve customer experience by responding to customer needs through co-created offerings. The knowledge of the factors which motivate customers to engage or disengage and prevailing customers’ level of engagement/disengagement may help in designing a robust classification and segmentation strategy. Hence, this study principally assists FinTech managers on the ways to devise and implement the right marketing strategy based on various customer needs leading to continued advocacy behaviours.\n\nThe data collected for this quantitative study was from the financial app users of the southern region of India alone, hence it may limit the external validity of its results. The respondents used an online form to share their responses during lockdown causing a biased response due to COVID-19. Also, since the study was purely quantitative, it would have failed to capture other dynamic and subjective ideas of engagement behaviour in this ever-evolving, emerging FinTech industry which would have been possible with a mixed-method approach involving both quantitative and qualitative techniques.\n\nThe study could be simulated for other service industries such as e-commerce, healthcare, education, tourism, media and entertainment which dwell on non-transactional behaviours. As observed, there are different types of CEBs such as e-WOM, referrals, reviews, recommendations, testimonials, and blogging, with CEBs being specific to the particular industry. Correspondingly, paths of customer predispositions>CEB>customer advocacy in this model for the FinTech industry can be studied with certain demographic variables as the moderators. Similar to customer predispositions influencing engagement and advocacy behaviours, a positive recommendation and e-WOM could trigger positive emotions, communal focus, self-concept or cost/benefit perceptions and make the customer engage with the brand. This circular nature of relationships is a promising new area for future research. Studies with various population groups and cultures, for firm-based, and context-based factors apart from customer-based factors is also a great possibility. A qualitative approach to understanding CEBs for a specific industry or a population group may prove insightful. A longitudinal study of CEBs may be desirable as the customers’ perceptions keep evolving with time as new products and technologies emerge. Moreover, future studies could also explore these C2C interactions in different product or market settings where the nature of the precursors to customer advocacy may be altered.\n\n\nConclusion\n\nIt is observed that the emerging financial services companies are continuing to digitise and technologically disrupt. Especially, during the COVID-19 pandemic, as the adoption of technology-enabled contactless financial services rises, it becomes vital to meet the increasing customer expectations by assisting them in making correct choices and accomplishing customer goals. Apart from that, firms need to individualise, engage, and personalise the offerings to stand out in the ever-growing competition. The study results indicate that a highly pre-dispositional customer possessing a high self-concept reciprocate positive e-WOM only when they are engaged with the financial application created through online influencer strategies. The positive CEBs get formed through self-concept, communal focus, emotions and perceived benefits related to the product helping to build advocacy behaviours. Results also indicate that emotions alone can directly influence advocacy for the FinTech industry. Thus, the emerging and competitive FinTech industry survives only if the emotionally connected customers, whose self-concept, communal focus and perceptions on product benefits are aligned with that of the companies demonstrating long-term brand engagement advocacy behaviours.\n\n\nData availability\n\nMendeley Data: Raw data CSV processed for use in smartPLS-Fintech India-customer predispositions-engagement-advocacy behaviour. https://doi.org/10.17632/5j6csksgb4.5 (Nayak Kini & Basri, 2021a).\n\nMendeley Data: Survey form - Fintech India Customer predispositions-Engagement-Advocacy. https://doi.org/10.17632/dfxjk69h8m.4 (Nayak Kini & Basri, 2021b).\n\nMendeley Data: Information sheet and written consent form - FinTech India. https://doi.org/10.17632/njz464h8f8.1 (Nayak Kini & Basri, 2021c).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAnderson EW, Fornell C, Mazvancheryl SK: Customer satisfaction and shareholder value. J. Mark. 2004; 68(4): 172–185. Publisher Full Text\n\nBagozzi RP, Gopinath M, Nyer PU: The role of emotions in marketing. J. Acad. Mark. Sci. 1999; 27(2): 184–206. Publisher Full Text\n\nBhat SA, Darzi MA: Customer relationship management. Int. J. Bank Mark. 2016; 34(3): 388–410. Publisher Full Text\n\nBlau PM: Justice in Social Exchange. Sociol. Inq. 1964; 34: 193–206. Publisher Full Text\n\nCerny CA, Kaiser HF: A study of a measure of sampling adequacy for factor-analytic correlation matrices. Multivar. Behav. Res. 1977; 12(1): 43–47. PubMed Abstract | Publisher Full Text\n\nConstantinides E, Fountain SJ: Web 2.0: Conceptual foundations and marketing issues. J. Direct Data Digit. Mark. Pract. 2008; 9(3): 231–244. Publisher Full Text\n\nCyrill M: Future of Fintech in India – Opportunities and Challenges, India Briefing. 2018, November 27. Reference Source\n\nErnst & Young: EY FinTech Adoption Index- The rapid emergence of FinTech. 2017. Reference Source\n\nFullerton G: Creating advocates: The roles of satisfaction, trust and commitment. J. Retail. Consum. Serv. 2011; 18(1): 92–100. Publisher Full Text\n\nFeyen E, Frost J, Gambacorta L, et al.: BIS Papers No 117 Fintech and the digital transformation of financial services: implications for market structure and public policy. 2021. Reference Source\n\nGarg N, Inman JJ, Mittal V: Incidental and task-related affect: a re-inquiry and extension of the influence of affect on choice. J. Consum. Res. 2005; 32(1): 154–159. Publisher Full Text\n\nGlavee-Geo R, Shaikh AA, Karjaluoto H, et al.: Drivers and outcomes of consumer engagement. Int. J. Bank Mark. 2019; 38(1): 1–20. Publisher Full Text\n\nGrisaffe DB, Nguyen HP: Antecedents of emotional attachment to brands. J. Bus. Res. 2011; 64(10): 1052–1059. Publisher Full Text\n\nHair JF, Hult GTM, Ringle CM, et al.: A Primer on Partial Least Squares Structural Equation Modeling (PLS-SEM). Thousand Oaks: Sage; 2013.\n\nHan X, Kwortnik RJ Jr, Wang C: Service loyalty: An integrative model and examination across service contexts. J. Serv. Res. 2008; 11(1): 22–42.\n\nHayashi F, Bradford T: Mobile payments: Merchants’ perspectives. Econ. Rev. 2014; 99: 5–30.\n\nHe X, Inman JJ, Mittal V: Gender jeopardy in financial risk taking. J. Mark. Res. 2008; 45(4): 414–424. Publisher Full Text\n\nHennig-Thurau T, Gwinner KP, Walsh G, et al.: Electronic word-of-mouth via consumer-opinion platforms: what motivates consumers to articulate themselves on the internet?. J. Interact. Mark. 2004; 18(1): 38–52. Publisher Full Text\n\nHenseler J, Ringle CM, Sarstedt M: Using partial least squares path modeling in advertising research: basic concepts and recent issues. Handbook of research on international advertising. 2012; 252. Publisher Full Text\n\nHenseler J, Ringle CM, Sarstedt M: A new criterion for assessing discriminant validity in variance-based structural equation modelling. J. Acad. Mark. Sci. 2015; 43(01): 115–135. Publisher Full Text\n\nHenson RK: Understanding internal consistency reliability estimates: A conceptual primer on coefficient alpha. Meas. Eval. Couns. Dev. 2001 Oct 1; 34(3): 177–189. Publisher Full Text\n\nHulland J: Use of partial least squares (PLS) in strategic management research: A review of four recent studies. Strateg. Manag. J. 1999; 20(2): 195–204. Publisher Full Text\n\nJaakkola E, Alexander M: The role of customer engagement behavior in value co-creation: a service system perspective. J. Serv. Res. 2014; 17(3): 247–261. Publisher Full Text\n\nJayasimha KR, Billore A: I complain for your good? Re-examining consumer advocacy. J. Strateg. Mark. 2016; 24(5): 360–376. Publisher Full Text\n\nKaiser HF: The application of electronic computers to factor analysis. Educ. Psychol. Meas. 1960; 20(1): 141–151. Publisher Full Text\n\nKumar V, Pansari A: Competitive advantage through engagement. J. Mark. Res. 2016; 53(4): 497–514. Publisher Full Text\n\nLee I, Shin YJ: Fintech: Ecosystem, business models, investment decisions, and challenges. Bus. Horiz. 2018; 61(1): 35–46. Publisher Full Text\n\nLevy S, Hino H: Emotional brand attachment: a factor in customer-bank relationships. Int. J. Bank Mark. 2016; 34(2): 136–150. Publisher Full Text\n\nMartin D, O'neill M, Hubbard S, et al.: The role of emotion in explaining consumer satisfaction and future behavioural intention. J. Serv. Mark. 2008; 22(3): 224–236. Publisher Full Text\n\nMoliner-Tena MA, Monferrer-Tirado D, Estrada-Guillén M: Customer engagement, non-transactional behaviors and experience in services: A study in the bank sector. Int. J. Bank Mark. 2019; 37(3): 730–754. Publisher Full Text\n\nMoliner MÁ, Monferrer-Tirado D, Estrada-Guillén M: Consequences of customer engagement and customer self-brand connection. J. Serv. Mark. 2018; 32(4): 387–399. Publisher Full Text\n\nMention AL: The age of FinTech: Implications for research, policy and practice. The Journal of FinTech. 2021; 01(01): 2050002. Publisher Full Text\n\nNayak Kini A, Basri S: Raw data CSV processed for use in smartPLS-Fintech India-customer predispositions-engagement-advocacy behaviour. Mendeley Data. 2021a; V5. Publisher Full Text\n\nNayak Kini A, Basri S: Survey form - Fintech India Customer predispositions-Engagement-Advocacy. Mendeley Data. 2021b; V4. Publisher Full Text\n\nNayak Kini A, Basri S: Information sheet and written consent form - FinTech India. Mendeley Data. 2021c; V1. Publisher Full Text\n\nOliver RL: Whence Consumer Loyalty?. J. Mark. 1999; 63(Special Issue): 33–44. Publisher Full Text\n\nPayments Council of India: Empowering payments: Digital India on the path of revolution. 2020. Reference Source\n\nPodsakoff PM, Organ DW: Self-reports in organizational research: Problems and prospects. J. Manag. 1986; 12(4): 531–544.\n\nRBI Bulletin: FinTech: The Force of Creative Disruption: RBI. (Accessed 11 November, 2021). Reference Source\n\nSashi CM: Customer engagement, buyer-seller relationships, and social media. Manag. Decis. 2012; 50(2): 253–272. Publisher Full Text\n\nSundaram DS, Mitra K, Webster C: Word-of-mouth communications: A motivational analysis. ACR North American Advances. 1998; 25: 527–531.\n\nvan Doorn J, Lemon KN, Mittal V, et al.: Customer engagement behavior: theoretical foundations and research directions. J. Serv. Res. 2010; 13(5): 253–266. Publisher Full Text\n\nWong A: The role of emotional satisfaction in service encounters. Managing Service Quality: An International Journal. 2004; 14(5): 365–376. Publisher Full Text"
}
|
[
{
"id": "119411",
"date": "27 Jan 2022",
"name": "Naveen Kumar K",
"expertise": [],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nWhile the number of FinTechs in India is on the rise to tap business opportunities emerging from the Covid-19 pandemic, the task before them is how to become friendlier to customers. In this regard, the paper aims at empirically testing the influence of customer-based antecedents such as emotions, moral identity, self-respect, customer focus, perceived cost, and product benefits for marketing. The paper considers major FinTechs operating in Karnataka State and concludes based on analysis of responses to the structured questionnaire from 380 customers from the same region. The paper employs Structural Equation Modeling using Smart Partial Least Square 3.0 to test the hypotheses. Results discussed in the paper are quite interesting, logically convincing, and practically oriented. Based on the study results, antecedents statistically found significant for engagement of customers include product benefits perception, self-respect, emotional contact, and customer predispositions.\n\nQ1. Is the work clearly and accurately presented and does it cite the current literature?\n\nYes, the research findings are clearly and accurately discussed in the paper. The author deserves appreciation in mentioning a large number of earlier studies on the related aspects of the subject and setting the hypotheses in continuation of findings of the same. Among the customer-based antecedents mentioned in the paper, it is suggested to examine the relationship between safety & security on one hand and customer advocacy on the other, based on the responses received from the respondents. This suggestion is made, taking into account the increasing number of frauds in online financial dealings in India. To elaborate, the share of suspected digital fraud attempts against financial services businesses increased by 89 percent during January-May, 2021.Therefore, the author is suggested to mention the importance of safety in FinTech dealings in the paper, which would be one of the considerations of customers. To know more about the current concerns relating to frauds in FinTech business, the author may go through these references: 1, 2, 3, 4\nQ2. Is the study design appropriate and is the work technically sound?\nYes, the study design seems to be appropriate and the work technology is also sound. One more consideration should be made regarding the sample design. Currently, digital payment is limited largely to the population in urban and metro areas. Therefore, there is a felt need to increase the penetration of FinTech to the vast sections of the population which is unbanked and lacks a smartphone. Towards this end, the author may discuss the location of 380 respondents into Metro and Urban and Semi-urban and Rural and analyse responses accordingly. Quite likely, expectations of the customers from FinTech shall vary from one area to another.\nQ3. Are sufficient details of methods and analysis provided to allow replication by others?\n\nYes. But, it is suggested to mention the following aspects in the paper::\nMajor contents of the questionnaire\n\nRegarding the selection of FinTechs, the Payment Banks are not considered. But, this bank has now more than 5 crores customers. Therefore, the reason for not including the same should be stated.\n\nDetails of the profession of the respondents in the sample should be shared in the paper, since the use of FinTech varies from fixed income group users to business income group users.\n\nQ4. If applicable, is the statistical analysis and its interpretation appropriate?\n\nStatistical analysis and interpretation are very much appropriate and impressive. Statistical tools/tests are also in line with the earlier studies referred to in the paper. Two suggestions are made relating to analysis and interpretation:\nThe significance of each statistical tool/test stated in the paper shold be explained in simple terms for the benefit of the readers and,\n\nThe paper should state whether it attempts to make any change in the statistical tools as employed in the earlier studies.\n\nQ5. Are all the source data underlying the results available to ensure full reproducibility?\nYes. Future work may be looked into the interaction between primary and secondary analysis.\n\nQ6. Are the conclusions drawn adequately supported by the results?\n\nThe author deserves full appreciation for carrying out the extensive statistical analysis to test the hypotheses. The results of the analysis are almost in line with the earlier studies. Findings of the study make a significant contribution to the existing fund of knowledge.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8267",
"date": "23 May 2022",
"name": "Archana Nayak Kini",
"role": "Author Response",
"response": "Q1. Is the work clearly and accurately presented and does it cite the current literature? Yes, the research findings are clearly and accurately discussed in the paper. The author deserves appreciation in mentioning a large number of earlier studies on the related aspects of the subject and setting the hypotheses in continuation of findings of the same. Among the customer-based antecedents mentioned in the paper, it is suggested to examine the relationship between safety & security on one hand and customer advocacy on the other, based on the responses received from the respondents. This suggestion is made, taking into account the increasing number of frauds in online financial dealings in India. Q1 Answer: The purview of our study is exclusively for a sample of customers who have adopted online payments using apps such as GooglePay, PhonePe, BHIM which is one of the broader offerings under FinTech. Other offerings include peer to peer lending, virtual currency such as cryptos and NFTs (non-fungible tokens), insurance as mentioned in the articles 1, 2, 3, 4 related to the online frauds in the FinTech industry. The security and fraud detection related to the online payments are already being managed using face recognition, AI (Artificial Intelligence) and ML (Machine Learning) (Tekkali & Vijaya, 2021). The Fraud Detection System allows one to detect illegal actions and malicious behaviours and efforts before they cause major damage to the firm and customers (Gupta & Jhamb, 2020; Samet, 2013). Online payments’ system design, architecture, authentication mechanisms and algorithms being system level factors which manage the security and privacy requirements are extrinsic in nature and are not considered for this study. This exclusion has been included as a research limitation of the study. The main focus thus is on the intrinsic factors of the customers such as emotions, their perceptions about product cost & benefits, their moral identity, self-concept and communal focus. These factors were identified from literature as they were predominantly influencing customer engagement behaviours in the tech-enabled financial services (Van Doorn et al., 2010. CEB (Customer Engagement Behaviour) is a behavioural construct that is primarily non-transactional in nature and goes beyond purchases and financial transactions. It is proven that emotional and behavioural factors, rather than a simply transactional strategy, influence a bank's relationship with consumers, resulting in bank advocacy (Levy & Hino, 2016; Bhat & Darzi, 2016). Q2. Is the study design appropriate and is the work technically sound? Yes, the study design seems to be appropriate and the work technology is also sound. One more consideration should be made regarding the sample design. Currently, digital payment is limited largely to the population in urban and metro areas. Therefore, there is a felt need to increase the penetration of FinTech to the vast sections of the population which is unbanked and lacks a smartphone. Towards this end, the author may discuss the location of 380 respondents into Metro and Urban and Semi-urban and Rural and analyse responses accordingly. Quite likely, expectations of the customers from FinTech shall vary from one area to another. Q2 Answer: On examining the sample, it is observed that 38% of the population is from urban, 46% from semi-urban areas, about 11% from metros and only about 3% from rural areas. As the majority of the sample population i.e. 84% is in semi-urban and urban, data analysis of this paper also demonstrates the expectations and behaviours of these customers. Therefore, future studies can focus on rural areas. The location of the sample is incorporated in the ‘Results’ section of the paper. Q3. Are sufficient details of methods and analysis provided to allow replication by others? Yes. But, it is suggested to mention the following aspects in the paper. Major contents of the questionnaire -Q3 >1 >Answer: The survey questionnaire used a 5-point Likert scale adapted tools from several researchers such as Levy and Hino (2016) to capture customers’ overall perceptions about self-concept having 5 items, van Doorn et al. (2010) for communal focus with 3 items, Hennig-Thurau et al. (2004) for moral identity having 4 items, Hayashi and Bradford (2014) for perceived cost having 3 items, perceived benefits having 6 items and Moliner et al. (2018), Kumar and Pansari (2016), for CEBs having 18 items, and Moliner et al. (2018) and Han et al. (2008) for advocacy concerning the specific apps they were using and having 5 items. For emotions, a 7-point Likert scale having 4 items which was adapted from Wong (2004) was used. The survey questionnaire can be found as ‘Extended data’ (Nayak Kini & Basri, 2021b).The number of items in the scale for each construct has been incorporated in the paper. Regarding the selection of FinTechs, the Payment Banks are not considered. But, this bank has now more than 5 crores customers. Therefore, the reason for not including the same should be stated. Q3> 2> Answer: Payment banks (PB) are a model of banks introduced to achieve financial inclusion in a cashless economy back in 2015. They accept cash deposits from customers which is stored in digital wallets and used for payments and remittances, but they do not offer loans and credits unlike traditional banks. The services targeted migrant labour, low income households, farmers, small businesses and other users in mind. Unfortunately, lower adoption rate was observed in lower income groups due to lack of awareness, low level of trust and lesser perceived need for these services (Pramani & Iyer, 2022). The PBs have continued to incur losses which have risen through 2017 till 2020 with the net consolidated loss as on March 2020 to be at INR 833 crores (RBI, 2020). On the other hand, based on the various research reports, FinTech adoption rate has been constantly rising and it was the highest for India surpassing China (Ernst & Young, 2021). Indian states such as Karnataka saw the highest rate of 26.64%, followed by Maharashtra (15.92%), and Delhi NCR (13%) (Razorpay, 2020). In terms of digital payments, post COVID-19 disease outbreak, PhonePe, Googlepay, Policybazaar and other similar financial apps were extensively adopted and used contributing to an exponential trend unlike payment banks (RBI 2021). Hence the purview of the study included only these app-oriented behaviours which are non-transactional in nature. Details of the profession of the respondents in the sample should be shared in the paper, since the use of FinTech varies from fixed income group users to business income group users. Answer to Q3>3: The study considered majorly the fixed income group individuals with only about 7% of the sample population being business income users. The moderation analysis considering occupation as the moderator did not show any differences between these two groups of users. We have excluded the write-up on this analysis for brevity of the paper. Q4. If applicable, is the statistical analysis and its interpretation appropriate? Statistical analysis and interpretation are very much appropriate and impressive. Statistical tools/tests are also in line with the earlier studies referred to in the paper. Two suggestions are made relating to analysis and interpretation: The significance of each statistical tool/test stated in the paper should be explained in simple terms for the benefit of the readers and, The paper should state whether it attempts to make any change in the statistical tools as employed in the earlier studies. Q4> 1> Answer : The sample was measured for sample adequacy using the KMO test and Bartlett’s Test of Sphericity using IBM SPSS 26.0. Structural equation modelling (SEM) stating the path model and estimation of various quality parameters was analysed and reported using the Smart PLS 3.00 software, abiding by the latest guiding principles on Partial Least Squares (Hair et al., 2013; Henseler et al., 2012). First, the measurement model was evaluated to check the reliability using cronbach’s alpha and composite reliability. Cronbach's α value for each construct is well above the threshold limit of α ≥ 0.70 (Henson, 2001). Indicator reliability for each indicator was observed to be 0.70 or higher and was found acceptable (Hulland, 1999). For validity, convergent validity and discriminant validity were assessed. Convergent validity was found to be acceptable as the average variance extracted (AVE) was greater than 0.5. Indicator reliability for each indicator was observed to be 0.70 or higher and was found acceptable (Hulland, 1999). Discriminant validity was assessed by heterotrait-monotrait (HTMT) ratio of correlation (Henseler et al., 2015), with values below the threshold of 0.9 acceptable. Multi-collinearity of each construct was checked where variance inflation factor (VIF) values were found to be below 5 hence they are moderately correlated and are not evidenced to create any issue. The structural model was assessed using the principal measure of assessment which is the coefficient of determination R2 (Henseler et al., 2012). The high R2 value of 0.465 for customer engagement behaviour and 0.495 for customer advocacy signifies that almost 46.5% of the variance in CEB is explained by its antecedents which are emotions, self-concept, communal focus, perceived cost and benefits.The high R2 values substantiate the model's predictive validity. The model fit indices were checked. SRMR value is 0.068 which is < 0.10 or 0.08 (Hu and Bentler, 1999) and NFI (normed fit index) of 0.668 represents an acceptable fit. RMS_theta is 0.104 which is well below the threshold value of 0.12. The hypotheses were tested by analysing the direct and indirect effects. The significance of the path was tested using the path co-efficient, p-value and t stats of the paths in the model. Similarly, the mediation effects and the level of partial mediation was measured using the VAF (Variance accounted for) value which is the amount of direct effect divided by the amount of the total effect (direct effect + indirect effect). The formula for VAF has been updated in the version 2 of the paper. Q4> 2> Answer: The study does not attempt to make any change in the statistical tool but adapts the scales for different constructs from several researchers. Q5. Are all the source data underlying the results available to ensure full reproducibility? Yes. Future work may be looked into the interaction between primary and secondary analysis. Answer to Q5: Sure, that can be one of the potential future studies. Q6. Are the conclusions drawn adequately supported by the results? The author deserves full appreciation for carrying out the extensive statistical analysis to test the hypotheses. The results of the analysis are almost in line with the earlier studies. The findings of the study make a significant contribution to the existing fund of knowledge. References Tekkali, C. G., & Vijaya, J. (2021, August). A Survey: Methodologies used for Fraud Detection in Digital Transactions. In 2021 Second International Conference on Electronics and Sustainable Communication Systems (ICESC) (pp. 1758-1765). IEEE. Samet, O. (2013). Introduction to online payments risk management. \" O'Reilly Media, Inc.\". Gupta, N., & Jhamb, D. (2020). How India can develop its payments fraud prevention model: A study of emerging best practices. Journal of Payments Strategy & Systems, 14(3), 237-255"
}
]
},
{
"id": "135480",
"date": "06 May 2022",
"name": "Prashant Kumar",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper is well written - it follows the structure of a standard journal article, starting with introduction, literature review, method, results and discussion. It explains the research gaps and discusses at the end how the study addressed the gaps. The analysis is extensive and results are well-presented.\n\nPlease address following comments:\nWrite hypotheses in cause and effect format e.g. emotions have a positive effect on CEB.\n\nIn measurement scales, write how many items each scale contained.\n\nIn sample size, include how many respondents were contacted and how many responded and thus what was the response rate.\nThank you.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8268",
"date": "23 May 2022",
"name": "Archana Nayak Kini",
"role": "Author Response",
"response": "Thank you for your review comments. Please find my point by point responses below. Q1. Write hypotheses in cause and effect format e.g. emotions have a positive effect on CEB. Answer: This has been revised as per suggestions and has been incorporated in the version 2 of the paper H1: There is a relationship between customer engagement behaviour (CEB) and customer advocacy. Changed to H1: Customer engagement behaviour positively impacts customer advocacy. H2: There is a relationship between emotions and CEB. Changed to H2: Emotions have a positive effect on CEB H3: There is a relationship between emotions and customer advocacy. Changed to H3: Emotions have a positive influence on customer advocacy. H4: There is a relationship between self-concept and CEB Changed to H4: Self-concept impacts CEB positively. H5: There is a relationship between self-concept and customer advocacy. Changed to H5: Self-concept impacts customer advocacy positively. H6: There is a relationship between moral identity and CEB. Changed to H6: Moral Identity influences CEB in a positive manner. H7: There is a relationship between moral identity and customer advocacy. Changed to H7: Moral Identity inspires customer advocacy in a positive manner. H8: There is a relationship between communal focus and CEB. Changed to H8: Presence of communal focus is positively associated with CEB. H9: There is a relationship between communal focus and customer advocacy. Changed to H9: Customer advocacy responds positively to moral identity. H10: There is a relationship between perceived cost and CEB. Changed to H10: CEB is positively influenced by perceived cost. H11: There is a relationship between perceived benefits and CEB. Changed to H11: CEB is positively motivated by perceived benefits. Q2: In measurement scales, write how many items each scale contained. Answer: The survey questionnaire used a 5-point Likert scale adapted from several researchers such as Levy and Hino (2016) to capture customers’ overall perceptions about self-concept having 5 items, van Doorn et al. (2010) for communal focus with 3 items, Hennig-Thurau et al. (2004) for moral identity having 4 items, Hayashi and Bradford (2014) for perceived cost having 3 items, perceived benefits having 6 items and Moliner et al. (2018), Kumar and Pansari (2016), for CEBs having 18 items, and Moliner et al. (2018) and Han et al. (2008) for advocacy concerning the specific apps they were using and having 5 items. For emotions, a 7-point Likert scale having 4 items which was adapted from Wong (2004) was used. The survey can be found as Extended data (Nayak Kini & Basri, 2021b). The number of items have been updated in the version 2 of the paper as well. Q3. In sample size, include how many respondents were contacted and how many responded and thus what was the response rate. Answer: We contacted 450 respondents and 420 of them responded with a response to complete the survey. Thus the response rate was (420/450) *100 = 93% Response rate has been updated in the Methods>Data Collection section of the paper as well."
}
]
}
] | 1
|
https://f1000research.com/articles/11-27
|
https://f1000research.com/articles/10-1144/v1
|
11 Nov 21
|
{
"type": "Research Article",
"title": "A Machine Learning Approach to Predictive Modelling of Student Performance",
"authors": [
"Hu Ng",
"Azmin Alias bin Mohd Azha",
"Timothy Tzen Vun Yap",
"Vik Tor Goh",
"Azmin Alias bin Mohd Azha",
"Timothy Tzen Vun Yap",
"Vik Tor Goh"
],
"abstract": "Background - Many factors affect student performance such as the individual’s background, habits, absenteeism and social activities. Using these factors, corrective actions can be determined to improve their performance. This study looks into the effects of these factors in predicting student performance from a data mining approach. This study presents a data mining approach in identify significant factors and predict student performance, based on two datasets collected from two secondary schools in Portugal. Methods – In this study, two datasets collected from two secondary schools in Portugal. First, the data used in the study is augmented to increase the sample size by merging the two datasets. Following that, data pre-processing is performed and the features are normalized with linear scaling to avoid bias on heavy weighted attributes. The selected features are then assigned into four groups comprising of student background, lifestyle, history of grades and all features. Next, Boruta feature selection is performed to remove irrelevant features. Finally, the classification models of Support Vector Machine (SVM), Naïve Bayes (NB), and Multilayer Perceptron (MLP) origins are designed and their performances evaluated. Results - The models were trained and evaluated on an integrated dataset comprising 1044 student records with 33 features, after feature selection. The classification was performed with SVM, NB and MLP with 60-40 and 50-50 train-test splits and 10-fold cross validation. GridSearchCV was applied to perform hyperparameter tuning. The performance metrics were accuracy, precision, recall and F1-Score. SVM obtained the highest accuracy with scores of 77%, 80%, 91% and 90% on background, lifestyle, history of grades and all features respectively in 50-50 train-test splits for binary classification (pass or fail). SVM also obtained highest accuracy for five class classification (grade A, B, C, D and F) with 39%, 38%, 73% and 71% for the four categories respectively.",
"keywords": [
"Student performance",
"data mining",
"support vector machine",
"naïve bayes",
"multilayer perceptron"
],
"content": "Introduction\n\nThe definition of a student is a person who attends school or any education institution level to achieve a certain level of knowledge or skill set in a course under the supervision of an educator. Almost everyone was once a student with responsibilities to acquire proper education. Acquiring knowledge by means of getting the right education is of utmost importance and each person should have basic equality in receiving education.\n\nWhen discussing education at the secondary level, a vital aspect to consider is student performance. Student performance can be assessed in a variety of dimensions, either through exam-based assessment or participation-based assessment. Exam-based assessment includes quizzes, midterms, and final exams, while participation-based assessment is a two-way communication during learning and group activities.\n\nApart from the obvious, there are so many factors that can affect student performance, such as individual habits, absenteeism, social activities after school and others. This gives way to having machines to learn patterns from data so that they can predict how well a student performs; by acknowledging these factors and subsequently detecting and improve their performance as early as possible. The objectives of this paper are to determine significant features with exploratory data analysis, which in turn can be used to develop various predictive models to ascertain student performance.\n\nStudent performance is an essential part in a secondary-level education as it will show where the student stands when continuing to higher education. Daud et al.1 noted that the ability to predict the success of a student is essential and seems to be a fascinating area to dig into.\n\nSokkhey et al.2 found out that mathematics is one of the subjects that has scientific progression on students. All aspects of human life at various levels are influenced by mathematics and there are no instances in life where mathematics is not used.\n\nAkhtar et al.3 discovered that social status is correlated with family’s social and monetary wealth. They managed to find the effect of monetary wealth on students’ grade in Pakistan.\n\nAmazona et al.4 adopted an educational data mining (EDM) method to perform gathering, achieving, and studying of information concerning student’s assessment and learning.\n\nExploratory data analysis (EDA)5 is a method of analyzing dataset to summarize the important features via visualization. EDA helps:\n\n• to find errors.\n\n• to check assumptions.\n\n• to determine the tentative choice of suitable models and tools.\n\n• to determine the relationship between the dependent and independent variables.\n\n• to detect the directions and size of the relationship between variables.\n\nFeature selection is a component of dimensionality reduction where it reduces the number of features to maximize the performance of a machine learning model. Too many features in a dataset can overwhelm a machine learning classifier and potentially reduce the efficacy.6\n\nThe Boruta feature algorithm is a wrapper algorithm that underpins the random forest model. From the results yielded by Tang et al.,6 feature selection is able to effectively recognize and improve overall evaluation metrics on their medical dataset research.\n\nSVM is able to build the best possible boundary of a line called hyperplanes, which can segregate dimensional spaces into classes. In the work of Sekeroglu et al.,7 they achieved good results with SVM on Mathematics and Portuguese subjects from two secondary schools.\n\nNaïve Bayes is based on Bayes rule of conditional probability and has high capabilities in dealing big datasets.4 The method is used to estimate the probability of a property given set of data as proof and Bayes’ theorem. The posterior is calculated from the product of likelihood and prior and divisible by its evidence.\n\nMultilayer perceptron underpins the artificial neutral network (ANN).4 It has an interconnection of perceptron in which it flows from the input to the output in a single direction with multiple routes.\n\nIn this research work, the approach consists of seven stages, namely data acquisition, data processing, data integration, data discretization, data transformation, feature selection and classification. The flow of the research is shown in Figure 1.\n\na) Data acquisition\n\nThe dataset of student performance is taken from a population of two Portuguese secondary schools namely Gabriel Pereira Secondary School (395 students)8 and Mousinho da Silveira Secondary School (649 students).9 In the survey, the students were taking the subjects, Mathematics and Portuguese. The two datasets were combined and consisted of 1044 students’ personal data and scores for the two subjects. The datasets are visualizations and shown in Figures 2 to 6.\n\nb) Data processing\n\nThis process helps to validate the two datasets by making sure there is no missing term in any feature.\n\nc) Data integration\n\nThe two datasets were combined and consisted of 1044 students’ records with 33 features. By adopting EDA,5 the selected features are then assigned into four groups comprising of student background (12 features), lifestyle (18 features), history of grades (three features) and all features. Tables 1 to 3 shown the features in student background, lifestyle, history of grades respectively. While the all the features group consists of the entire 33 features.\n\nd) Data discretization\n\nThe values for G1, G2 and G3 in Table 3 are discretized into binary and 5-level classifications. Tables 4 and 5 show the binary classification and 5-level classification.\n\ne) Data transformation\n\nThe features are normalized with linear scaling to avoid bias on heavy weighted attributes.\n\nf) Data selection\n\nNext, Boruta feature selection was performed to remove irrelevant features.\n\ng) Classification\n\nThree supervised machine learning techniques were implemented which are support vector machine, naïve Bayes, and multilayer perceptron 60–40 and 50–50 train-test splits and 10-fold cross validation. Four categories that comprise of student background, student lifestyle, student history of grades (history) and all features. Experiments are carried out on binary and five-level classification. Binary classification will indicate fail or pass, meanwhile for the five-level classification is for student scores F, D, C, B and A.\n\nGridSearchCV is applied to perform hyperparameter tuning. The performance metrics are accuracy, precision, recall and F1-Score. The experiments results are shown from Tables 6 to 11.\n\nSVM obtained the highest accuracy, with scores of 77%, 80%, 91% and 90% on background, lifestyle, history of grades and all features respectively in 50–50 train–test splits for binary classification (pass or fail). SVM also obtained highest accuracy for the five-class classification (grade A, B, C, D and F) with 39%, 38%, 73% and 71% for the four categories respectively. Based on the results, history of student grades shows significant contribution to a good student performance, where the classification rates obtained are the highest among the four respective categories in each respective classifier. This finding is consistent with the observations from Hwang et al.,10 Mega et al.11 and Waheed et al.,12 that the students’ performance is highly related to the previous results obtained.\n\nTable 12 shows the comparison of our models with other research work in 50–50 train–test splits for binary classification (pass or fail) on the dataset with population of two Portuguese secondary schools.\n\n\nConclusions\n\nThe paper presented predictive modelling of student performance based on four categories. Based on the results, history of student grades shows significant contribution to a good student performance. The study looks at data only from Portugal and may not reflect a general view of the case. Future work will include more datasets from difference country.\n\n\nData availability\n\nKaggle: A machine learning approach to predictive modelling of student performance\n\nhttps://www.kaggle.com/larsen0966/student-performance-data-set\n\nand\n\nhttps://archive.ics.uci.edu/ml/datasets/Student+Performance\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nEthics approval\n\nEthical Approval Number: EA1612021 (From Technology Transfer Office (TTO), Multimedia University).",
"appendix": "References\n\nDaud A, Aljohani NR, Abbasi RA, et al.: Predicting student performance using advanced learning analytics. Proceedings of the 26th international conference on world wide web companion. 2017, April; (pp. 415–421). Publisher Full Text\n\nSokkhey P, Okazaki T: Comparative Study of Prediction Models on High School Student Performance in Mathematics. 34th International Technical Conference on Circuits/Systems, Computers and Communications (ITC-CSCC). 2019, June; (pp. 1–4). IEEE.Publisher Full Text\n\nAkhtar Z: Socio-economic status factors effecting the students achievement: a predictive study. Int. J. Soc. Sci. Educ. . 2012; 2(1): 281–287.\n\nAmazona MV, Hernandez AA: Modelling student performance using data mining techniques: Inputs for academic program development. Proceedings of the 2019 5th International Conference on Computing and Data Engineering. 2019, May; (pp. 36–40). Publisher Full Text\n\nKomorowski M, Marshall DC, Salciccioli JD, et al.: Exploratory data analysis. Secondary analysis of electronic health records. 2016; 185–203. Publisher Full Text\n\nTang R, Zhang X: CART Decision Tree Combined with Boruta Feature Selection for Medical Data Classification. 2020 5th IEEE International Conference on Big Data Analytics (ICBDA). 2020, May; (pp. 80–84). IEEE. Publisher Full Text\n\nSekeroglu B, Dimililer K, Tuncal K: Student performance prediction and classification using machine learning algorithms. Proceedings of the 2019 8th International Conference on Educational and Information Technology. 2019, March; (pp. 7–11). Publisher Full Text\n\nCortez P, Silva A: Student Performance Data Set. 2014. cited as 2 October.Reference Source\n\nCortez P, Silva A: Using data mining to predict secondary school student performance. 15th European Concurrent Engineering Conference 2008, ECEC 2008-5th Future Business Technology Conference, FUBUTEC 2008. 2008; 2003(2000): 5–12\n\nHwang A, Kessler EH, Francesco AM: Student networking behavior, culture, and grade performance: An empirical study and pedagogical recommendations. Acad. Manag. Learn. Edu. 2004; 3(2): 139–150. Publisher Full Text\n\nMega C, Ronconi L, De Beni R: What makes a good student? How emotions, self-regulated learning, and motivation contribute to academic achievement. J. Educ. Psychol. 2014; 106(1): 121–131. Publisher Full Text\n\nWaheed H, Hassan SU, Aljohani NR, et al.: Predicting academic performance of students from VLE big data using deep learning models. Comput. Hum. Behav. 2020; 104: 106189. Publisher Full Text"
}
|
[
{
"id": "99883",
"date": "18 Nov 2021",
"name": "Sadiq Hussain",
"expertise": [
"Reviewer Expertise Educational Data Mining",
"Medical Analytics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper presented a predictive model on student performance based on the data from schools in Portugal. Student grades are the most important feature observed in the study. The study is complete from an experimental perspective, but it needs improvement in related works and the introduction section. After these modifications, the study will be approvable.\nThere are grammatical errors in this paper, which should be revised.\n\nThe literature review should be more in detail and add at least five more papers.\n\nThe conclusion should also be elaborated a little more. The major findings in their study should be discussed. For example, out of the classifiers applied, which classifier demonstrated the best accuracy? An evaluation of the methodology that the authors deployed would be welcome.\n\nThe introduction section should also focus on the research problem. Why this kind of research is beneficial, and to whom? How can management take advantage of it and how can companies evaluate these results to find the best students/universities for job placements?\n\nWas the dataset balanced? What was the imbalance ratio?\n\nKindly provide justification for using the applied classifiers only: why were other classifiers not considered?\n\nWhat were the most influential features in student performance? Was there any unnecessary feature that was taken into account?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8260",
"date": "23 May 2022",
"name": "Hu NG",
"role": "Author Response",
"response": "Dear Prof Sadiq Hussain, We are greatly appreciative of the insightful comments and helpful suggestions that you have provided. The following are our response on the issues that you have highlighted: Your comment: a) There are grammatical errors in this paper, which should be revised. Our response: The paper has been proofread for grammatical errors. Thank you for pointing this out. Your comment: b) The literature review should be more in detail and add at least five more papers. Our response: Six papers on student dropout, interpersonal influences, as well as career decisions have been added to the Literature Review. Hussain, S., Dahan, N. A., Ba-Alwib, F. M., & Ribata, N. (2018). Educational data mining and analysis of students’ academic performance using WEKA. Indonesian Journal of Electrical Engineering and Computer Science, 9(2), 447-459. Chung, J.Y.; Lee, S. Dropout early warning systems for high school students using machine learning. Child. Youth Serv. Rev. 2019, 96, 346–353. Nauta, M.M.; Saucier, A.M.; Woodard, L.E. Interpersonal influences on students’ academic and career decisions: The impact of sexual orientation. Career Dev. Q. 2001, 49, 352–362. Lee, P.C.; Lee, M.J.; Dopson, L.R. Who influences college students’ career choices? An empirical study of hospitality management students. J. Hosp. Tour. Educ. 2019, 31, 74–86. Kim, S.-Y.; Ahn, T.; Fouad, N. Family influence on Korean students’ career decisions: A social cognitive perspective. J. Career Assess. 2016, 24, 513–526. Wang, Z., Liang, G., & Chen, H. (2022). Tool for Predicting College Student Career Decisions: An Enhanced Support Vector Machine Framework. Applied Sciences, 12(9), 4776. Your comment: c) The conclusion should also be elaborated a little more. The major findings in their study should be discussed. For example, out of the classifiers applied, which classifier demonstrated the best accuracy? An evaluation of the methodology that the authors deployed would be welcome. Our response: The conclusion has been elaborated with the results. The following has been added: SVM obtained the highest accuracy with scores of 77%, 80%, 91% and 90% on background, lifestyle, history of grades and all features respectively in 50-50 train-test splits for binary classification (pass or fail). SVM also obtained highest accuracy for five class classification (grade A, B, C, D and F) with 39%, 38%, 73% and 71% for the four categories respectively. Your comment: d) The introduction section should also focus on the research problem. Why this kind of research is beneficial, and to whom? How can management take advantage of it and how can companies evaluate these results to find the best students/universities for job placements? Our response: The following statements have been added to the Introduction to address this: This will assist educators to form corrective or remedial actions can help to improve student performance. In addition, this may also assist in formulating curriculums that may direct students to career pathways that are most suitable for them. For management and companies, this is not in the scope of this research and will be explored in future work. Your comment: e) Was the dataset balanced? What was the imbalance ratio? Our response: The original datasets are not balanced due to the distribution of grades. In order to overcome this, in this work we performed discretization, to form 2 groups – binary levels and 5 levels. As per referred to the work from Hussain, S., Dahan, N. A., Ba-Alwib, F. M., & Ribata, N. (2018). Educational data mining and analysis of students’ academic performance using WEKA. Indonesian Journal of Electrical Engineering and Computer Science, 9(2), 447-459. Your comment: f) Kindly provide justification for using the applied classifiers only: why were other classifiers not considered? Our response: Due to previous work, we found out that these classifiers work well for our use cases, that is why in this work we have only applied these. We will compare other classifiers in future work. Your comment: g) What were the most influential features in student performance? Was there any unnecessary feature that was taken into account? Our response: The most influential features come from the history of student grades (Table 3). The following statement can be found in the discussions of the classification result: Based on the results, history of student grades shows significant contribution to a good student performance, where the classification rates obtained are the highest among the four respective categories in each respective classifier. No unnecessary features were taken into account."
}
]
},
{
"id": "136540",
"date": "12 May 2022",
"name": "Huiling Chen",
"expertise": [
"Reviewer Expertise data mining"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors propose a data mining approach to identify significant factors and predict student performance, based on two datasets collected from two secondary schools in Portugal. The overall structure of the article is also reasonable. The interpretation and description of the experimental results are also detailed. The experimental results show that the proposed method is excellent in terms of accuracy, precision, recall, and F1 score. In my opinion, this method has some practical value.\nHowever, this manuscript suffers from a number of weak points, it should be further improved before being considered for indexing. Let’s elaborate on some of them:\nIn the results of the Abstract, the authors summarize the classification results of SVM on the dataset. However, we do not see the impact and contribution of the proposed method on the experimental results.\n\nIntroduction - include the description of the innovations, contributions, and the structure of the article.\n\nIn the introduction, I also suggest the authors make a comprehensive investigation on the machine learning method such as the works by Wang et al. (20221) and Wang et al. (20222), in the literature in the introduction part and give analysis of the existing works to make the whole work more in-depth.\n\nThe title of the fourth part of the paper, “Methodology”, should be changed to “Methodology and Experimental Results”.\n\nThe number of students aged 20 and 21 is not given in Figure 2, is it a problem with the data set？\n\nWith the experimental results in Table 6-11, there are differences in the results obtained by different classifiers. What is the theoretical basis of the paper for the choice of classifier?\n\nIn the conclusion, the contributions and flaws of the proposed method are not discussed.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8261",
"date": "23 May 2022",
"name": "Hu NG",
"role": "Author Response",
"response": "Dear Prof Huiling Chen, We are greatly appreciative of the insightful comments and helpful suggestions that you have provided. The following are our response on the issues that you have highlighted: Your comment: In the results of the Abstract, the authors summarize the classification results of SVM on the dataset. However, we do not see the impact and contribution of the proposed method on the experimental results. Our response: Thank you for the comments. From this research work, we found out that history of grades forms significant influence on the student performance. This is the main impact and contribution. Your comment: 2. Introduction - include the description of the innovations, contributions, and the structure of the article. Our response: The last 2 paragraphs of the Introduction have been rewritten to reflect this. The contributions of this paper are the identification of significant features that influence student assessment, which in turn can be used to develop various predictive models to ascertain student performance. This will assist educators to form corrective or remedial actions can help to improve student performance. In addition, this may also assist in formulating curriculums that may direct students to career pathways that are most suitable for them. The paper is structured as follows: Related Works, Methodology and Results, followed by Conclusions. Your comment: 3. In the introduction, I also suggest the authors make a comprehensive investigation on the machine learning method such as the works by Wang et al. (20221) and Wang et al. (20222), in the literature in the introduction part and give analysis of the existing works to make the whole work more in-depth. Our response: We have added one of the papers recommended into the Related Works. Thank you for the recommendation. Wang, Z., Liang, G., & Chen, H. (2022). Tool for Predicting College Student Career Decisions: An Enhanced Support Vector Machine Framework. Applied Sciences, 12(9), 4776. Your comment: 4. The title of the fourth part of the paper, “Methodology”, should be changed to “Methodology and Experimental Results”. Our response: The title has been rephrased to ‘Methodology and Results’. Your comment: 5. The number of students aged 20 and 21 is not given in Figure 2, is it a problem with the data set？ Our response: Figure 2 had been edited to show the number of students aged 20 and aged 21. Your comment: 6. With the experimental results in Table 6-11, there are differences in the results obtained by different classifiers. What is the theoretical basis of the paper for the choice of classifier? Our response: Due to previous work, we found out that these classifiers work well for our use cases, that is why in this work we have only applied these. We will compare other classifiers in future work. Your comment: 7. In the conclusion, the contributions and flaws of the proposed method are not discussed. Our response: The conclusions have been revised to include the significant results, contribution and the weakness, which will be addressed in future work."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1144
|
https://f1000research.com/articles/11-556/v1
|
23 May 22
|
{
"type": "Research Article",
"title": "Clinical profile and outcome of acute kidney injury in a tertiary care center of eastern Nepal",
"authors": [
"Dipendra Singh",
"Bishal Thapaliya",
"Gaurab Bhatta",
"Dipak Kumar Yadav",
"Shailendra Shrestha",
"Jitendra Singh",
"Sandesh Shah",
"Bishal Thapaliya",
"Gaurab Bhatta",
"Shailendra Shrestha",
"Jitendra Singh",
"Sandesh Shah"
],
"abstract": "Background Acute kidney injury (AKI) is a global problem and it is encountered both in community and in-hospital patients. AKI has caused very significant damage to the health sector with high morbidity and mortality rates as well as a financial burden to the family. AKI contributes to a 3% incidence of end-stage renal disease (ESRD). Sepsis and hypovolemia-associated ischemia is the most common cause of AKI. AKI has various risk factors, modes of presentation and outcomes. Also, the prevalence varies across the different populations. There is a paucity of data about the clinical profile of AKI in the eastern part of Nepal. This study aims to assess the age, comorbid conditions, the severity of AKI, mode of treatment, and outcome of patients with AKI admitted to the Nobel Medical College and Teaching Hospital, Biratnagar, Nepal. Methods This is a cross-sectional analytical study conducted at a Nobel Medical College Teaching Hospital, Biratnagar, Nepal from July 2018 to June 2019 AD. Results In this study, 192 patients diagnosed with AKI were included. Male patients accounted for 52.7%. The mean age was 48.6±18.73 years. Most of the patients (74.5%) were below <60 years of age. The average duration of hospital stay was 8 days. The common cause of AKI was sepsis in 71.9%. Diabetes mellitus (DM) was seen in 52.6% of patients. Most of the patients (41%) were at stage III AKI at the time of admission. Hemodialysis was done in 14.6% and 85.4% were managed conservatively. Average sessions of hemodialysis were 3.61. Complete recovery was seen in 69.8% of the patients. Conclusions We observed that early diagnosis, avoidance of nephrotoxic agents, and early, aggressive, and appropriate interventions result in improved patient outcomes. However late presentations of AKI have a higher hospital mortality rate.",
"keywords": [
"Acute kidney injury",
"qSOFA",
"Hemodyalysis",
"sepsis",
"renal",
"creatinine",
"urea"
],
"content": "Introduction\n\nThe abrupt and usually reversible decline in glomerular filtration rate (GFR) over days to weeks is defined as acute kidney injury (AKI).1 This term also highlights that injury to the kidney that does not result in “failure” is also of great clinical significance. The definition has evolved from the Risk, Injury, Failure, Loss, End-stage (RIFLE) criteria in 2004 to the AKI Network (AKIN) classification in 2007.2,3 In 2012, both were merged resulting in the Kidney Disease Improving Global Outcomes (KDIGO) classification.4 Accordingly, AKI is diagnosed if serum creatinine increases by ≥0.3 mg/dl within 48 hours or rises ≥1.5 times from the baseline within 7 days, and urine volume <0.5 mL/kg/hr for 6 hours. AKI stages are defined by the maximum serum creatinine or urine output change.\n\nThe epidemiology and outcome of AKI differ significantly across the industrialized and underdeveloped worlds.5 Developing countries account for more than 85% of the worldwide burden of AKI. 6 In Nepal higher burden of community acquired AKI is seen in younger age group.7 Even a modest type of AKI is linked to higher long-term mortality in ICU survivors, as well as an elevated risk of chronic and end-stage kidney disease and significant cardiovascular events. 8,9 Specific organ system failures occur at varying rates among AKI patients admitted to the ICU, with varying degrees of correlation between individual organ system failures and ICU mortality. qSOFA is very useful tool to access the extent of organ dysfunction seen in critically ill patient with AKI.10,11 Sequential (Sepsis-related) Organ Failure Assessment score (SOFA) is modified to form qSOFA score. Components of qSOFA comprises of respiratory rate>22 bpm, SBP<100 mmHg, altered Glasgow coma scale (GCS) and one point is allocated to each component. To indicate organ dysfunction, qSFOA score must be ≥2.\n\nqSOFA ≥2 was highly specific for identifying organ dysfunction and mortality (96.1% and 91.3% respectively), but sensitivity was poor (29.7% and 49.1% respectively).12 Low-and middle income like Nepal lack adequate information, healthcare resources, and patient adherence to the treatment protocol. Additionally, data on AKI is not sufficiently available in the literature. Therefore, this study aimed to assess the clinical profile and short-term outcomes of acute kidney injury in single-center hospitalized patients.\n\n\nMethods\n\nEthical clearance (ref. no. 171/2018) was granted from the ethics and research committee of Nobel Medical College Teaching Hospital, Biratnagar, Nepal on 22nd June 2018. Written informed consent was obtained from participants and from parents for the participants who were <18 years for the publication of their clinical details.\n\nThis is a cross-sectional analytical study conducted at Nobel Medical College Teaching Hospital, Biratnagar, Nepal from July 2018 to June 2019 AD. The study population was all patients admitted at Nobel Medical College with a diagnosis of AKI. Non-probability convenient sampling method was used. The research team approached all the admitted patients with the diagnosis of AKI. Patients meeting the inclusion and exclusion criteria were recruited.\n\nInclusion criteria include age >15 years, and all patients admitted in the ICU and ward with a diagnosis of AKI meeting criteria as per KDIGO guidelines 2012.\n\nExclusion criteria include preexisting chronic kidney disease (CKD) with baseline CKD EPI (chronic kidney disease epidemiology collaboration) eGFR (estimated glomerular filtration rate) <60 ml/min/1.73 m2 before the onset of illness or dialysis-dependent, suspected or biopsy-proven glomerulonephritis as a cause of AKI and suspected or diagnosed case of heart failure with functional class 3 or 4. eGFR was calculated at time of study to determine if participants were suitable to take part.\n\nVariables assessed in this study were age, gender, duration of hospital stay, comorbidities, cause of AKI, mode of management, and qSOFA score.\n\nAs per the hospital data, around 160 patients were annually admitted with the diagnosis of AKI. So, with 20 allowable error, minimum of 140 cases were selected over the study duration.\n\nContinuous variables were expressed as means±standard deviation (SD). Categorical variables were expressed as proportions and compared with the chi-squared test at 95% confident interval where level of significance considered at p≤0.05. Statistical Package for Social Sciences (SPSS) 25th version was used for analysis.\n\nAKI is defined as any of the following:\n\n• An absolute increase in serum creatinine of 0.3 mg/dl or more (26.4 micro-mol/L or more) within 48 hours, or\n\n• Increase in serum creatinine to 1.5 times or more from baseline, which is known or presumed to have occurred within the prior 7 days, or\n\n• Urine output of less than 0.5 ml/kg per hour for more than 6 hours.\n\nqSOFA scoring includes:\n\n• Low blood pressure (SBP ≤ 100 mmHg)\n\n• High respiratory rate (≥ 22 breaths/min)\n\n• Altered mentation (GCS < 15)\n\n\nResults\n\nThe study was carried out on 192 patients who were admitted with the diagnosis of AKI.30 The demographic and clinical profiles of the patients are shown in Table 1.\n\nThe mean duration of hospital stays (ICU and ward) of the patients was 8.91±4.38 days. Almost 88% of patients had hospital stays of ≤2 weeks. Comorbidities were seen in 76 (39.5%) patients. Among patients with comorbidities, 40 (52.6%) had diabetes mellitus, 21 (27.6%) patients had chronic obstructive pulmonary disease (COPD), and 15 (19.8%) patients had hypertension. The common cause of AKI was sepsis in 138 patients (71.9%), hypovolemia in 30 patients (15.6%), obstructive uropathy in 17 patients (8.9%), surgical cause in 4 (2.1%), and drug-related in 3 (1.6%). Most of the patients (79; 41.1%) were at stage III of AKI at the time of admission as shown in Table 2.\n\nAt admission, 25 patients had a qSOFA score of 3 as shown in Table 3.\n\n28 patients i.e. 14.60% underwent renal replacement therapy (RRT) in the form of hemodialysis whereas 164 patients i.e. 85.4% were conservatively managed. The average number of sessions of hemodialysis was 3.61 (1-8) sessions. Out of all patients, 90 were managed in the ICU and among those 23 (25.56%) were ventilated. The average duration of ventilation was 3.43 days (1-7 days). The number of patients who completely recovered was 134 (69.8%), followed by 52 patients (27.1%) who had partial recovery and 6 patients (3.1%) died during the hospital stay.\n\nAmong 138 patients with sepsis, 18 patients (13.0%) were ventilated and 120 patients (87.0%) were not ventilated. Among 30 patients with hypovolemia, 3 patients (10.0%) were ventilated, 27 patients (90.0%) were not ventilated. All 17 patients with obstructive uropathy didn’t require ventilatory support. The cause of AKI was insignificantly (x2=8.46, df=4, p=0.076) associated with the need to use ventilatory support for the patient.\n\nAmong 106 patients with a qSOFA score of 0, 8 patients (7.5%) underwent hemodialysis, and 98 patients (92.5%) were managed conservatively. Among the 31 patients who had a qSOFA score of 1, 3 patients (9.7%) underwent hemodialysis and 28 patients (90.03%) were managed conservatively. Among 30 patients with a qSOFA score of 2, 5 patients (16.7%) underwent hemodialysis, 25 patients (83.3%) were managed conservatively. Also, among the 106 patients with a qSOFA score of 3, 12 patients (48.0%) underwent hemodialysis, and 13 patients (52.0%) were managed conservatively. The score of qSOFA was significantly (x2=24, df=6, p=0.01) associated with the outcome of the patient.\n\n28 patients underwent hemodialysis out of which 3 patients (10.7%) died, 13 patients (46.4%) had partial recovery, and 12 patients (42.9%) had a complete recovery. In the 164 patients under conservative treatment, 3 patients (1.8%) died, 39 patients (23.8%) had partial recovery, 122 patients (74.4%) had a complete recovery. Chi-square statistics were used to examine the association between categorical variables (mode of treatment and outcome). There is a significant association at a 5% significance level between mode of treatment and outcome (x2=13.97, df=2, p=0.01).\n\nAmong 138 patients with sepsis, 22 patients (15.90%) underwent RRT in the form of hemodialysis. 3 patients (10%) with hypovolemia and 3 patients (17.6%) with obstructive uropathy also received hemodialysis, whereas 164 patients were conservatively managed. There is an insignificant association at a 5% significance level between the cause of AKI and outcomes (x2=14.83, df=8, p=0.062).\n\n\nDiscussion\n\nIn our study, the mean age at presentation was 48.60±18.73 years ranging from 16 years to 89 years. Mean age varies in different studies. In the study by Vikrant et al.13 it was 49±18.1, 45 in Khakhurel et al.,14 32±16.85 in Aggrawal et al.15 and 65.8±14.1 in a study by Teo et al.16\n\nIn the present study, 143 (74.5%) patients were 60 years or older, and the remaining 49 (25.5%) patients were below 60 years. This signifies that the younger population is also affected in a big proportion. In the study done by Chhetri PK et al.17 in Nepal Medical College Teaching Hospital, Kathmandu, 64% of patients belonged to the age group 21-60 years which is different than our study and this might be due to the small study sample of 45 in the study by Chhetri PK et al.\n\nIn our study, the mean duration of the patient’s hospital stay was 8.91±4.38. Almost 88% of patients had a hospital stay of ≤2 weeks. In a study by Khakurel et al.14 in Bir Hospital Kathmandu, the mean hospital stay was 13.6 days. In a study done by Patel et al.18 Northern Railway Central Hospital, New Delhi, India, most patients (approximately 81%) required hospitalization for around or <2 weeks. This variation in in-hospital stay may be due to inclusion criteria, sample size, socioeconomic status, and nutritional status of patients.\n\nIn our study 70 patients (39.5%) had comorbid conditions, among them 40 patients (52.6%) with DM, 21 patients (27.6%) with COPD, and 15 patients (19.8%) had hypertension (HTN). In a study done by Maskey et al.19 30 patients (35.7%) had DM, 24 (29.7%) had HTN, 14 patients (16.6%) had COPD, and malignancy was found in 6 patients (7%). In a study done by Rathnamalala et al., 24 patients (35.3%) had DM followed by HTN in 6 patients (8.8%), CLD in 2 patients (2.9%), and other conditions were reported in 2 patients (2.9%).20 In a study done by Ghimire et al.21 among co-morbid conditions, 9.4% of subjects had DM, followed by 3% with COPD. Therefore, the findings of our study are consistent with the finding from the above studies.\n\nIn the present study, 71.9% of patients had sepsis as the major cause of AKI followed by hypovolemia in 15.6% and obstructive uropathy in 8.9%.\n\nIn a study by Ghimire et al.21 sepsis was seen in 47% of the patients as the cause of AKI. In another study in Srilanka by Rathnamalala et al.,22 sepsis was also the most common (41.2%) cause of AKI. Above mentioned studies by Ghimire et al. 21 and Rathnamalala et al.22 are consistent with our findings. Whereas, in studies by Khakurel et al.14 and Chhetri et al.,17 gastroenteritis was the leading cause of AKI followed by sepsis.\n\nIn the present study, most (41%) of the patients were in stage III at the time of admission followed by 30.7% in stage II and 28.1% in stage I. Our findings are consistent with the study by Aggarwal et al.15 where 58.92% were of stage III, 21.4% of stage II, and 19.64% of stage I. Similar observations are seen in other studies. In a study done by Bhadade et al.23 at the Topiwala National Medical College and Hospital, Mumbai, Maharashtra, India out of 316 patients there was 27 (8.6%) in stage I, 64 (20.20%) in stage II, and 225 (71.2%) in stage III. In a study by Effa et al.24 out of 42 patients there were none in stage I, 17 (40.5%) in stage II, and 25 (59.5%) in stage III.\n\nThe result of the maximum stage of AKI during the hospital stay as shown in Table 4 is consistent with the study by Wang et al.25 whereas it differs from the study by Fuhrman et al.26 and this variation may be due to the larger study sample in Fuhrman et al.\n\nIn the present study, 14.6% of patients underwent renal replacement therapy in the form of hemodialysis and 85.4% were managed conservatively. The average number of sessions of hemodialysis was 3.61. In a study by Maskey et al.,19 15% required hemodialysis with the average number of sessions of hemodialysis being 3.4. Similarly, in a study by Shrestha et al.,27 26.7% of the patients received hemodialysis. Our findings are consistent with these studies.\n\nIn the present study, 69.8% of patients had complete recovery, 27.1% had partial recovery, and 3.1% had in-hospital mortality. Our findings are consistent with the study by Maskey et al.19 where 52% showed complete recovery, 37% had partial and 3% had in-hospital mortality.\n\nThe score of qSOFA was significantly (x2=24, df=6, p=0.01) associated with the outcome of the patient. This association shows that with an increase in the score of qSOFA there is an increase in the number of patients who underwent dialysis. So, an increase in qSOFA score at the time of admission increases the requirement for dialysis. A qSOFA score of ≥2 points indicates organ dysfunction. qSOFA ≥2 was highly specific for identifying organ dysfunction and mortality (96.1% and 91.3% respectively).28\n\nIn our study, there is a significant association at a 5% significance level between mode of treatment and outcome (x2=13.97, df=2, p=0.01). This signifies that fewer patients died in conservative treatment compared to hemodialysis. Also, more patients survived with conservative treatment. Our findings are in agreement with two large randomized controlled trials which have also failed to show any significant benefit on mortality even in those with more intensive dialysis.2,29 However, our findings need to be interpreted with caution as more deaths in the hemodialysis group may simply reflect that they were sicker (i.e. they had a higher AKI stage at the time of admission, had higher qSOFA score, and were more ventilated) than the patients on conservative treatment.\n\n\nConclusion\n\nSepsis is the most common cause of AKI in our study. Most of the patients present late i.e. stage III of AKI. Patients who presented with stage III AKI, had a qSOFA score of 2, and who were ventilated had higher mortality. AKI patients can be treated without doing RRT if the patient’s conditions are detected early with judicial investigations. However late stages in AKI have a poorer prognosis even with RRT. Careful monitoring of urine output, serum creatinine, and blood urea should be done in all patients admitted to the hospital especially in critical care to predict AKI. Timely diagnosis will surely improve the outcome and survival chances of patients drastically.\n\n\nData availability\n\nfigshare: Clinical Profile and Outcome of Acute Kidney Injury in a Tertiary Care Center of Eastern Nepal, https://doi.org/10.6084/m9.figshare.19610070.v3.30\n\nThis project contains the following underlying data:\n\n- data.xlsx (raw data sheet)\n\nfigshare: Clinical Profile and Outcome of Acute Kidney Injury in a Tertiary Care Center of Eastern Nepal, https://doi.org/10.6084/m9.figshare.19610070.v3.30\n\nThis project contains the following extended data:\n\n- Proforma.pdf (patient details form)\n\n- Consent form nobel pdf.pdf (consent form)\n\n- Data key pdf.pdf (data key for the xlsx file)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nLameire N, Hoste E: Reflections on the definition, classification, and diagnostic evaluation of acute renal failure. Curr. Opin. Crit. Care. 2004; 10: 468–475. Publisher Full Text\n\nBellomo R, Ronco C, Kellum JA, et al.: Acute renal failure–definition, outcome measures, animal models, fluid therapy and information technology needs the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit. Care. 2004; 8: 1–9.\n\nMehta RL, et al.: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit. Care. 2007; 11: 1–8.\n\nKellum JA, et al.: Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. Suppl. 2012; 2011(2): 1–138.\n\nWaikar S, Bonventre J: Acute kidney injury. Harrison’s principles of internal medicine. 19th ed.New York: McGraw-Hill; 2015; 1799–1810.\n\nPonce D, Balbi A: Acute kidney injury: risk factors and management challenges in developing countries. Int. J. Nephrol. Renov. Dis. 2016; 9: 193–200. PubMed Abstract | Publisher Full Text\n\nCerdá J, Bagga A, Kher V, et al.: The contrasting characteristics of acute kidney injury in developed and developing countries. Nat. Clin. Pract. Nephrol. 2008; 4: 138–153. PubMed Abstract | Publisher Full Text\n\nLinder A, et al.: Small acute increases in serum creatinine are associated with decreased long-term survival in the critically ill. Am. J. Respir. Crit. Care Med. 2014; 189: 1075–1081. PubMed Abstract | Publisher Full Text\n\nChawla LS, Amdur RL, Amodeo S, et al.: The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int. 2011; 79: 1361–1369. PubMed Abstract | Publisher Full Text\n\nde Mendonça A , et al.: Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score. Intensive Care Med. 2000; 26: 915–921. PubMed Abstract\n\nLin Y-F, et al.: A modified sequential organ failure assessment score to predict hospital mortality of postoperative acute renal failure patients requiring renal replacement therapy. Blood Purif. 2008; 26: 547–554. PubMed Abstract | Publisher Full Text\n\nAndaluz D, Ferrer R: SIRS, qSOFA, and organ failure for assessing sepsis at the emergency department. J. Thorac. Dis. 2017; 9: 1459–1462. PubMed Abstract | Publisher Full Text\n\nVikrant S, Gupta D, Singh M: Epidemiology and outcome of acute kidney injury from a tertiary care hospital in India. Saudi J. Kidney Dis. Transpl. 2018; 29: 956. Publisher Full Text\n\nKhakurel S, Satyal PR, Agrawal RK, et al.: Acute renal failure in a tertiary care center in Nepal. J. Nepal Med. Assoc. 2005; 44. Publisher Full Text\n\nAggarwal HK, Jain D, Singh A, et al.: Spectrum and outcome of acute kidney injury: A tertiary care centre experience from north india.\n\nTeo SH, et al.: A prospective study of clinical characteristics and outcomes of acute kidney injury in a tertiary care Centre. BMC Nephrol. 2019; 20: 1–8.\n\nChhetri PK, Manandhar DN, Pahari LR, et al.: Acute renal failure in Nepal medical college teaching hospital. Nepal Med. Coll. J. 2008; 10: 132–135. PubMed Abstract\n\nPatel UR, et al.: Clinical profile of acute kidney injury in a tertiary care center in the Tropical Region. Journal of Integrative Nephrology and Andrology. 2018; 5: 130. Publisher Full Text\n\nMaskey A, et al.: Acute Kidney Injury: Clinical Characteristics And Outcomes. Nepal Med. Coll. J. 2015; 17: 95–97.\n\nRathnamalala N: Clinical characteristics and outcomes of patients with acute kidney injury: A single-center study. Saudi J. Kidney Dis. Transpl. 2013; 24: 813. Publisher Full Text\n\nGhimire M, et al.: Outcome of sepsis-associated acute kidney injury in an intensive care unit: an experience from a tertiary care center of central Nepal. Saudi J. Kidney Dis. Transpl. 2014; 25: 912–917. PubMed Abstract | Publisher Full Text\n\nBernard G: Recombinant human activated protein C worldwide evaluation in severe sepsis (PROWESS) study group: efficacy and safety of recombinant human acitvated protein C for severe sepsis. N. Engl. J. Med. 2001; 344: 699–709. Publisher Full Text\n\nBhadade R, De’Souza R, Harde MJ, et al.: A prospective study of acute kidney injury according to KDIGO definition and its mortality predictors. J. Assoc. Physicians India. 2016; 64: 22–28. PubMed Abstract\n\nWachukwu CM, Emem-Chioma PC, Wokoma FS, et al.: Pattern and outcome of renal admissions at the University of Port Harcourt Teaching Hospital, Nigeria: A 4 years review. Ann. Afr. Med. 2016; 15: 63–68. PubMed Abstract | Publisher Full Text\n\nWang X, et al.: Risk factors for mortality in patients with septic acute kidney injury in intensive care units in Beijing, China: a multicenter prospective observational study. Biomed. Res. Int. 2014; 2014: 1–10. Publisher Full Text\n\nFuhrman DY, Kane-Gill S, Goldstein SL, et al.: Acute kidney injury epidemiology, risk factors, and outcomes in critically ill patients 16–25 years of age treated in an adult intensive care unit. Ann. Intensive Care. 2018; 8: 1–11.\n\nShrestha B, et al.: Clinical profile and outcome of acute kidney injury in intensive care unit of a teaching hospital. J. Chitwan Med. Coll. 2018; 8: 32–35. Publisher Full Text\n\nAndaluz D, Ferrer R: SIRS, qSOFA, and organ failure for assessing sepsis at the emergency department. J. Thorac. Dis. 2017; 9: 1459–1462. Publisher Full Text\n\nFaulhaber-Walter R, et al.: The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for treatment of patients with acute kidney injury in the intensive care unit. Nephrol. Dial. Transplant. 2009; 24: 2179–2186. Publisher Full Text\n\nSingh D, Thapaliya B, Bhatta G, et al.: Clinical Profile and Outcome of Acute Kidney Injury in a Tertiary Care Center of Eastern Nepal. figshare. Dataset. 2022. Publisher Full Text"
}
|
[
{
"id": "150049",
"date": "26 Sep 2022",
"name": "Konlawij Trongtrakul",
"expertise": [
"Reviewer Expertise Critical Care Nephrology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: The study was performed cross-sectionally at the Nobel Medical College Teaching Hospital in Biratnagar, Nepal, from July 2018 to June 2019 AD. There were 192 AKI patients included in the study. Most of them were older (75% were 65 years old or above) and were diagnosed with sepsis (72%). Renal replacement therapy was performed in nearly 15% of the patients. Several issues need to be corrected or clarified as follows:\nAbstract\nPlease provide the definition of AKI as used in this study.\n\nBe reminded to check whether most patients are over 60 or less than 60 years old. There is a discrepancy in the manuscript.\n\nThe abstract has no data for “late AKI presentation” and “mortality rate.” Thus, be cautious of making this conclusion.\n\nMethod\nPlease provide a sufficient sample size calculation.\n\nThis data seems to be a prospective or retrospective observational study rather than a cross-sectional study. Please consider clarifying.\n\nResults\nThe authors can also report certain information in a table format —for instance, qSOFA, comorbidity, % of sepsis, % renal function recovery.\n\nDiscussion\nThe discussion part should contain a summary of the study, comparing it with another study in terms of significant similarities and differences, the strengths of the study, and the limitations.\n\nThe authors may relocate some information in the discussion section to the results section. Additionally, please make the discussion more concise as necessary. It would be easier for readers to follow the report smoothly without being overwhelmed by too much information.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "148583",
"date": "17 Nov 2022",
"name": "Anupama YJ",
"expertise": [
"Reviewer Expertise Nephrology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have studied the clinical profile and outcome of acute kidney injury (AKI) in a tertiary care center of eastern Nepal and describe their findings from a sample of 192 patients.\nThe study method is sound and appropriate. However, from the description of the methods, it appears to be a prospective observational study. This may please be corrected both in the abstract and the body of the article.\nThe results are also well described and tabulated. However, there is an error - probably by oversight. The authors have looked at qSOFA score and the RRT outcome. In the fourth line of that paragraph, the figure 106 must be changed to 25. It should read as \"25 patients with a qSOFA score of 3...\" etc.\nThe discussion however is patchy and not robust. The authors may please summarize their key findings in the first paragraph and then proceed with the discussion. Here, emphasis should be put on those two/three major findings from the study and how it differs from or concurs with other studies. It is not necessary to compare all points. For example, in this paper, the authors even compare the comorbidities among the various studies. This is not required. In the study on AKI, the key points to be examined would be clinical severity, any etiologic differences, duration of hospital stay, duration of ICU stay, outcome and renal replacement therapy requirement. The authors have touched upon these things but need to elaborate a little bit more about these key points. It is also concluded by the authors that conservative treatment is superior to dialysis in the management of AKI. The authors make a weak statement that it may be because of sicker patients. But they need to emphasize this clearly and boldly that the patients receiving RRT and those on conservative treatment are strictly not comparable and this they can substantiate with qSOFA score and stage of AKI. Clinically, the sicker patients are taken up for RRT and there is an element of confounding here which needs to be stated. Strengths and limitations of this study should be described. Further, the conclusions in the abstract section and in the main text are not congruent. Conclusions in the abstract may please be changed in line with that in the main text.\n\nThere are a few other minor points in the article that need to be corrected.\nThe authors have to correct the grammar and the language in a few places. For example, in the second and third sentences in the abstract, the authors are writing about the same condition, but in the second sentence, it is in the past tense; in the third, it is in the present tense.\n\nThe authors should expand qSOFA term.\n\nSPSS version is mentioned, but not in the standard way (Version 23, vendor's name in brackets etc).\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-556
|
https://f1000research.com/articles/11-555/v1
|
23 May 22
|
{
"type": "Genome Note",
"title": "Genome of the lepidopleurid chiton Hanleya hanleyi (Mollusca, Polyplacophora)",
"authors": [
"Rebecca M. Varney",
"Meghan K. Yap-Chiongco",
"Nina T. Mikkelsen",
"Kevin M. Kocot",
"Rebecca M. Varney",
"Meghan K. Yap-Chiongco",
"Nina T. Mikkelsen"
],
"abstract": "Mollusca is the second most species-rich phylum and includes animals as disparate as octopuses, clams, and chitons. Dozens of molluscan genomes are available, but only one representative of the subphylum Aculifera, the sister taxon to all other molluscs, has been sequenced to date, hindering comparative and evolutionary studies. To facilitate evolutionary studies across Mollusca, we sequenced the genome of a second aculiferan mollusc, the lepidopleurid chiton Hanleya hanleyi (Bean 1844), using a hybrid approach combining Oxford Nanopore and Illumina reads. After purging redundant haplotigs and removing contamination from this 1.3% heterozygous genome, we produced a 2.5 Gbp haploid assembly (>4X the size of the other chiton genome sequenced to date) with an N50 of 65.0 Kbp. Despite a fragmented assembly, the genome is rather complete (92.0% of BUSCOs detected; 79.4% complete plus 12.6% fragmented). Remarkably, the genome has the highest repeat content of any molluscan genome reported to date (>66%). Our gene annotation pipeline predicted 69,284 gene models (92.9% of BUSCOs detected; 81.8% complete plus 11.1% fragmented) of which 35,362 were supported by transcriptome and/or protein evidence. Phylogenomic analysis recovered Polyplacophora sister to all other sampled molluscs with maximal support. The Hanleya genome will be a valuable resource for studies of molluscan biology with diverse potential applications ranging from evolutionary and comparative genomics to molecular ecology.",
"keywords": [
"Aculifera",
"Lepidopleurida",
"genome",
"repetitive DNA"
],
"content": "Introduction\n\nMollusca is the second most diverse animal phylum and includes many economically and ecologically important species. Molluscs have been the focus of significant genomic research in recent years, which has enabled exciting comparative and evolutionary genomic investigations (reviewed by Gomes-dos-Santos et al. 2020). However, although dozens of molluscan genomes have been sequenced to date, all but one belong to the subphylum Conchifera, which includes the familiar gastropods, bivalves, and cephalopods. The subphylum Aculifera, which includes the eight-shelled chitons (Polyplacophora) and worm-like aplacophorans (Solenogastres and Caudofoveata), is the sister taxon to all other molluscs (Kocot et al. 2020). Surprisingly, just one species from this clade, the chiton Acanthopleura granulata (Gmelin, 1791), has been sequenced to date (Varney et al. 2021). Aculiferans are of great interest because as the sister taxon of all other molluscs they are important to understanding molluscan evolution. Further, species in this clade exhibit interesting traits such as iron-hardened teeth (Brooker and Shaw 2012), a complex armature of scales and spines (García-Álvarez & Salvini-Plawen 2007), and the only eyes in a living animal with a mineralized lens (Speiser et al. 2011).\n\nHere, we expanded available genomic resources for Aculifera by sequencing and annotating the genome of the chiton Hanleya hanleyi (Bean 1844). Extant chitons can be divided into two major clades: Chitonida, the clade represented by the previously published Acanthopleura genome, and Lepidopleurida, which includes Hanleya. Lepidopleurida is interesting from an evolutionary standpoint as these chitons are thought to be plesiomorphic, with shell features like those of ancient fossil chitons, gills restricted to the posterior region of the body, and simple gamete structure (Sigwart et al. 2011). Because of this suite of putatively ancestral characteristics and its phylogenetic position as the sister taxon to all other chitons, Lepidopleurida is thought to be critical to understanding large-scale patterns in molluscan evolution (Sigwart 2008). Hanleya hanleyi is a widely distributed, sponge-feeding lepidopleurid that is relatively common off Bergen, Norway and it is the largest lepididopleurid chiton known (Sirenko et al. 2016), making it an excellent choice for genome sequencing.\n\n\nMethods\n\nThe specimen of Hanleya hanleyi used for genome sequencing (Figure 1A) was collected by N.T.M. off Bergen, Norway in 2018 and is deposited in the University Museum of Bergen under catalog number ZMBN 146951. The genome was sequenced with a combination of short and long reads. To produce short-read data, genomic DNA was extracted from 96% ethanol-preserved samples of foot tissue using a CTAB-phenol-chloroform method following Varney et al. (2021). A sequencing library was prepared in-house using the Illumina TruSeq DNA PCR-Free kit with dual indexing according to the manufacturer’s instructions. This library was sequenced by Macrogen USA on one lane of the Illumina HiSeq X instrument with 150 bp paired-end (PE) sequencing. To produce long-read data via Oxford Nanopore sequencing, genomic DNA was extracted with an EZNA Tissue DNA Kit (Omega Bio-tek) and cleaned and enriched for high-molecular-weight fragments with the Short-Read Eliminator kit (Circulomics) according to the manufacturer’s instructions. Three sequencing libraries were prepared with the LSK-109 ligation-based library preparation kit and sequenced in-house on three R9.4.1RevD flow cells on a GridION. Reads were base called with Guppy 4.0 and trimmed with PoreChop (Wick 2018) with the --discard_middle flag.\n\nA different specimen of Hanleya hanleyi collected by dredging near Bergen, Norway in summer 2008 was gifted to the authors by Dr. Hans Torre Rapp for transcriptome sequencing and is deposited in the Alabama Museum of Natural History under catalog number ALMNH:Inv:23399. Notably, tissue from this same individual was used to generate the 454 pyrosequencing-based foot tissue transcriptome for this species (SRR108987) published by Kocot et al. (2011). For Illumina transcriptome sequencing, RNA extraction was performed on mantle tissue preserved in RNAlater and stored at -80°C using the Omega Bio-tek EZNA Mollusc RNA Extraction Kit with an on-column DNAse digestion. RNA concentration was measured using a Qubit 3.0 (Thermo Fisher) fluorometer with the RNA High Sensitivity kit, RNA purity was assessed by measuring the 260/280 nm absorbance ratio using a Nanodrop Lite (Thermo Fisher), and RNA integrity was evaluated using a 1% SB agarose gel. RNA was sent to Psomagen (Cambridge, MA, USA) for Illumina TruSeq RNA v2 library preparation (polyA enrichment) and sequencing on the Illumina HiSeq 2500 system with 100 bp PE sequencing.\n\nGenome size and heterozygosity were estimated based on the PE Illumina reads using GenomeScope 2 (Ranallo-Benavidez et al. 2020) with a k-mer of 21. Hybrid genome assembly was performed with MaSuRCA 3.3.5 (Zimin et al. 2017), which consolidates PE data into super reads and then uses long-read data to scaffold and gap-fill. Recommended settings for eukaryotes with >20X Illumina coverage and “PE= pe 587 88” were used. At this point (and after each step involving filtering or polishing the genome assembly; see below), we assessed assembly quality with QUAST 5.0.2 (Mikheenko et al. 2018) and completeness with BUSCO 5.1.3 (Manni et al. 2021) using the Metazoa odb_10 dataset and the “--long” flag. We then removed redundant haplotigs with purge_dups. Finally, the remaining scaffolds were polished with POLCA (Zimin & Salzberg 2020) using the Illumina paired-end reads, which were first quality- and adapter-trimmed with trimmomatic 1.8.0 (Bolger et al. 2014) using the following settings: “ILUMINACLIP:adapters.fasta:2:30:10 LEADING 10 TRAILING 10 SLIDINGWINDOW:4:15 MINLEN:50.”\n\nContamination was then screened for and removed with BlobTools2 (Challis et al. 2020). The POLCA-polished assembly was searched against the Uniprot reference proteomes (02-Jun-2021 release) with Diamond 2.0.14 (Buchfink et al. 2015) using the following settings: “--sensitive --index-chunks 1 --block-size 10 --max-target-seqs 1 -evalue 1e-25 --outfmt 6.” The quality- and adapter-trimmed genomic PE reads were then mapped to the genome with minimap 2.23 (Li 2018) with the following settings: “-ax sr.” The output of these tools as well as full_table.tsv generated by BUSCO were then used as input files to run BlobTools2. We removed scaffolds with fewer than 10 mapping Illumina reads, scaffolds not annotated as Metazoa, and scaffolds with a GC content <0.30 or >0.55, which appeared as clear outliers when GC content was plotted against coverage.\n\nFor genome annotation, repeats in the final contamination-filtered assembly were annotated and softmasked with RepeatMasker using a custom repeat database generated with RepeatModeler (Smit & Hubley 2015). For RepeatModeler, a maximum genome sample size of 1M and the --LTRStruct option were used. For RepeatMasker, the slow and gccalc options were used. The engine used for both programs was rmblast. Available chiton and select other mollusc proteomes (see data on Dryad for details) were then mapped to the final genome assembly with ProtHint 2.6 (Brůna et al. 2020) with an e-value cutoff of 1e-25. We ran TrimGalore (Krueger et al. 2021) on the transcriptome reads with the following settings: “-q 30 --illumina --trim-n.” The trimmed and filtered transcriptome reads were then mapped to the genome using STAR 2.4.0k (Dobin et al. 2013) with “--genomeChrBinNbits 15 --chimSegmentMin 50.” Annotation of protein-coding genes was performed with BRAKER 2.1.6 (Bruna et al. 2021) using the output of ProtHint and STAR with the following settings: “--eptmode --softmasking --crf.” Predicted transcripts with at least partial support from the Hanleya transcriptome and/or other chiton proteomes were identified with the selectSupportedSubsets.py bundled with BRAKER.\n\nBuilding on the phylogenomic analysis of Varney et al. (2021), we identified homologous protein sequences in the full set of Hanleya hanleyi gene models (including those with no transcript or protein evidence) to the complete proteome of the only other available chiton genome, Acanthopleura granulata, and the proteomes of 19 other lophotrochozoans, including 14 other molluscs, 2 annelids, 1 brachiopod, 1 phoronid, and 1 nemertean using OrthoFinder 2.4.0 (Emms & Kelly 2019). We then identified orthologous genes from the homogroups produced by OrthoFinder using the pipeline of Varney et al. (2021) except we retained only genes sampled for 18/21 taxa using PhyloPyPruner. Phylogenetic analysis on the concatenated supermatrix in IQ-Tree 2.1.3 (Minh et al. 2020) using the best-fitting model for each partition (-m MFP). The tree was arbitrarily rooted with all non-molluscan taxa.\n\n\nResults\n\nIllumina transcriptome sequencing yielded 25.8M reads or 5.8 Gbp. For the genome, Oxford Nanopore sequencing of three flowcells yielded 13.30, 12.47, and 13.91 Gbp (4,401,106, 4,551,630, and 7,027,597 reads respectively) and Illumina sequencing yielded 129 Gbp (860,037,886 reads). GenomeScope analysis of the PE genomic data inferred a genome size of 1.89 Gbp and a heterozygosity of 1.3% (Figure 1B). Assembly with MaSuRCA yielded an initial assembly consisting of 81,742 scaffolds totaling 3.11 Gbp with an N50 of 59.9 Kbp. After polishing and purging redundant haplotigs, the assembly was reduced to 62,284 scaffolds totaling 2.77 Gbp with an N50 of 66.1 Kbp. Despite being somewhat fragmented, the resulting assembly is rather complete with 94.9% of BUSCOs detected (83.3% complete plus 11.6% fragmented). After removing putative contaminant scaffolds – those with fewer than 10 mapping Illumina reads, not annotated as Metazoa (Proteobacteria, Firmicutes, and “Bacteria-undef”) or as “no-hit” in BlobTools, and/or with a GC content <0.30 or >0.55 – the final assembly consisted of 57,495 scaffolds totaling 2.52 Gbp with an N50 of 65.0 Kbp, an N90 of 19.97 Kbp, an L50 of 10.42 Kbp, an L90 of 38.44 Kbp, and a longest scaffold of 0.8 Mbp. After removal of putative contamination, 92.0% of BUSCOs could be detected (79.4% complete [74.4% single-copy and 5.0% duplicated], 12.6% fragmented, and 8.0% missing).\n\nAt 2.5 Gbp, the Hanleya hanleyi genome is over four times the size of that of the only other chiton with a genome sequenced to date, Acanthopleura granulata. RepeatModeler identified 327 families of repeats across five major classes (Table 1). The diversity of repetitive DNA motifs in the Hanleya genome is on par with that of other molluscan genomes with the exception of long terminal repeats (LTRs), which are much more diverse (100 different types) in Hanleya than any other molluscan genome we examined. A majority of repeats were annotated by RepeatClassifier as unclassified, likely because there are still few molluscan genomes incorporated in repetitive element databases. The genome of Hanleya has more than double the total repetitive content of that of Acanthopleura: 66.41% total interspersed repeats in Hanleya compared to 23.56% in Acanthopleura (Varney et al. 2020). Moreover, to our knowledge, the genome of Hanleya has an overall repetitive content higher than any mollusc sequenced to date (Gomes-dos-Santos et al. 2020).\n\nBRAKER predicted 69,284 gene models with 92.9% of BUSCOs detected (81.8% complete [75.6% single-copy and 6.2% duplicated], 11.1% fragmented, and 7.1% missing). Of these, 35,362 were supported by transcriptome and/or protein evidence. Removal of gene models not supported by transcriptome or protein evidence had little effect on the estimated completeness of the gene models as 92.2% of BUSCOs were detected (81.3% complete [75.2% single-copy and 6.1% duplicated] 10.9% fragmented, and 7.8% missing).\n\nComparison of the full set of Hanleya gene models to the gene models from 20 other lophotrochozoans in OrthoFinder resulted in 185,272 groups of homologous sequences. Our pipeline selected 2,331 single-copy genes sampled for at least 18 of the 21 taxa. Of these, Hanleya was sampled for 2,168 genes (93%), further demonstrating the completeness of this genome. For comparison, Lottia gigantea (Gastropoda) was sampled for 2,243, Crassostrea virginica (Bivalvia) was sampled for 2,076, and Acanthopleura granulata (Polyplacophora) was sampled for 1,999. Concatenation resulted in a supermatrix 831,793 amino acids in length with 16.7% missing data. Phylogenetic analysis resulted in a strongly supported tree with maximal support for Polyplacophora and placement of Polyplacophora as sister to all other sampled molluscs (Figure 1C).\n\nSequencing data has been uploaded to NCBI SRA (see Underlying data) and all other results to Figshare (see Extended data (Kocot 2022)).\n\n\nConclusions\n\nDespite challenges in assembling this relatively large (2.5 Gbp), heterozygous (1.3%), and repetitive (66.4%) genome, BUSCO analysis indicates that it is rather complete with 92.0% of BUSCOs detected in the final, decontaminated genome and 92.9% and 92.2% of BUSCOs detected in the full and evidence-supported predicted transcript sets, respectively. Our orthology inference pipeline recovered 93% of the genes sampled from at least 18/21 lophotrochozoan genomes in the Hanleya, further supporting the near completeness of this genome.\n\n\nData availability\n\nNCBI Sequence Read Archive (SRA): RNA-Seq of Hanleya hanleyi mantle. Accession number SRX8235059. https://identifiers.org/ncbiprotein:SRX8235059.\n\nNCBI SRA: Illumina Sequencing of Hanleya hanleyi gDNA. Accession number SRR18273088. https://identifiers.org/ncbiprotein:SRR18273088.\n\nNCBI SRA: GridION Sequencing of Hanleya hanleyi gDNA. Accession numbers SRX14411365, https://identifiers.org/ncbiprotein:SRX14411365; SRX14411366, https://identifiers.org/ncbiprotein:SRX14411366; and SRX14411367, https://identifiers.org/ncbiprotein:SRX14411367.\n\nFigshare: Hanleya hanleyi genome extended data. https://doi.org/10.6084/m9.figshare.19672449.v2 (Kocot 2022).\n\nThis project contains the following extended data:\n\n- 01_Jellyfish_and_GenomeScope.zip (Jellyfish and GenomeScope results)\n\n- 02_MaSuRCA.zip (genome assembly produced by MaSuRCA)\n\n- 03_purge_dups.zip (heterozygosity-purged genome assembly)\n\n- 04_POLCA.zip (purge_dups output polished with Illumina reads in POLCA)\n\n- 05_QUAST_and_BUSCO_on_final_genome_assembly.zip (QC of final assembly after POLCA)\n\n- 06_RepeatMasker_and_RepeatModeler.zip (RepeatMasker & RepeatModeler output)\n\n- 07_BlobTools.zip (BlobTools contamination screening results)\n\n- 08_BRAKER.zip (Genome annotation with BRAKER)\n\n- 09_BUSCO_on_gene_models.zip (QC on final gene models produced by BRAKER)\n\n- final_genome_assembly_and_annotations.zip (final genome assembly and annotation)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nEthical approval\n\nEthics permits were not required to undertake this research because Institutional Animal Care and Use Committee (IACUC) review is not required for use of invertebrates in research activities at the University of Alabama.",
"appendix": "Acknowledgments\n\nWe thank the late Dr. Hans Tore Rapp for gifting us the specimen of Hanleya hanleyi that inspired this project. We thank Dr. John Sutton for advice regarding Oxford Nanopore library preparation.\n\n\nReferences\n\nBlaxter M, Challis R: BlobToolkit. BlobToolKit; 2018. Reference Source\n\nBolger AM, Lohse M, Usadel B: Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15): 2114–2120. PubMed Abstract | Publisher Full Text\n\nBrooker LR, Shaw JA: The chiton radula: a unique model for biomineralization studies. Advanced Topics in Biomineralization. 2012; 1: 65–84.\n\nBrůna T, Hoff KJ, Lomsadze A, et al.: BRAKER2: automatic eukaryotic genome annotation with GeneMark-EP+ and AUGUSTUS supported by a protein database. NAR Genom. Bioinform. 2021; 3(1): lqaa108. PubMed Abstract | Publisher Full Text\n\nBrůna T, Lomsadze A, Borodovsky M: GeneMark-EP+: eukaryotic gene prediction with self-training in the space of genes and proteins. NAR Genom. Bioinform. 2020; 2(2): lqaa026. PubMed Abstract | Publisher Full Text\n\nBuchfink B, Xie C, Huson DH: Fast and sensitive protein alignment using DIAMOND. Nat. Methods. 2015; 12(1): 59–60. PubMed Abstract | Publisher Full Text\n\nChallis R, Richards E, Rajan J, et al.: BlobToolKit – Interactive Quality Assessment of Genome Assemblies. G3 Genes|Genomes|Genetics. 2020; 10(4): 1361–1374. Publisher Full Text\n\nDobin A, Davis CA, Schlesinger F, et al.: STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013; 29(1): 15–21. PubMed Abstract | Publisher Full Text\n\nEmms DM, Kelly S: OrthoFinder: phylogenetic orthology inference for comparative genomics. Genome Biol. 2019; 20(1): 1–14. Publisher Full Text\n\nGarcía-Álvarez O, Salvini-Plawen LV: Species and diagnosis of the families and genera of Solenogastres (Mollusca). Iberus. 2007; 25(2): 73–143.\n\nGomes-dos-Santos A, Lopes-Lima M, Castro LFC, et al.: Molluscan genomics: the road so far and the way forward. Hydrobiologia. 2020; 847(7): 1705–1726. Publisher Full Text\n\nKocot K: Hanleya hanleyi genome extended data. figshare. [Dataset].2022. Publisher Full Text\n\nKocot KM, Poustka AJ, Stöger I, et al.: New data from Monoplacophora and a carefully-curated dataset resolve molluscan relationships. Sci. Rep. 2020; 10(1): 101–108. PubMed Abstract | Publisher Full Text\n\nKrueger F: 2017. TrimGalore. Reference SourceReference Source\n\nLi H: Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics. 2018; 34(18): 3094–3100. PubMed Abstract | Publisher Full Text\n\nManni M, Berkeley MR, Seppey M, et al.: BUSCO Update: Novel and Streamlined Workflows along with Broader and Deeper Phylogenetic Coverage for Scoring of Eukaryotic, Prokaryotic, and Viral Genomes. Mol. Biol. Evol. 2021; 38(10): 4647–4654. PubMed Abstract | Publisher Full Text\n\nMikheenko A, Prjibelski A, Saveliev V, et al.: Versatile genome assembly evaluation with QUAST-LG. Bioinformatics. 2018; 34(13): i142–i150. PubMed Abstract | Publisher Full Text\n\nMinh BQ, Schmidt HA, Chernomor O, et al.: IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era. Mol. Biol. Evol. 2020; 37(5): 1530–1534. PubMed Abstract | Publisher Full Text\n\nRanallo-Benavidez TR, Jaron KS, Schatz MC: GenomeScope 2.0 and Smudgeplot for reference-free profiling of polyploid genomes. Nat. Commun. 2020; 11(1): 1432. PubMed Abstract | Publisher Full Text\n\nSigwart JD: Gross anatomy and positional homology of gills, gonopores, and nephridiopores in “basal” living chitons (Polyplacophora: Lepidopleurina). Am. Malacol. Bull. 2008; 25(1): 43–49. Publisher Full Text\n\nSigwart JD, Schwabe E, Saito H, et al.: Evolution in the deep sea: a combined analysis of the earliest diverging living chitons (Mollusca: Polyplacophora: Lepidopleurida). Invertebr. Syst. 2011; 24(6): 560–572. Publisher Full Text\n\nSirenko BI, Sigwart J, Dell'Angelo B: Hanleya hanleyi (Bean in Thorpe, 1844) (Mollusca, Polyplacophora) and the influence of the Gulf Stream System on its distribution. Ruthenica. 2016; 26(2).\n\nSmit AFA, Hubley R: RepeatModeler Open-1.0. (2008-2015). Accessed December 29, 2020. Reference Source\n\nSpeiser DI, Eernisse DJ, Johnsen S: A Chiton Uses Aragonite Lenses to Form Images. Curr. Biol. 2011; 21(8): 665–670. Publisher Full Text\n\nVarney RM, Speiser DI, McDougall C, et al.: The iron-responsive genome of the chiton Acanthopleura granulata. Genome Biol. Evol. 2021; 13(1). PubMed Abstract | Publisher Full Text\n\nWick RR: Porechop (Version 0.2.1) [Computer software].2018. Reference Source\n\nZimin AV, Puiu D, Luo M-C, et al.: Hybrid assembly of the large and highly repetitive genome of Aegilops tauschii, a progenitor of bread wheat, with the MaSuRCA mega-reads algorithm. Genome Res. 2017; 27(5): 787–792. PubMed Abstract | Publisher Full Text\n\nZimin AV, Salzberg SL: The genome polishing tool POLCA makes fast and accurate corrections in genome assemblies. PLoS Comput. Biol. 2020; 16(6): e1007981. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "138695",
"date": "24 Jun 2022",
"name": "Vanessa L. Gonzalez",
"expertise": [
"Reviewer Expertise Biodiversity Genomics",
"Invertebrate Biology",
"Bioinformatics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript is clear, concise, well written and scientifically sound. This phylogenetically important taxon’s genome assembly is a much-needed addition to the currently sampling of available molluscan genomes. All methods are explicitly outlined and are appropriate for the genome assembly (hybrid assembly, annotation & phylogenetic methods). The outcome of the annotation process is expected with the resulting contiguity of the genome (fragmented).\nNot sure if I have missed it in the text, but is seems as though the database and database version that was used to calculate the BUSCO scores is not listed (maybe Metazoa?). If it was the Metazoan database, I think it would be helpful to also add the BUSCO scores for the Molluscan specific database as well.\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Yes",
"responses": []
},
{
"id": "145650",
"date": "10 Aug 2022",
"name": "Samuel Abalde",
"expertise": [
"Reviewer Expertise Phylogenomics",
"Bioinformatics",
"Genomics",
"Invertebrate Biology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nMollusca is an important animal phylum, and as such it has received a lot of attention from the scientific community. However, it is important to note that much of this attention has been drawn towards the three most diverse and economically important molluscan classes, while all other have been relatively neglected. From a genomic perspective the scenario is similar, with all but two mollusk genomes published to date sequenced from the same three classes. Despite the importance of the Aculifera, the clade containing chitons and aplacophorans, one of the two main clades of mollusks and hence fundamental to fully understanding mollusk evolution, only one genome has been generated to date, hampering comparative studies.\nIn this manuscript, Varney et al. report the complete genome of the chiton Hanleya hanleyi, the second aculiferan (and chiton) genome. The genome is relatively fragmented but seems to be very complete, and it will become an important addition to future studies of mollusk evolution.\nI would like to congratulate the authors for their work. The manuscript is concise but it presents all the relevant information and the methods look sound. I have only three minor comments that, although will not change substantially the manuscript, I think the authors should consider:\n“Extant chitons can be divided into two major clades: Chitonida, the clade represented by the previously published Acanthopleura genome, and Lepidopleurida, which includes Hanleya.” I am not an expert on chiton systematics, but to the best of my knowledge there are three main groups: Callochitonida, Chitonida, and Lepidopleurida. The same three groups were recovered in a recent phylogeny1. I am not aware of more recent updates on this matter, but if so then I think this should be referenced in the text to avoid misunderstandings.\n\nPertaining to the previous comment: “Because of this suite of putatively ancestral characteristics and its phylogenetic position as the sister taxon to all other chitons, Lepidopleurida is thought to be critical to understanding large-scale patterns in molluscan evolution.” If we accept there are only two main groups, then Lepidopleurida is as sister to all other chitons as Chitonida, so this sentence is technically correct but misleading, because it makes you think of a ladderized tree and not in a sister relationship. If we consider the three groups mentioned above, then this sentence is correct.\n\nAs for the repeat content, I wonder about their distribution in the genome. This number is not high enough to rise suspicions, there are other genomes above 50%, but since it will set the new upper limit for repeat content in molluscan genomes I would like to double check this figure is correct. Are the repeats scattered around the genome? Is it possible that they might be concentrated in a few contigs that should be quality-checked?\n\nAre the rationale for sequencing the genome and the species significance clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of the sequencing and extraction, software used, and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a usable and accessible format, and the assembly and annotation available in an appropriate subject-specific repository? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-555
|
https://f1000research.com/articles/11-554/v1
|
20 May 22
|
{
"type": "Policy Brief",
"title": "Promoting access of hydroxyurea to sickle cell disease individuals: Time to make it an essential medicine",
"authors": [
"Manase Kilonzi",
"Hamu Mlyuka",
"Agnes Jonathan",
"Hilda Tutuba",
"Lulu Chirande",
"Paschal Rugajo",
"Irene Kida",
"Emmanuel Balandya",
"Julie Makani",
"Nathanael Sirili",
"Hamu Mlyuka",
"Agnes Jonathan",
"Hilda Tutuba",
"Lulu Chirande",
"Paschal Rugajo",
"Irene Kida",
"Emmanuel Balandya",
"Julie Makani",
"Nathanael Sirili"
],
"abstract": "Hydroxyurea (HU) alone has the potential to prevent one out of every three deaths due to sickle cell disease (SCD) and almost all forms of disabilities caused by SCD. However, in Tanzania, only one out of every six registered SCD patients in the SPARCO-Tanzania Sickle Cell Cohort use HU. We conducted studies to understand factors influencing utilization of HU in Tanzania and discovered that among the reason for low utilization of HU include HU is classified as anticancer medication, only hematologists are supposed to prescribe HU, limited HU prescription to only National and Specialized hospitals, a special permit is required to access HU using National Health Insurance Fund (NHIF) scheme and limited importation and absence of local manufacturing of HU limit availability of this important drug in Tanzania. Therefore, with this brief, the government should allow prescription of HU to the district hospitals level, should allow all clinicians with a minimum of a Bachelor of Medicine to prescribe HU, and accessibility of HU through NHIF should be friendly.",
"keywords": [
"Hydroxyurea",
"Quality of Life",
"Sickle Cell Disease and Tanzania"
],
"content": "Introduction\n\nSickle cell disease (SCD) is an inheritable lifetime disease whereby red blood cells (RBC) (which are the vehicles for transportation and distribution of oxygen in the body) change shape and appear as a sickle. The sickled RBCs fail to pass smoothly in small blood vessels hence they accumulate and cause occlusion.1 The blockage of the blood vessels results in poor blood supply, episodes of severe pain, and damage of affected parts of the body, particularly the brain, kidney, spleen, lungs, bones, and heart. This reduces the quality of life, and when unattended, results in 50-90% risk of deaths,2 brings social and economic burden to the affected one, family and the nation at large.3\n\nTanzania has the fourth highest burden of SCD in the world. Every year more than 11,000 children are born with SCD in Tanzania.2 In the absence of care, the majority of children with SCD will not live to adulthood. In Tanzania, SCD contributes to approximately 7% of all deaths among children below five years of age.4 In addition, the mean lifespan of Tanzanians with SCD is 33 years4 which is half the average lifespan of the general population.\n\nAvailable interventions to improve the quality of life of the individuals with SCD include awareness creation, newborn screening, preventive treatment and vaccines against bacterial infections, daily Vitamin B9 supplement, malaria prevention, and medications, routine blood transfusion, bone marrow transplant (a cure but expensive and not readily available), correction of the defective gene (a cure but expensive and not readily available) and use of hydroxyurea (HU). Of all the interventions, HU has proved to be cost-effective and safe. Currently, HU is the only medication used by those with SCD and its benefit have outweighed the risk. The uses of HU among SCD individuals have the following benefits: prevention of brain damage by stroke, prevention of renal failure, liver failure, and infections. Furthermore, HU prevents malaria infection, reduces the frequency of blood transfusion and the risk of death.\n\nDespite HU being a simple oral medication with more than 30 years of evidence of being very effective and safe, it is not readily available, affordable, and accessible to patients with SCD in Tanzania.5 So far, out of 5,064 registered SCD patients at SPARCO-Tanzania Sickle Cell Cohort, only 15.68% (794) receive HU.\n\n\nMethods\n\nThis policy brief has been prepared after conducting two qualitative pieces of research and managed to establish reasons for the underutilization of HU among SCD individuals in Tanzania.6,7 Additionally, we conducted a literature review to gather information with regards to SCD and the uses of HU. One five year follow-up study involving 1,700 participants established reasons for mortality among patients with SCD in Tanzania.3 Another three year randomized controlled clinical trial involving 600 participants established the effectiveness, safety, and feasibility of HU among patients with SCD in East and Central Africa.8 Another study followed up 299 patients with SCD for 17.5 years to establish the long-term risks and benefits of HU.9 Other sources of data came from two scoping reviews articles from Tanzania,1,2 Tanzania National Treatment Guideline and Essential Medicines List,10,11 Health Sector Strategic Plan 2021-202612 and Strategic and Action Plan for Prevention and Control of Non-Communicable Diseases in Tanzania 2016-2020.13\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Com-mittee) of MUHAS (Ref. No. DA. 282/298/01.C/. and 31/07/2020).\n\nWritten informed consent was obtained from all subjects involved in the study.\n\nPolicy gaps to be addressed (Figure 1)\n\nWhat should be done to improve utilization of HU among SCD individuals in Tanzania\n\nTo achieve the goal of ensuring 70% of SCD patients receive standardized care and treatment and reduction of 50% of SCD-related deaths as stated in the strategic and action plan for the prevention and control of non-communicable diseases in Tanzania 2016 – 2020 (section 3.9 Expected Outcomes),13 the Ministry of Health should consider:\n\n1. Extending prescription of HU to patients with SCD attending regional and district hospitals which have laboratory facilities for monitoring of blood parameters for patients on treatment.\n\n2. Re-categorizing HU as the medication for cancer and non-cancer diseases.\n\n3. Discussing with NHIF and remove the need for a special permit when issuing HU to SCD individuals.\n\n4. Providing HU to individuals with SCD under a vertical program.\n\n• Capitalize on the experiences from tuberculosis, HIV/AIDS, and Neglected Tropical Diseases control programs.\n\n5. Including HU in the subsidization scheme as an additional incentive on top of its inclusion in the Tanzania Orphan Drug Regulation of 2018.\n\n• Capitalize on the experiences from antimalarial medications, particularly Artemether-Lumefantrine.\n\n6. Providing a more supportive environment (in collaboration with Ministries responsible for Finance, Industry, and Business) to local pharmaceutical manufacturers in terms of more subsidization of raw materials and infrastructures for manufacturing of HU for SCD in Tanzania.\n\n• This will help to realize priory number VIII in the health sector strategic plan 2021-202612 which aims at “Improvement of research and development in health services to establish and strengthen research mechanisms on domestic pharmaceutical manufacturing that meet international standards for domestic and export use”.\n\n7. Creating (in collaboration with health research institutions) an easily accessible platform of reliable data on the burden of SCD and the need for HU in Tanzania which will help local pharmaceutical importers and manufacturers during the establishment of estimated demand and application for registration of HU.\n\n\nData availability\n\nData availability statement: Data are not available publicly because they contain sensitive inter-view information and participants did not consent for their interviews to be shared publicly. The data are available from The Directorate of Research and Publication Muhimbili University of Health and Allied Sciences (contact via drp@muhas.ac.tz Tel.: +2552150302-6) for researchers who will be able to explain the reasons why they want access to the confidential information. Furthermore, the researcher should be affiliated to the registered institution.\n\n\nAuthors contribution\n\nMK, HJM and NS prepared the first draft of the policy brief. AJ, LC, IMK, HT, PR, EB and JM reviewed and improved the policy brief. All authors have read and agreed to the submitted policy brief draft.",
"appendix": "Acknowledgments\n\nAuthors acknowledge the support of Sickle-Pan African Research Consortium (SPARCO)-Tanzania under the Muhimbili Sickle Cell Program at the Muhimbili University of Health and Allied Sciences (MUHAS) for their support towards the realization of this policy brief.\n\n\nReferences\n\nLuzzatto L, Makani J: Hydroxyurea — An Essential Medicine for Sickle Cell Disease in Africa. N. Engl. J. Med. 2019; 380: 187–189. PubMed Abstract | Publisher Full Text\n\nTluway F, Makani J: Sickle cell disease in Africa: an overview of the integrated approach to health, research, education and advocacy in Tanzania, 2004–2016. Br. J. Haematol. 2017; 177: 919–929. PubMed Abstract | Publisher Full Text\n\nMakani J, et al.: Mortality in sickle cell anemia in Africa: A prospective cohort study in Tanzania. PLoS One. 2011; 6: e14699. PubMed Abstract | Publisher Full Text\n\nMakani J, et al.: Health policy for sickle cell disease in Africa: Experience from Tanzania on interventions to reduce under-five mortality. Trop. Med. Int. Heal. 2015; 20: 184–187. PubMed Abstract | Publisher Full Text\n\nTaher AT: Making hydroxyurea affordable for sickle cell disease in Tanzania is essential (HASTE): How to meet major health needs at a reasonable cost.2020; 2–5. Publisher Full Text\n\nKilonzi M, et al.: Barriers, and Facilitators of Use of Hydroxyurea among Children with Sickle Cell Disease: Experiences of Stakeholders in Tanzania. Hemato. 2021; 2: 713–726. Publisher Full Text\n\nMlyuka HJ: PLOS ONE Barriers, and facilitators of availability of hydroxyurea for sickle cell disease in Tanzania; a qualitative study of pharmaceutical manufacturers, importers, and regulators.2018.\n\nTshilolo L, et al.: Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa. N. Engl. J. Med. 2019; 380: 121–131. PubMed Abstract | Publisher Full Text\n\nSteinberg MH, et al.: The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5-year follow-up. Am. J. Hematol. 2010; 85: 403–408. PubMed Abstract | Publisher Full Text\n\nMHCDGEC: Standard treatment guidelines & national essential medicines list, Tanzania mainland.2019; 453.\n\nHussein Mwinyi H: the United Republic of Tanzania Standard Treatment Guidelines and Essential Medicines List Ministry of Health and Social Welfare Fourth Edition. Tanzania Ministry. Heal. Soc. Welf. 2013; 42–43.\n\nMoHCDGEC: Tanzania Health Sector Strategic Plan 2021-2026.2021; 2026: 104.\n\nThe United Republic of Tanzania: Strategic Action Plan for Prevention and control of non-communicable diseases in Tanzania 2016-2020. Minist. Heal. Community Dev. Gender, Elder. Child. 2016; 117."
}
|
[
{
"id": "193815",
"date": "16 Aug 2023",
"name": "Angela E. E. Rankine-Mullings",
"expertise": [
"Reviewer Expertise Sickle Cell Disease and Hydroxyurea Utilization for Improved Disease Outcomes"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper summarizes reasons for underutilization of hydroxyurea in Tanzania among persons with sickle cell disease and gives recommendation on how to promote access of hydroxyurea to persons with sickle cell disease. Importantly the authors show how existing resources can be utilized to improve accessibility of hydroxyurea in Tanzania. I believe this is an extremely important topic and this manuscript is very helpful to inform public health interventions aimed at improving disease outcome among persons with sickle cell disease. Thus, I reviewed this paper with great appreciation of the authors efforts.\nPlease note minor corrections and suggestions:\nThe term Persons/individuals with SCD is preferred to SCD individuals.\nAbstract: The writers may wish to add to the phrase “clinicians with a minimum of a Bachelor of Medicine to prescribe HU” after appropriate basic training to prescribe hydroxyurea for persons with sickle cell disease.\nThis is not critical, and I leave this to the author to decide, Based on my experience optimizing hydroxyurea treatment among persons with sickle cell disease is also dependent on physician knowledge and experience.\nFigure 1 should be referenced and labelled comprehensively to stand alone and represent the manuscript fully if anyone should read the figure without reading the text. For example: Figure 1. Summary of the reasons found in previous qualitative research in the underutilization of HU among individuals with SCD in Tanzania and its consequences6,7\n\nActions to improve utilization of HU among individuals with SCD in Tanzania should be categorized for easier reading. For example:\nRecommendations to improve the availability of hydroxyurea among persons with sickle cell disease in Tanzania\n6. Providing a more supportive environment to local pharmaceutical manufacturers in terms of more subsidization of raw materials and infrastructures for manufacturing of HU for SCD in Tanzania (in collaboration with Ministries responsible for Finance, Industry, and Business).\n• This will help to realize priory number VIII in the health sector strategic plan 2021-202612 which aims at “Improvement of research and development in health services to establish and strengthen research mechanisms on domestic pharmaceutical manufacturing that meet international standards for domestic and export use”.\n\n7. Creating (in collaboration with health research institutions) an easily accessible platform of reliable data on the burden of SCD and the need for HU in Tanzania which will help local pharmaceutical importers and manufacturers during the establishment of estimated demand and application for registration of HU.\nRecommendations to increase the accessibility of hydroxyurea to persons with SCD in Tanzania\n\n1. Extending prescription of HU to patients with SCD attending regional and district hospitals which have laboratory facilities for monitoring of blood parameters for patients on treatment.\n\n3. Discussing with NHIF and remove the need for a special permit when issuing HU to SCD individuals.\nRecommendations to improve patient acceptability and affordability of hydroxyurea to persons with SCD in Tanzania\n2. Re-categorizing HU as the medication for cancer and non-cancer diseases.\n\n4. Providing HU to individuals with SCD under a vertical program.\n• Capitalize on the experiences from tuberculosis, HIV/AIDS, and Neglected Tropical Diseases control programs.\n\n5. Including HU in the subsidization scheme as an additional incentive on top of its inclusion in the Tanzania Orphan Drug Regulation of 2018.\nCapitalize on the experiences from antimalarial medications, particularly Artemether-Lumefantrine.\n\nIt would be interesting to examine the experience of hydroxyurea accessibility in Tanzania among patients that are prescribed hydroxyurea for other indications outside of sickle cell disease. Is it easily available or are there issues with supply and demand? Networking with health care providers in other areas where hydroxyurea is prescribed may also be useful when setting up the “accessible platform of reliable data on the burden of SCD and the need for HU in Tanzania”\n\nDoes the paper provide a comprehensive overview of the policy and the context of its implementation in a way which is accessible to a general reader? Yes\n\nIs the discussion on the implications clearly and accurately presented and does it cite the current literature? Yes\n\nAre the recommendations made clear, balanced, and justified on the basis of the presented arguments? Yes",
"responses": []
},
{
"id": "193800",
"date": "25 Aug 2023",
"name": "Lewis Hsu",
"expertise": [
"Reviewer Expertise Sickle cell disease",
"implementation science",
"community engagement"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis Policy Brief presents the benefits of hydroxyurea (HU) for sickle cell disease (SCD) and urges policy changes to increase access to hydroxyurea in Tanzania.\n\nCurrent data about SCD are concisely presented, including the large number of Tanzanians affected, the high morbidity and mortality, and the range of treatments available. The solid evidence on safety and benefits of HU for reducing SCD acute and chronic complications are presented, as well as ease of use. The policy steps proposed are very likely to increase access to HU, and very likely to reduce morbidity and mortality of SCD in Tanzania.\n\nMinor critique\nIntroduction, third paragraph. \"HU prevents malaria infection\" seems too strong. Consider modifying to be more precise: \"HU reduces malaria mortality\" (Olupot-Olupot P, Tomlinson G, Williams TN, Tshilolo L, Santos B, Smart LR, McElhinney K, Howard TA, Aygun B, Stuber SE, Lane A, Latham TS, Ware RE. Hydroxyurea treatment is associated with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa. Blood. 2023 Mar 23;141(12):1402-1410. doi: 10.1182/blood.2022017051.)\n\nThere is strong evidence that blood transfusion and hospitalizations are reduced by HU. Will the reduction per person be offset by the greater number of individuals with SCD surviving to adulthood on HU in Tanzania?\nConsider clarifying in this Policy Brief whether achieving the goal of 50% reduction of SCD-related deaths assumes that HU is started at a specific age (9 months? 2 years?) and a minimum proportion of the individuals with SCD?\nThe paper focuses on increasing access to HU, which is necessary but not sufficient for large-scale implementation of HU for the SCD population in Tanzania. Will a public education campaign be needed to persuade parents that SCD could be less fatal with hydroxyurea, and accept the costs of coming to continue prescriptions for young children? What will be the effect on the patient volume of primary health centers? Can the hydroxyurea and lab test monitoring be tracked adequately in settings other than the tertiary care medical centers? Will patients stay consistently on the treatment, especially in the 5-17year-old age range which when previous work from Tanzania showed were likely to be \"Lost to Follow-up\" (LTFU)? (Masamu U, Sangeda RZ, Kandonga D, Ondengo J, Ndobho F, Mmbando B, Nkya S, Msami K, Makani J. Patterns and patient factors associated with loss to follow-up in the Muhimbili sickle cell cohort, Tanzania. BMC Health Serv Res. 2020 Dec 14;20(1):1141. doi: 10.1186/s12913-020-05998-6. PMID: 33317526; PMCID: PMC7737273.) Could lessons be learned from implementation of ART drug use in HIV-infected patients, or even build SCD services with the same infrastructure? Would systems and programs that lower LTFU in HIV/AIDS be applied to SCD: adherence support programs, outreach to patients, and community-based adherence support clubs?\n\nDoes the paper provide a comprehensive overview of the policy and the context of its implementation in a way which is accessible to a general reader? Yes\n\nIs the discussion on the implications clearly and accurately presented and does it cite the current literature? Yes\n\nAre the recommendations made clear, balanced, and justified on the basis of the presented arguments? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-554
|
https://f1000research.com/articles/11-553/v1
|
20 May 22
|
{
"type": "Research Article",
"title": "The role of endothelial microparticles in children with asthma: Does it promote atherosclerosis progress?",
"authors": [
"Lisa Adhia Garina",
"Bambang Supriyatno",
"Faisal Yunus",
"Ina Susianti Timan",
"Bambang Hermani",
"Aria Kekalih",
"Cissy B. Kartasasmita",
"Suhendro Suwarto",
"Bambang Supriyatno",
"Faisal Yunus",
"Ina Susianti Timan",
"Bambang Hermani",
"Aria Kekalih",
"Cissy B. Kartasasmita",
"Suhendro Suwarto"
],
"abstract": "Background: Asthma is a chronic inflammatory airway disease that has been linked to enhanced risks for atherosclerosis. The impact of asthma on cardiovascular disease risk in children is less well established. Asthma is defined by a history of respiratory symptoms and accompanied by airflow limitation, with heterogeneous clinical manifestations, and variability in the intensity of airway inflammation and remodeling. Endothelial microparticles (EMP) are biomarkers of endothelial dysfunction in several chronic diseases. Endothelial microparticles initiate an event of atherosclerotic plaque formation. Our study aimed to evaluate the role of endothelial microparticles in children with asthma.\nMethods: A cross-sectional study was performed on a total of 50 children with asthma aged seven‒17 years. Children with asthma exacerbations, infections, and steroid use were excluded. Endothelial microparticles were measured with beads, and the fluorescence signal was measured using a flow cytometer. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA) method. Results: Based on the results from 50 asthmatic children, it was found that most children had a normal nutritional status, intermittent, and allergic asthma. The results of this study also showed that the circulation of asthmatic children found that the mean levels (µL) of CD31+/CD62E+, CD31+/CD62E-, and CD62E+/CD31- were 2,392.99 ± 7,787.94; 922.14 ± 1,554.03; 198.97 ± 387.68, with the average ratio of CD31+/CD62E+, which was ≤1.0 and identifies apoptosis. Path analysis results found that IL-6, TNF-α, and CD31+/CD62E- EMP played a role in peak expiratory flow rate (%PEFR, p = 0.02; p = 0.003; p = 0.04) in children with allergic asthma.\nConclusions: Endothelial microparticles play a role on peak expiratory flow rate (PEFR) in children with allergic asthma. Further study is needed to investigate the role of these biomarkers and their correlation with pro-inflammatory cytokines in the mechanism of atherosclerosis progression.",
"keywords": [
"asthma",
"children",
"endothelial dysfunction",
"microparticles"
],
"content": "Introduction\n\nAsthma is still a global health problem with an increasing prevalence, especially in children.1 The prevalence of asthma has continued to increase in both children and adults over the last two decades, especially in developing countries with low incomes.2,3 Asthma is defined by a history of respiratory symptoms and is accompanied by airflow limitation, with heterogeneous clinical manifestations, and varied intensity of airway inflammation and remodeling.4\n\nAsthma is usually characterized by chronic airway inflammation associated with type 2 cytokines, which promote airway eosinophilia, mucus overproduction, bronchial hyperresponsiveness, and immunoglobulin E synthesis, with a potential systemic impact,1,5,6 and an important mechanism of susceptibility to asthma exacerbation.7 Although the previous studies identified increased Th2 inflammation in 70% of asthmatic patients, 30% of the cohort did not present evidence of airway Th2 inflammation.8\n\nCytokines produced by CD4+ Th2 play a role in bronchial inflammation and remodeling, whereas eosinophils and myofibroblasts have an impact on airway damage and remodeling.9 Previous studies have focused on several cytokines, such as IL-4, IL-5, IL-13 and IL-17, whereas IL-6 was previously known to be the result of ongoing inflammation in respiratory airways. IL-6, along with other inflammatory markers in the lung, can be a modulator of an immune response.10 the production of IFN-α and IL-6 was also found to be significantly higher in dendritic cells (DCs) with age.11\n\nInflammation in asthma is characterized by the infiltration of inflammatory cells and differs in the inflammatory process.12 Several diseases characterized by chronic inflammation have been linked to enhanced atherosclerosis,13 one of them being allergic asthma, which is associated with distinct atherosclerotic artery changes.5 Asthma is related to an increased cardiovascular disease (CVD) risk in adults, but the effect on CVD risk in children is inadequately established.14 In a large multiethnic cohort, persistent asthmatics had a higher CVD event rate than non-asthmatics.15\n\nA decrease in the elastic properties of the walls of blood vessels, and a violation of the endothelial structure is seen in children with asthma, which is a pathological process. The extensive impact of the manifestations of the bronchial obstruction on the functional state of the vascular endothelium is proved by the presence of an association with pulmonary function.16 Allergic asthma and atopic children had higher right carotid bifurcation (RCB) intima-media thickness (IMT) compared to those without these conditions.14\n\nDevelopment endothelial dysfunction is accompanied by activation of endothelial cells, which activates mediators of inflammation and adhesion molecules.16,17 Inflammation leads to endothelial cells activation, endothelial cells play a role and are controllers of the inflammatory process and intracellular adhesion molecules.16 Increased endothelin-1 (ET-1) expression and decreased endothelial nitric oxide synthase (eNOS) can impact the proliferation and pulmonary vascular vasospasm induced by endothelial dysfunction due to pulmonary arterial hypertension (PAH). Study results have shown an association between endothelial function and vasculature remodeling in PAH.17\n\nThe evidence for the cause of endothelial dysfunction in asthma is still unclear. In patients with asthma or chronic bronchitis, increased vascular endothelial growth factor (VEGF) and vascular remodeling in the airways may have a more critical role.18 The endothelial dysfunction in asthmatic children has been defined in exacerbation and remission. The severity of the disease leads to a degree of damage to endothelial dysfunction.16 Previous research has found that there is a correlation between a history of childhood asthma on arterial stiffness and its progress in young adults with overweight, obese or hypertension.19\n\nPrevious research has proven that endothelial dysfunction also appears in asthma and involves the regulation of endothelial progenitor cells. The inflammation mechanism may cause alterations in the endothelium; some treatments could target these mechanisms and enhance underlying endothelial function.18 The presence of tissue damage, cellular activation, and apoptosis releases microparticles (MP). MPs in circulation come from several cell types, namely endothelial cells, monocytes, leukocytes, platelets, T cells, and neutrophils. Bioactive molecules, including receptors, ligands, functional RNA, and enzymes, may be activated by MPs based on their origin.20\n\nMPs also have potential roles in patients with asthma, diffuse parenchymal lung disease, thromboembolism, lung cancer, and pulmonary arterial hypertension.21 Endothelial cell activation with TNF-α increases the production of CD62E, CD54, and CD106. Levels of CD31, CD105, and CD144 were found to increase in endothelial cells undergoing apoptosis. The CD31 (PECAM-1) release tends to be stimulated by apoptosis of damaged endothelial cells.22 A previous study found that the high E-selectin endothelial microparticles (EMPs) levels predict rapid FEV1 decline.23\n\nEMPs release is triggered by various stimulations followed by various pathways that can collectively promote atherogenesis; increased EMP levels in circulation are a biomarker of alteration in vascular function. Endothelial dysfunction is a critical initiating event in atherosclerotic plaque formation,24 smooth muscle cells (SMCs) are known to contribute to increased airway thickening and narrowing during airway remodeling. Several studies have suggested that the exact mechanisms of SMC activation and phenotypic changes apply to both the airway and vasculature. SMC migration and proliferation are features of atherosclerotic lesion intima thickening and airway narrowing.25\n\nSeveral techniques can evaluate endothelial function; the results of endothelial function investigation have prognostic implications and are a predictor of atherosclerosis progression and cardiovascular events.26 The purpose of this study was to detect the levels and role of CD31 and CD62E, which are EMP markers of endothelial dysfunction and a critical occurrence event in atherosclerosis formation in clinically stable children with intermittent asthma. The evidence that EMPs are a biomarker of endothelial dysfunction in asthma is scarce. Further research is needed to identify biomarkers, as well as the mechanism of atherosclerosis in children with asthma.\n\n\nMethods\n\nThis study was conducted in a government school in Bandung City, West Java Province, Indonesia. A cross-sectional study in children with asthma was conducted from September 2020 to March 2021. The inclusion criteria were children with confirmed asthma aged seven–17 years willing to participate. The exclusion criteria in this study were children who were experiencing asthma exacerbations, inflammation (cough, runny nose, fever, or diarrhoea), and were taking oral or inhaled steroids during the study. The minimum sample size of 49 children was calculated to represent the mean population in the region. The sample was collected based on a purposive sampling procedure resulting in 50 children with asthma. Research subjects with clinical asthma and allergy based on the ISAAC questionnaire27 were contacted about their willingness to participate and written informed consent was signed by the parents for children aged seven–11 years, and informed consent was obtained from adolescents aged twelve–17 years as well as their guardians. The diagnosis of asthma used peak expiratory flow (PEFR) examination to determine the value of reversibility test with an increase in PEFR >15% after 15 minutes of administration of salbutamol 200-400 mcg,28 with the use of an Ultechnovo peak flow meter by a pulmonologist. The spirometry examination was not used in this study to avoid aerosol transmission of viruses during the coronavirus disease 2019 (COVID-19) pandemic. The schematic flowchart for the selected subject is shown in Figure 1.\n\nClinical data\n\nThe PEFR values were determined after three examinations with a maximum difference of 20 points. The highest value was taken, and the PEFR percentage was determined based on Godfrey's nomogram for boys and girls aged five–18 years. The diagnosis and severity of asthma were conducted based on the National Guidelines for Paediatrics Asthma (Pedoman Nasional Asma Anak/PNAA) from The Indonesian Paediatrics Association (IDAI),3 and Global Initiative for Asthma (GINA).1 Nutritional status was measured based on body mass index (BMI) based on the the World Health Organization (WHO) child growth standard (WCGS) using Z-score.\n\nTo obtain platelet-free plasma (PFP), MPs were isolated from 3 ml blood samples added with 3.2% sodium citrate, followed by centrifugation at 1,500 rpm for 15 minutes at room temperature, then at 14,000 rpm for two minutes at room temperature. The PFP was centrifuged again at 4,000 RPM for 20 minutes at 4°C to obtain pellets of MPs.29 The MP levels in plasma can be determined using standard beads (YG). The examination was carried out in the Clinical Pathology study laboratory of Cipto-Mangunkusumo Hospital, Jakarta, Indonesia.\n\n100 μL aliquot samples were stained. Two reagents from different antibody combinations were examined, namely PE mouse anti-human CD31-phycoerythrin (PE, clone MBC 78.2 or PECAM-1,2:1,2, 5μl/test) and PE-CyTM 5 mouse anti-human CD62E (clone68-5H11, 20μl/test) were obtained from Becton Dickinson Biosciences (BD Biosciences, San Diego, CA, USA). 10 μL aliquots were stained and added to the bead containing TruCountTM BD (catalogue number 340334). The total volume was obtained from the addition of buffer and double filter and analyzed on the BD Facs Calibur (BD Biosciences). MP size gate range was set between 1 μm and 3 μm calibration (Spherotech, Chicago) by flow cytometry and considered EMPs when they were less than 1.0 μm in diameter. Positive and negative isotypes were used as controls.\n\nAbsolute count of EMPs (μL) was determined from the following formula: (number of events in the quadrant containing cell population) / (number of events in absolute count bead region) x total number absolute count beads (47,150 or 47,500) /test volume 100μL. The ratio of CD62E+/CD31+ EMP population rather than absolute count, was described as a criterion for distinguishing activation versus apoptosis. A ratio ≥10 identified activation while a ratio ≤1.0 identified apoptosis.30\n\nThe enzyme-linked immunosorbent assay (ELISA) method was used to examine pro-inflammatory cytokines (IL-6 and TNF-α). The IL-6 concentration was based on the standard curve obtained from the assay procedure according to the Quantikine Elisa human R & D system, USA, while the TNF-α standard curve was obtained from the assay procedure according to Elabscience, USA.\n\nComplete blood count examination was carried out directly from 3 mL of blood sample plus EDTA anticoagulant using automated haematology analyzers; the differential blood count was also measured to determine the percentage of eosinophils in allergic asthma.\n\nThe data was analyzed using the IBM Social Science Statistics Package v.20.0 (IBM Corp, Armonk, USA). The numeric variables were examined for a normal data distribution using mean median difference, standard deviation, skewness, kurtosis, and Kolmogorov-Smirnov test. Descriptive data were presented as the mean and standard deviation for numerical data, whereas categorical data were presented as number and percentage. The correlation test between two variables was analyzed using Spearman Rho analysis. The Structural Equation Modelling (SEM) analysis for regression coefficient (p-value) using JASP statistical software version 0.16.1 (Department of Psychological Methods University of Amsterdam, Amsterdam, The Netherlands, https://jasp-stats.org/).\n\nThis study obtained ethical approval from the ethical committee of The Faculty of Medicine Universitas Indonesia, ethical approval number KET-161/UN2.F1/ETI/PPM.00.02/2020, protocol number 19-12-1465.\n\n\nResults\n\nOf a total of 206 children aged seven-17 years who were clinically diagnosed with asthma and allergy in the study region, the parents of 51 children (24.8%) agreed to the test, although one child was not ready for the physical and laboratory examination. Of the remaining 50 children with asthma, most were male, the mean age was 12 ± 2 years, with normal nutritional status and intermittent asthma (Table 1 presents characteristics and clinical features of the research subjects).\n\nOur study also found that most asthmatic children with a history of allergy (76%), no history of rhinitis (60%), had a mean PEFR % of 75 ± 12 liter/minute.\n\nBased on laboratory examination, results found that mean leucocyte, platelet and other differential counts were within normal limits, while mean eosinophil counts were increased (7 ± 4, %). Mean pro-inflammatory cytokine TNF-α counts were 4.2 ± 2.8, and IL-6 was 1.6 ± 1 (pg/mL). Results of this study also showed that in the circulation of children with asthma who were found to have EMPs, the mean levels of CD31+/CD62E+ were higher than CD31+/CD62E- and CD62E+/CD31- EMP, and the average ratio of CD31+/CD62E+ ≤1.0 indicated apoptosis (as shown in Table 2).\n\nOur results also found a significant correlation between the level of TNF-α with CD31+/CD62E+, CD31+/CD62E- EMP (p = 0.001, r = 0.5; p = 0.02, r = 0.3), showing that an increase in TNF-α would be accompanied by an increase in EMPs. Our study also found a significant correlation between the percentage of neutrophils and the level of IL-6 (p = 0.002, r = 0.4), suggesting that an increase in neutrophils would be accompanied by an increase in IL-6.\n\nTo evaluate which inflammatory factors and EMPs play a role in the PEFR in allergic asthma (38 children) and without allergic asthma (12 children), a SEM analysis was done. Regression coefficient results of the SEM analysis found that TNF-α (p = 0.003), IL-6 (p = 0.02), and CD31+/CD62E- MP (p = 0.04) had an effect on the PEFR in allergic asthma children, compared to TNF-α (p = 0.51), IL-6 (p = 0.94), and CD31+/CD62E- (p = 0.59) in children without allergic asthma. In asthmatic children without allergies, none of the pro-inflammatory cytokines and EMPs affected the PEFR (Figure 2a and 2b).\n\n\nDiscussion\n\nPrevious research in animal models and humans found a higher chance of atherosclerosis event and mean carotid artery intima-media thickness (IMT) in an adult with asthma. To our knowledge, few studies investigating EMPs as a biomarker of endothelial dysfunction in children with asthma, and the results are still controversial. The results of our study show that in the circulation of children with asthma were found have CD31+/CD62E+, CD31-/CD62E+, and CD62E+/CD31- EMPs, with the mean levels of CD31+/CD62E+ were higher than CD31+/CD62E- and CD62E+/CD31- EMPs.\n\nIn children with asthma, the levels of CD31+/42b+ and CD31+/42b+/AnV+ platelet MPs were significantly higher even after being analyzed with other confounding factors. The level of CD31+/42b-/AnV+ EMPs (apoptotic EMP) increased significantly but became insignificant after multivariate analysis with other risk factors31; from the results of our study, the average ratio of CD31+/CD62E+ was found to be ≤1.0, indicating apoptosis. Similarly, previous research in diabetic patients found that the ratio of CD62E/CD31 EMP populations reflected an apoptotic process.30 It is known that two cellular processes can trigger the formation of MPs, namely chemical, physical activation, and apoptosis.32 EMPs are small vesicles from activated or apoptotic endothelial cells and are involved in cellular cross-talk mechanism.30\n\nShear stress, cytokines, thrombin, reactive oxygen species (ROS), oxidized low-density lipoprotein, C-reactive protein, plasminogen activator inhibitor, lipopolysaccharide can induce endothelial cells to release microparticles into the circulation. The release of MPs has detrimental effects such as endothelial activation, arterial stiffness, thrombosis, and inflammation.33 In our study, increased levels of TNF-α were accompanied by increased levels of CD31+/CD62E+ and CD31+/CD62E- EMP. Similarly to previous research, it was found that endothelial cell activation with TNF-α increases the production of CD62E, CD54, and CD106. Production of CD31, CD105, and CD144 were increased in endothelial cells undergoing apoptosis. The CD31 (PECAM-1) release tends to be stimulated by apoptosis of damaged endothelial cells.22\n\nAsthma is also characterized by an increase of circulating pro-inflammatory and Th2 cytokines, indicating that blood vessels are exposed to the inflammation in the lung.34 The best-known phenotype of allergic asthma is caused by an immunological response driven by Th2. Th2 has controversy in relation to its association with atherosclerosis-related CVD in asthma, and classically Th1 has dominated pathologies.34 Our results found proinflammatory cytokine (IL-6 and TNF-α), and CD31+/CD62E- EMPs played a role in PEFR in children with allergic asthma. Similarly to previous research comparing FEV1 with endothelial function in children with asthma, stiffness of vasculature was found to be inversely proportional to FEV1 in children with asthma.35\n\nInterestingly, a higher level of IL-6 may lead to CVD comorbidity in asthma. Other cytokines such as TNF-α have been implicated in both asthma and CVD, at first appears to be a potential target for further study in shared dysregulation in these two pathologies.34 The inflammation mechanism that can result in arterial injury and increased CVD risk are not been understood in asthma and atopic disease.14 Inflammation plays a role in both atherosclerosis and asthma; potential targets are cytokines whose dysregulation have a notable effect in both conditions.34\n\nThe current concept of the pathogenesis of asthma is a characteristic chronic inflammatory process involving the walls of the airways, increasing airway reactivity and causing airflow limitation. The hyperreactivity predisposes to narrowing of the airways in response to various stimuli.3,36,37 EMPs are described as 0.1 to 1.0 𝜇m vesicle-like structures released from endothelial cell activation or apoptosis. Endothelial MPs have physiological and pathological effects and may activate oxidative stress and vascular inflammation, released by inducers like angiotensin II, lipopolysaccharide, and hydrogen peroxide, leading to the progression of atherosclerosis.24 Therefore, other inflammatory cells and mechanisms also participate in the pathogenesis of both asthma and atherosclerosis diseases.25\n\nSome limitations of our study are that as an observational study, the described association do not confirm causation. We did not measure lung function parameters from spirometry examination to prevent the spread of aerosols during the COVID-19 pandemic, so the severity of asthma could not be determined accurately. It is essential to investigate further other factors affecting the number of EMPs, such as asthma control, lung function, diet, and environmental conditions; these factors may be associated with endothelial dysfunction, which is a hallmark of the process of atherosclerosis in future studies.\n\n\nConclusions\n\nEMPs affect the PEFR in children with allergic asthma. Few studies have investigated EMPs as a biomarker of endothelial dysfunction in children. Further study is needed to investigate the role of these biomarkers in the mechanism of atherosclerosis progression at different asthma severities and with a large number of subjects.\n\n\nData availability\n\nFigshare: Datasheet_Characteristic_Lisa Adhia Garina.csv, https://doi.org/10.6084/m9.figshare.1938256738\n\n- This project contains the raw data characteristics of participants\n\nFigshare: Datasheet lung function and asthma severity_Lisa Adhia Garina, https://doi.org/10.6084/m9.figshares1938262139\n\n- This project contains the PEFR and severity of asthma data\n\nFigshare: Datasheet laboratory examination of research subject-Lisa Adhia Garina, https://doi.org/10.6084/m9.figshare.19394627.v240\n\nFigshare: Datasheet Elisa absorbance data-Lisa Adhia Garina, https://doi.org/10.6084/m9.figshare.19640478.v241\n\n- This project contains the absorbance data from IL-6 and TNF-α ELISA assays\n\nFigshare: Datasheet flow cytometry-Lisa Adhia Garina, https://doi.org/10.6084/m9.figshare.19640493.v142\n\nFigshare: Figure standard curve IL-6_ Lisa Adhia Garina, https://doi.org/10.6084/m9.figshare.19640499.v143\n\nFigshare: Figure standard curve TNF alpha-Lisa Adhia Garina, https://doi.org/10.6084/m9.figshare.19640514.v244\n\nFigshare: Godfrey’s nomogram, http://doi/10.6084/m9.figshares1966882245\n\n- This project contains the reference: nomogram of peak flow meter for children\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nThe Global Initiative for Asthma (GINA): Global strategy for asthma management and prevention.2020. Reference Source\n\nThe Global Initiative for Asthma (GINA): Pocket guide for asthma management and prevention.2018. Reference Source\n\nRahajoe N, Kartasasmita CB, Supriyatno B, et al., editors. National Guideline Paediatrics Asthma (PNAA) from The Indonesian Paediatrics Association (IDAI). Jakarta, Indonesia: 2016.\n\nPapi A, Brightling C, Pedersen SE, et al.: Asthma. Lancet. 2018; 391: 783–800. Publisher Full Text\n\nTuleta I, Skowasch D, Aurich F, et al.: Asthma is associated with atherosclerotic artery changes. PLoS One. 2017; 12(10): 1–11. Publisher Full Text\n\nLambrecht BN, Hammad H, Fahy JV: The cytokines of asthma. Immunity. 2019; 50(4): 975–991. Publisher Full Text\n\nDunican EM, Fahy JV: The role of type 2 inflammation in the pathogenesis of asthma exacerbations. Ann. Am. Thorac. Soc. 2015; 12: 144–149.\n\nPeters MC, Mekonnen ZK, Yuan S, et al.: Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J. Allergy Clin. Immunol. 2014; 133(2): 388–394.e5. PubMed Abstract | Publisher Full Text\n\nCorrigan C: Mechanisms of asthma. Medicine. 2008; 36(4): 177–180. Publisher Full Text\n\nRincon M, Irvin CG: Role of IL-6 in asthma and other inflammatory pulmonary diseases. Int. J. Biol. Sci. 2012; 8(9): 1281–1290. PubMed Abstract | Publisher Full Text\n\nAgrawal A, Tay J, Ton S, et al.: Increased reactivity of dendritic cells from aged subjects to selfantigen, the human DNA. J. Immunol. 2009; 182: 1138–1145. PubMed Abstract | Publisher Full Text\n\nBarnes PJ: Pathophysiology of asthma. Eur. Respir. Mon. 2003; 23: 84–113.\n\nKnoflach M, Kiechl S, Mayr A, et al.: Allergic rhinitis, asthma, and atherosclerosis in the Bruneck and ARMY Studies. Arch. Intern. Med. 2005; 165: 2521–2526. PubMed Abstract | Publisher Full Text\n\nTattersall MC, Evans MD, Korcarz CE, et al.: Asthma is associated with carotid arterial injury in children: The Childhood Origins of Asthma (COAST) Cohort. PLoS One. 2018; 13(9): 1–12. Publisher Full Text\n\nTattersall MC, Guo M, Korcarz CE, et al.: Asthma predicts cardiovascular disease events: the multi-ethnic study of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2015; 35(6): 1520–1525. Publisher Full Text\n\nMakieieva N, Butov D, Morozov O, et al.: Endothelial dysfunction in children with clinically stable and exacerbated asthma. Adv. Respir. Med. 2019; 87: 7–13.\n\nFuji S, Matsushita S, Hyodo K, et al.: Association between endothelial function and micro-vascular remodeling measured by synchrotron radiation pulmonary micro-angiography in pulmonary arterial hypertension. Gen. Thorac. Cardiovasc. Surg. 2016; 64(10): 597–603. PubMed Abstract | Publisher Full Text\n\nGreen CE, Turner AM: The role of the endothelium in asthma and chronic obstructive pulmonary disease (COPD). Respir. Res. 2017; 18(1): 1–20.\n\nSun D, Li X, Heianza Y, et al.: History of asthma from childhood and arterial stiffness in asymptomatic young adults: the Bogalusa heart study. Hypertension. 2018; 71(5): 928–936. PubMed Abstract | Publisher Full Text\n\nFavretto G, Cunha RSD, Dalboni MA, et al.: Endothelial microparticles in uremia: biomarkers and potential therapeutic targets. Toxins. 2019; 11(5): 1–16. Publisher Full Text\n\nNieri D, Neri T, Petrini S, et al.: Cell-derived microparticles and the lung. Eur. Respir. Rev. 2016; 25(141): 266–277. Publisher Full Text\n\nDeng F, Wang S, Zhang L: Endothelial microparticles act as novel diagnostic and therapeutic biomarkers of circulatory hypoxia-related diseases: a literature review. J. Cell. Mol. Med. 2017; 21(9): 1698–1710. PubMed Abstract | Publisher Full Text\n\nTakahashi T, Kobayashi S, Fujino N, et al.: Annual FEV1 changes and numbers of circulating endothelial microparticles in patients with COPD: a prospective study. BMJ Open. 2014; 4(3): e004571–e004578. Publisher Full Text\n\nPaudel KR, Panth N, Kim DW: Circulating endothelial microparticles: a Key hallmark of atherosclerosis progression. Scientifica. 2016; 2016: 1–9. PubMed Abstract | Publisher Full Text\n\nLiu CL, Zhang JY, Shi GP: Interaction between allergic asthma and atherosclerosis. Transl. Res. 2016; 174: 5–22. PubMed Abstract | Publisher Full Text\n\nBehrendt D, Ganz P: Endothelial function: from vascular biology to clinical applications. Am. J. Cardiol. 2009; 90: L40–L48. Publisher Full Text\n\nThe ISAAC Steering Committee: The international study of asthma and allergies in childhood manual.1993. Reference Source\n\nAdeniyi B, Erhabor GE: The peak flow meter and its use in clinical practice. African J. Resp. Med. 2011; 1: 5–8.\n\nKlaihmon P, Phongpao K, Kheansaard W, et al.: Microparticles from splenectomized beta-thalassemia/HbE patients play roles on procoagulant activities with thrombotic potential. Ann. Hematol. 2017; 96(2): 189–198. PubMed Abstract | Publisher Full Text\n\nTramontano AF, Lyubarova R, Tsiakos J, et al.: Circulating endothelial microparticles in diabetes mellitus. Mediat. Inflamm. 2010; 1: 1–8.\n\nDuarte D, Taveira-Gomes T, Sokhatska O, et al.: Increased circulating platelet microparticles as a potential biomarker in asthma. Allergy. 2013; 68(8): 1073–1075. PubMed Abstract | Publisher Full Text\n\nKheirandish-Gozal L: The endothelium as a target in pediatric OSA. Front. Neurol. 2012; 3: 1–6. Publisher Full Text\n\nDignat-George FBC: The many faces of endothelial microparticles. Arterioscler. Thromb. Vasc. Biol. 2011; 31(1): 27–33. PubMed Abstract | Publisher Full Text\n\nGurgone D, McShane L, McSharry C, et al.: Cytokines at the Interplay between asthma and atherosclerosis?. Front. Pharmacol. 2020; 11: 166–179. PubMed Abstract | Publisher Full Text\n\nKarakaya Z, Cavkaytar O, Tosun O, et al.: Subclinical cardiovascular dysfunction in children and adolescents with asthma. J. Asthma. 2022; 59(3): 451–461. PubMed Abstract | Publisher Full Text\n\nHolgate ST, Sly PD: Asthma Pathogenesis. Adkinson JNF, Bochner BS, Burks AW, et al., editors. Middleton's Allergy Principles & Practice. Elsevier Inc; 2014; 812–39.\n\nSupriyatno B, Wahyudin B: Pathogenesis and pathophysiology in paediatrics asthma. Rahajoe NN, Supriyatno B, Setyanto DB, editors. Textbook of Paediatric Respirology. Jakarta, Indonesia: Indonesian Paediatric Association (IDAI) Publisher; 2018\n\nGarina LA: Datasheet_Characteristic_Lisa Adhia Garina.csv. figshare. Dataset. 2022. Publisher Full Text\n\nGarina LA, Supriyatno B, Yunus F, et al.: Datasheet lung function and asthma severity_Lisa Adhia Garina. figshare. Dataset. 2022. Publisher Full Text\n\nGarina LA, Supriyatno B, Yunus F, et al.: Datasheet laboratory examination of research subject-Lisa Adhia Garina. figshare. Dataset. 2022. Publisher Full Text\n\nGarina LA, Supriyatno B, Yunus F, et al.: Datasheet Elisa absorbance data-Lisa Adhia Garina. figshare. Dataset. 2022. Publisher Full Text\n\nGarina LA, Supriyatno B, Yunus F, et al.: Datasheet flow cytometry-Lisa Adhia Garina. figshare. Dataset. 2022. Publisher Full Text\n\nGarina LA, Supriyatno B, Yunus F, et al.: Figure standard curve IL-6_ Lisa Adhia Garina. figshare. Figure. 2022. Publisher Full Text\n\nGarina LA, Supriyatno B, Yunus F, et al.: Figure standard curve TNF alpha-Lisa Adhia Garina. figshare. Figure. 2022. Publisher Full Text\n\nGarina LA, Supriyatno B, Yunus F, et al.: Godfrey's normogram. figshare. Figure. 2022. Publisher Full Text"
}
|
[
{
"id": "195035",
"date": "19 Sep 2023",
"name": "Susetta Finotto",
"expertise": [],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThere are no control subjects in this study. How can the authors conclude about the causality of the results with asthma?\nIt is also not clear why the authors eliminated so many groups of asthmatics that would be relevant for the study.\nIn the methods the authors claimed that most of the asthmatic children were male but in table 1 it says that they were 50% male.\nThe cytokine levels are too low. How was the range of the standard curve?\nIn the table 2 why did the authors not show the value for allergic asthma versus non allergic asthma?\nThe figures are tables and not figures\nIn figure 2 the authors should have shown the regression curves.\nLiterature: the first author reports many of her references( ref. 38-45)\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "225019",
"date": "28 Dec 2023",
"name": "Sy Duong-Quy",
"expertise": [
"Reviewer Expertise Asthma",
"COPD",
"OSA",
"PH",
"IPF"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript entitled \"The role of endothelial microparticles in children with asthma: Does it promote atherosclerosis progress?\" done by Lisa Adhia Garina et al. is interesting in the filed of asthma in children. The main results of this study showed that the pro-inflammatory cytokine TNF-α and IL-6 levels were increased; mean levels of CD31+/CD62E+ were higher than CD31+/CD62E- and CD62E+/CD31- EMP; the average ratio of CD31+/CD62E+ ≤1.0. There was shown a significant correlation between the level of TNF-α with CD31+/CD62E+, CD31+/CD62E- EMP (p = 0.001, r = 0.5; p = 0.02, r = 0.3). The study results also demonstrated that TNF-α (p = 0.003), IL-6 (p = 0.02), and CD31+/CD62E- MP (p = 0.04) had an effect on the PEFR in allergic asthma children, compared to TNF-α (p = 0.51), IL-6 (p = 0.94), and CD31+/CD62E- (p = 0.59) in children without allergic asthma. However, there are many mojor issues which should be clarified and elicited by the authors to complete the study objectives as mentioned below: 1- The concept of atherosclerosis in asthmatic children is not relevant in clinical practice because this disease owns the complex mechanism and related to multi risk factors 2- Atherosclerosis has not been considered currently as the direct consequence of asthma in adults, but rather the comorbidities 3- Methods: the diagnosis of asthma in children > 5 years should be followed the GINA recommendations 4- Exclusion criteria: asthmatic childrens treated by ICS or OCS were excluded; it means that they only have intermittent asthma or mild asthma? 5- The high level of CD31, CD62-E, TNFalpha, IL6 due to other causes should be screened in the study asthmatic children 6- The link beetween biomarkers of endothelial dysfunction measured by CD31/CD62-E and Peakflow is not relevant because peakflow measurement is very varied during the day and individual differences in different health status 7- The use of CD62-E to evaluate the progress of atherosclerosis is not accurate because this biomarker is linked strongly to inflammation rather than atherosclerosis 8- The direct biomarkers of endothelial dysfunction should be done by measuring the level of NO production quantified indirectly by measuring the level of nitrit and nitrat in plasma 9- The study population was small for having a accurate conclusion as stated by the authors suc as \"endothelial microparticles play a role on peak expiratory flow rate (PEFR) in children with allergic asthma\".\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-553
|
https://f1000research.com/articles/10-1109/v1
|
03 Nov 21
|
{
"type": "Systematic Review",
"title": "Unleashing frugal innovation in private higher education institutions via intellectual capital: a systematic literature review",
"authors": [
"Jayamalathi Jayabalan",
"Magiswary Dorasamy",
"Murali Raman",
"Murali Sambasivan",
"Sharbani Harun",
"Murali Raman",
"Murali Sambasivan",
"Sharbani Harun"
],
"abstract": "Background: Given the persistent challenges to the higher education business model, private higher education institutions (PHEIs) are exploring myriad ways to increase enrolment and income, while aggressively managing spending. Many PHEIs are facing financial distress and struggling because of decreasing budgets and declining revenue. Thus, carving unique strategies that direct the institution to focus on its core competencies, making additional budget cuts without compromising quality, developing new revenue streams, embracing new technology, and offering affordable programs, will ultimately lead to financial success. Frugal innovation (FI) can shed light on these challenges. Methods: This paper presents a systematic literature review to investigate and analyse prior research that focused on FI within the sphere of intellectual capital (IC) and information technology capabilities (ITC) research, and their relationships in PHEIs. Transfield’s five phases were employed to extract journal articles published over a thirty-year period (1990 to 2020) from major online databases using keyword searches. Although an initial search generated 76,025 papers, the search for IC and FI yielded 41 papers, and finally only two papers were selected as they clearly related IC with FI. Results: There was a research gap in the literature published from 1990 to 2020 regarding IC applications to achieve FI. This work revealed that IC and ITC research for FI in PHEI remain insufficiently explored.\n\nConclusions: Further research is required on the evaluation model of IC, ITC and FI, methodologies, empirical analysis, and the development of measurement metrics. A limitation to this study is the number of keywords selected.",
"keywords": [
"Intellectual capital",
"frugal innovation",
"IT capabilities",
"higher education institution",
"private university",
"systematic literature review",
"business sustainability",
"innovative paradigm"
],
"content": "Introduction\n\nOver the recent decades, higher education institutions (HEIs) have been challenged by the shifting landscape of employment, technologies and demand. In the globalisation era, HEIs require a paradigm shift which is expected to focus more on ‘global, digital and information’-based rather than being conventionally ‘national, analogue, industrial economy’-orientated.1 HEIs play a critical role in the knowledge-based society and serve as a reservoir of knowledge. Recently, HEIs faced considerable competition and challenging situations to gain a competitive advantage in national and international settings. In particular, private higher education institutions (PHEIs) encounter considerable challenges to strike a balance between maximising shareholders’ financial growth and improving educational quality. Many local PHEIs are encountering difficulties to persist in the industry, with 53% of PHEIs incurring losses before taxes and 55% incurring losses after taxes.2 This tremendous fiscal strain has caused various impacts including of job losses and learning disruptions for approximately 5,800 academic staff and 121,000 students in Malaysia, given the inadequate quality of education in unprofitable institutions.2\n\nIn addition, PHEIs have been blooming in Malaysia to meet the increasing population demand.3 As a result, intense competition is apparent among PHEIs. PHEIs are transforming education into a business model where the curriculum and programmes are tailored to accommodate the masses and are expected to generate high commercial value. Reductions in funding will have implications on the quality of education.4 An urgent need exists for quality revolution in PHEIs, and for building a 21st century model to adapt to current social and technological changes. PHEIs should be ready to explore and innovate their curriculum design to produce graduates with high competency and skills. Furthermore, PHEIs must secure additional resources to finance their modernisation and development in a period of tight or decreasing public budgets, without forcing students to pay for the benefits of higher education which accrue to society at large.5-7\n\nRecently, PHEIs have been experiencing unexpected challenges because of limited budgets, declining revenues, resources constraints and increasing cost.8 Therefore, business sustainability has become the main issue for the higher education system. Sazonov et al.9 asserted that only HEIs with stable and sound financial positions will be able to persist and meet the requirements of their various stakeholders, to provide high quality yet equitable and affordable education while maximising shareholder wealth. Additionally, PHEIs face pressure from industry and academia to boost innovation through alternative approaches in a resource-constrained environment without considerable investment,10 and provide solutions that are substantially more affordable.11 Therefore, financially challenged PHEIs are adopting low-cost approaches which require new innovative paradigms such as frugal innovation (FI).12\n\nMost importantly, a paradigm shift in the mindset and approach among leaders is needed and will require PHEIs to respond to a rapidly changing environment, by aligning their strategies to meet the current landscape.13,14 Moreover, according to,15,16 private education has been the main contributor to the nation’s economic development and gross domestic product (GDP). A consistent increase in GDP contribution has arisen between 2015 and 2019, at RM14.09bil, RM14.84bil, RM15.70bil, RM16.62bil and RM30bil.17 Moreover, PHEIs must focus on core functions, create closer integration with industry, collaborate with local and international communities and promote greater efficiency in operations.\n\nIntellectual capital (IC) is an emerging issue for academics, governments and investors18 and has been studied in developed countries, as it is regarded as a crucial indication of organisational development in a knowledge economy.19 Youndt et al.20 asserted that, in knowledge-intensive organisations such as universities, prudent management of IC can ensure that procedures are successful and that entities can produce value. IC is vital in improving PHEI performance, innovation and creativity.21,22 Several calls have been made for research on improving the management of IC in PHEIs.23,24 However, studies that focuses on IC management and resource efficiency in PHEI are still limited.25,26\n\nFI involves managing the entire value chain with limited physical and financial resources, resulting in improved product quality and cost savings. Therefore, a company can benefit through cost reduction, because of prudent resource management, full utilisation of existing components, adoption of cost-effective technology, and simplified design.27,28 By adopting FI, PHEIs will be able to meet stakeholder expectations and eventually lead to increased profitability and sustainability. Therefore, developing a resource-saving agenda and services, by aiming at core elements and avoiding wasteful spending, is crucial in a resource-constrained environment. FI is observed as ‘core functionality’, is performance-based, focuses on usage of resources, ‘ruggedisation’, cost saving, ‘no-frills strategy’ and environmental concern.12,29-32\n\nInformation technology capability (ITC) supports innovation processes for increasing productivity, improving customer relationships and lowering operating expenses. An organisation’s success is not solely contributed to by investing in an IT system, but also arises from the ability of firms to acquire ITC in an ever-changing business environment. Brown and Sambamurth33 defined capability as ‘the distinctive organisational skills for combining available resources and sustaining superior performance’. Thus, ITC refers to particular resources, skills, information, knowledge, procedures and relationships that empower companies to viably acquire, adopt and control IT applications and administrations, to gain innovations and superior performance.34 As such, a PHEI with efficient IC management can develop strong ITC, as the institutions would be able to scan the environment and sense, monitor and strengthen their organisational capabilities.\n\nIC, ITC and FI together will be able to provide new opportunities for PHEIs to redesign their business processes and model. Therefore, this gap prompted the researchers to investigate and analyse prior research that focused on FI, within the sphere of IC and ITC literature and their relationships in PHEIs.\n\nGiven this backdrop, the research questions for this study were as follows:\n\n1. How did the corresponding literature of IC and FI in PHEIs evolve?\n\n2. What are the research gaps on the influence of ITC on IC and FI in PHEI?\n\n3. What are the possible future research directions?\n\nThe objectives of this study were as follows:\n\n1. To identify the main areas of IC and FI in the PHEI context.\n\n2. To analyse research gaps in the literature on the influence of ITC on IC and FI.\n\n3. To identify the possible future research directions.\n\nHence, the main contribution of this paper is to fill the gap in existing literature on PHEI, underlining the growing importance of IC and FI. In addition, the researchers aim to provide a review on past studies related to applying IC to achieve FI in PHEI. This paper is organised as follow: first, the scope of this research is explained; the following section describes the method to collect and compare the existing literature; the Results section represents keyword search result, and gap analysis; the Discussion provides avenue for future research, and the Conclusions section outlines the conclusions of this research.\n\n\nMethods\n\nThis paper was designed to present a systematic literature review on effects of IC on FI. Our assessment of the literature was based on the five steps of systemic review that were presented by,35 which entails five phases as shown and described in Figure 1. Major online databases that were selected include IEEE, Sage Publications, Emerald, JSTOR, Scopus, ProQuest, and Science Direct. The search technique employed in each database differed depending on the terms and the capacity to combine the terms using Boolean operators, and the usage of truncations such as ‘intellectual capital’ AND ‘information technology capability’ AND ‘frugal innovation’ AND ‘Higher education institution’ OR ‘higher learning institution’ OR ‘university’ OR ‘institute of higher learning’. The final search method was customised for each database to optimise the retrieval of relevant research. Each article was reviewed for eligibility after checking title, abstract and keyword. Two authors (JJ, MD) independently filtered papers that discussed IC and FI. Any disputes about study inclusion were solved by negotiations among the authors until consensus was reached. The papers analysed were further selected based on inclusion and exclusion criteria as shown in Figure 2, and the selection process is shown in Figure 3 (Prisma extraction flow). Studies were included if they were (i) published between 1990 and 2020, (ii) peer-reviewed journal articles and (iii) focused specifically on IC and FI. Studies were excluded if they were (i) discussing only one term i.e., either IC or FI without relating them, (ii) not published in English and (iii) books, conference proceedings, dissertation or magazines. Prior to the screening procedure, duplicate studies were eliminated. Relevant data were extracted and summarised in tables based on study design, paper type, methodology and publication trend by year. There are a few limitations to this systematic study that should be mentioned. First, because the articles included were only acquired from journal publications, the data on the IC and FI may be incomplete. Second, the review only considered English-language publications. Several publications discovered in this review were in foreign languages, however they were removed as the authors did not have the capacity to comprehend them.\n\nDuring the data charting, we will test a predefined data extraction sheet that has been accepted by consensus of authors (JJ, MD). We will extract year of publication, source of information, design and study-specific information, and findings that address our research questions. The first author (JJ) extracted the data while the second author (MD) carried out a cross-check to provide an overview of the extracted data items in the results. Results are presented graphically. JJ provided a summary of the study's features based on both abstract and full-text screening and a random check conducted by the second reviewer. The full spreadsheet listing all extracted items was stored in a database and included in the ‘Data availability’ section and reference list. Figure 3 illustrates the process of document selection based on title and abstract, followed by full text selection. Only published, peer-reviewed journal articles were considered while other publications such as newspaper articles, books and conference proceedings were not included.\n\nThis study was approved by the Research Ethical Committee (REC) of the Multimedia University (EA1362021). The study was conducted according to the guidelines of and was approved by the REC.\n\n\nResults\n\nThe authors used a thematic analysis, summarizing the results by year, source database, methodology used in the study and classification by type of paper. A total of 76,025 papers was obtained with the keyword ‘intellectual capital’. For the keywords search of ‘information technology capability’ and ‘frugal innovation’, 14,122 and 2,320 journal papers were listed, respectively. However, when the researcher entered a combination of ‘intellectual capital’, ‘information technology capability’ and ‘frugal innovation’ keywords, no journal was found. Similarly, when the researcher used the keyword sets ‘intellectual capital’ + ‘information technology capability’ + ‘frugal innovation’ + ‘Higher education institution’ or ‘higher learning institution’ or university or ‘institute of higher learning’, no papers were obtained.\n\nThe authors selected journal articles from five main databases from the year 1990 to 2020 (Figure 7). The authors analyzed the trend of publication over the years for IC and FI (34 articles). Increasing trends were observed in terms of number of publications over the years (Figure 7). There was also a drastic increase during the year 2020, which indicates the topic gained popularity.\n\nFrom the collection of articles, this section aims to discuss the main methodology applied by each paper. Table 3 describes the themes associated to each publication based on whether they used quantitative methods (survey or archival), qualitative (case study approach or observation), or conceptual model approaches (literature review studies or theoretical concept). As summarized in Figures 5 and 6, approximately 44% were empirical papers, followed by conceptual papers (41%) and reviews (15%).\n\nThe articles were grouped according to whether they were obtained from searching IEEE, Sage Publications, Emerald, JSTOR, Scopus, ProQuest, and Science Direct to analyse the one yielding the most publications. Paper grouping per database is presented in Table 2 and Figure 4. As shown in Table 1, 41 papers were listed for IC and FI. The 41 papers were obtained from five online databases as shown in Table 2 and Figure 3. Most papers were published in Emerald and ProQuest. Only 34 papers were related to IC and FI from the total of 41 papers. The seven remaining papers were duplicates which appeared in multiple online databases and were removed from the analysis. Further investigation of the 34 papers revealed only two papers related to IC and FI.36,37 The search using online databases did not exclusively list papers with the given keywords. Therefore, the selection criteria involved accepting all papers that discussed IC and FI (Table 1) and rejecting those that discussed either IC or FI without relating them to each other. The search for IC and FI yielded 41 papers but only two clearly related IC with FI. Referring to Table 2 and Figure 4, 51% of the papers were from ProQuest database, followed by Emerald (39%).\n\nFrom a comparison of the articles published over the years, research on IC and FI was found to be discussed in 34 papers after removing duplicate publications. Further screening on titles resulted in the selection of 12 papers relevant to the research topic. Furthermore, the authors’ abstract screening led to only six papers being selected while others were excluded, as they were not widely discussing the research topic. Finally, full-text screening was carried out by the authors, and it appeared only two papers appeared had carried out relevant research on the topic. The remaining four articles excluded were either discussing only one of the concepts (IC or FI) and no relationship was found to be explored between the two, or they discussed general issues in innovation (as shown in Figure 3). Of the two papers (Tables 3 and 4), Dost et al.36 investigated the effect of internal and external sources of knowledge management on FI, which is moderated by technological turbulence and market turbulence. Bencsik et al.37 wrote a conceptual paper on FI and knowledge management. The goal of FI does not only focus on providing low-cost products and services, but rather on establishing a flexible thinking to uncover human knowledge, and the capability and usage of internal or external technologies, resulting in lower innovation cost of processes and products.38 Thus, this study aims to enhance the understanding of the components of IC: ‘human capital’, ‘structural capital’, and ‘relational capital’ as main factors in the generation of FI through ITC.\n\nSome of the challenges faced throughout the search included selecting the right keywords and terms during the data extraction process, where there is a risk of either too much or not enough results being obtained, depending on the keywords use. Apart from that, the description of inclusion and exclusion criteria can have practical implications too. Finally, ‘low recall’ for keywords such as IC, ITC and FI altogether seems to be not appearing in HEIs context. Finding the optimum combination of keywords and adjusting the precision to maximize system accuracy is difficult. The goal of this systematic reviews was to include knowledge from all relevant research. Some of the limitations include a lack of information from some research, which can jeopardize the validity of a review. This is due to inadequate data due to only a few studies being published, or because of insufficient reporting within a published article. These issues fall under “publication biases”, even though these biases are due to unpublished comprehensive research and the publication of selected results in relation to authors’ conclusions.\n\nThis study adds to the improvement of IC research in the education sector, in which experiences from FI play an essential role in the growth of HEIs’ performance. The present article classification can assist future scholars in reviewing references based on their study requirements. Future research can utilize this literature review as a starting point to further comprehend FI to obtain quality literature. In the field of IC, scholars may involve more information system application, as well as Artificial Intelligence in their future work including system development, methodologies and strategies for PHEIs.\n\n\nDiscussion\n\nPrior research has thus far considered the key components of IC and its measurement indicators. PHEI performance levels are measured through ranking, teaching, research, internationalisation and other academic indicators. However, an innovative operational approach has remained largely unaddressed in PHEIs. Therefore, PHEIs must adopt new business approaches and methods that have been developed by the business sectors, such as FI. Accordingly, this study seeks to fill the gap by examining the effect of IC on FI through ITC dimensions.\n\nFour research gaps (Table 5) identified in this study were as follows:\n\nGap 1. PHEIs under resources constraint must emphasise utilising internal and external knowledge to build learning skills in a frugal environment, so that they may continue to deliver value-added service to their clients and increase shareholder wealth. Scholars have found that IC has a crucial role in generating innovation in a firm.39-42 Thus, further investigations that evaluate the impact of IC are necessary to ensure sustained and improved firm performance using new context or perspectives, i.e., FI. Therefore, future research must address this significant issue by examining the extent to which IC in PHEIs can develop capabilities to fulfil the criteria identified in FI.\n\nGap 2: Technology and IT management will increase IC utilisation by exploiting technology in information management and processing, to enhance business capabilities and generate benefits for the organisation.43,44 Hence, the effectiveness of IC management and utilisation is driven by the effectiveness of ITC and subsequently facilitate creation of value.\n\nGap 3: As IT becomes a fundamental business operation resource, employees with superior business knowledge would be able to utilise viable IT solutions and use their specialised technical skills to realign business strategies to meet the needs in a dynamic business environment, by creating business procedures and cost-feasible frameworks to achieve competitive advantage.45-47 Many studies have revealed the relationship between ITC and competitive advantage.45,48,49 Meanwhile,50,51 argued that financial performance is higher for firms with higher digital innovation capabilities. Therefore, the ability of ITC to influence FI in PHEI must be emphasised.\n\nGap 4: As no studies focused on the effect of IC on FI through IT capability, the rationale behind the mediation effect of ITC is that a firm with a strong IC management is in a better position to deliver ITC to satisfy customers and optimise their resources to ‘produce more with less resources’ for cost efficiency. This situation mainly arises because of the high possibility that the relationship between IC and FI is not exclusively direct. Conceptually, ITC plays an important role in PHEI that has the attributes to gather all organisational knowledge resources and convert them to achieve FI (refer to Figure 8). Hence, a PHEI must have the capacity to effectively utilise its knowledge resources to generate dynamic capabilities that allow businesses to respond rapidly to changes in the environment.14 The prevailing knowledge created from IC can create an opportunity to be ‘sensed and transformed’ to influence ITC, to enhance organisational efficiency and effectiveness through FI. As such, ITC can play a mediating role by translating IC into better performance to achieve FI (Figures 8 and 9).\n\nThe authors engaged in examining the relationship among IC, IT capability and FI, possibly may consider the main findings of this paper to examine the opportunities for future research. The two major themes for future articles include\n\n• Theme 1: Evaluation model of IC, IT capability and FI in PHEIs\n\n• Theme 2: Investigating the methodologies.\n\n• Theme 3: Empirical analysis and developing measurement metrics for each variable.\n\nThis study is limited by the number of keywords selected. Keyword selection is based on research focus. However, it would be possible to obtain more articles if the keywords were expanded to fields of study that are not specific in nature, such as PHEI. This could possibly lead to a publication bias.\n\n\nConclusions\n\nAs mentioned in the Introduction, research that explores the relationships between organisational IC dimensions, ITC and FI in the PHEIs in Malaysia remains insufficient. Thus, PHEIs should concentrate more on core activities, improve industry integration, engage with local and international communities, and increase operational efficiency. This study aims to inform IC scholars about the research gaps in the literature published from 1990 to 2020 regarding IC applications to achieve FI. The findings of this review suggest three major issues: firstly, an urgent need exists for scholars to streamline the use of concepts pertaining to FI in PHEIs. Secondly, more work is required to ascertain if IC and ITC share similar goals or otherwise to achieve FI. Finally, the use of the FI approach and its relationship with IC and ITC remains unexplored in the literature. Therefore, the extent to which the IC dimension interacts with FI in the PHEI context could be further explored. Finally, additional empirical research is needed to fully comprehend the relationship between IC, ITC and FI in the context of PHEIs.\n\n\nData availability\n\nAll data underlying the results is available as part of the article and no additional source data are required.\n\nFigshare: Data file.xlsx, https://doi.org/10.6084/m9.figshare.14881437.v1.92\n\nThis project contains the following underlying data:\n\n- Data analysis: theories, type of papers, methods and findings\n\n\nReporting guidelines\n\nPRISMA checklist for “Unleashing frugal innovation in private higher education institutions via intellectual capital: a systematic literature review”, URL/DOI: https://doi.org/10.6084/m9.figshare.16726282.93\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nHughes JC: Are our universities ready for a paradigm shift? The Globe and Mail.2013. Retrieved May 25, 2021. Reference Source\n\nWilliams G: Private varsities struggling. New Straits Times. 2018, December 3. Reference Source\n\nTajudeen ABA, Raja SS: Malaysia's Private Higher Education Sector As Provider Of Accessibility: A Wider View Of Its Historical Growth And Roles Vis-À-Vis The Public Higher Education Sector. Sejarah: Journal of the Department of History. 2021; 30(1).\n\nMgaiwa SJ: The Paradox of Financing Public Higher Education in Tanzania and the Fate of Quality Education: The Experience of Selected Universities. SAGE Open. 2018; 8: 215824401877172. Publisher Full Text\n\nHalai N: Quality of private universities in Pakistan. Int. J. Educ. Manag. 2013; 27(7): 775–786. Publisher Full Text\n\nMpezamihigo M: Challenges of maintaining quality education in private universities in Uganda: A case study of the Islamic University in Uganda. Paper presented 18th Conference of Commonwealth Education Ministers Mauritius, August 28-31. 2012.\n\nSarker F, Davis H, Tiropanis T: A review of higher education challenges and data infrastructure responses. International Conference for Education Research and Innovation (ICERI 2010), Madrid Spain, November 15-17. 2010.\n\nLapovsky L: The higher education business model: Innovation and financial sustainability.2014. Reference Source\n\nSazonov SP, Kharlamova EE, Chekhovskaya IA, et al.: Evaluating financial sustainability of higher education institutions. Asian. Soc. Sci. 2015; 11(20): Publisher Full Text\n\nSecundo G, Margherita A, Elia G, et al.: Intangible assets in higher education: mission, performance or both?. J. Intellect. Cap. 2010; 11(2): 140–157. Publisher Full Text\n\nZeschky M, Widenmayer B, Gassmann O: Organizing for reverse innovation in Western MNCs: the role of frugal product innovation capabilities. Int. J. Technol. Manag. 2014; 64(2-4): 255–275. Publisher Full Text\n\nWeyrauch T, Herstatt C: What Is Frugal Innovation? Three Defining Criteria. Journal of Frugal Innovation. 2016; 2(1): 1–17. Publisher Full Text\n\nBhuian SN: Evidences of service quality from an emerging educational hub, Qatar. Int. J. Manag. Educ. 2016; 10(4): 353–369. Publisher Full Text\n\nTseng SM, Lee PS: The Effect of Knowledge Management Capability and Dynamic Capability on Organizational Performance. J. Enterp. Inf. Manag. 2014; 27: 158–179. Publisher Full Text\n\nAntha A: “An analysis of globalization and higher education in Malaysia”, Australian. J. Bus. Manag. Res. 2011; 1(9): 73–81. Reference Source\n\nBecket N, Brookes M: Quality Management Practice in Higher Education -- What Quality Are We Actually Enhancing?. J. Hosp. Leis. Sport Tour. Educ. 2008; 7: 40–54. Publisher Full Text\n\nDepartment of Statistics Malaysia: Annual Economic Statistics 2018 Education Services. Putrajaya: 2018. Reference Source\n\nBezhani I: Intellectual capital reporting at UK universities. J. Intellect. Cap. 2010; 11(2): 179–207. Publisher Full Text\n\nLev B, Zambon S: Intangibles and intellectual capital: an introduction to a special issue. Eur. Account. Rev. 2003; 12(4): 597–603. Publisher Full Text\n\nYoundt MA, Snell SA: Human resource configurations, intellectual capital, and organizational performance. J. Manag. Issues. 2004; 16(3): 337–360.\n\nSharabati A, Jawad S, Bontis N: Intellectual Capital and Business Performance in the Pharmaceutical Sector of Jordan. Manag. Decis. 2010; 48(1): 105–131. Publisher Full Text\n\nKhalique M, Shaari JA, Isa AH, et al.: Relationship of Intellectual Capital with The Organizational Performance of Pharmaceutical Companies in Pakistan. Aust. J. Basic Appl. Sci. 2011; 5(12): 1964–1969.\n\nSánchez MP, Elena S, y Castrillo R: Discussing the dynamics in Intellectual Capital in Universities. A model for reporting. Journal of Intellectual Capital, próxima aparicición. 2008.\n\nLeitner KH, Curaj A, Elena-Perez S, et al.: 2014. A Strategic Approach for Intellectual Capital Management in EuropeanUniversities. Guidelines for Implementation, UEFISCDI Blueprint Series, No. 1, Executive Agency for Higher Education, Research, Development and Innovation Funding, Bucharest.\n\nBolisani E: Knowledge management for adult and higher education: mapping the recent literature. Fedeli M, Bierema L, editors. Connecting Adult Learning and Knowledge Management. Knowledge Management and Organizational Learning. Cham: Springer; 2019; (8).\n\nSangiorgi D, Siboni B: The disclosure of Intellectual Capital in Italian Universities: What has been done and what should be done. J. Intellect. Cap. 2017; 18(2): 354–372. Publisher Full Text\n\nTiwari R, Herstatt C: Assessing India’s lead market potential for cost-effective innovations. Journal of Indian Business Research. 2012; 4(2): 97–115. Publisher Full Text\n\nRao BC: How disruptive is frugal?. Technol. Soc. 2013; 35(1): 65–73. Publisher Full Text\n\nKuo A: Creating social value through frugal innovation. Tsai SDH, Liu TYC, Jersan Hu J, et al.: Entrepreneurship in Asia: social enterprise, network and grassroots case studies. Singapore: World Scientific Publishing Co. Pte. Ltd.; 2014; 53–70.\n\nBasu RR, Banerjee PM, Sweeny EG: Frugal innovation: core competencies to address global sustainability. Journal of Management for Global Sustainability. 2013; 1(2): 63–82. Publisher Full Text\n\nKuo A: Harnessing frugal innovation to foster clean technologies. Clean Techn. Environ. Policy. 2016; 1–12.\n\nAngot J, Plé L: Serving poor people in rich countries: the bottom-of-the pyramid business model solution. J. Bus. Strateg. 2015; 36(2): 3–15. Publisher Full Text\n\nBrown CV, Sambamurthy V: Repositioning the IT Organization to Enable Business Transformation. Cincinnati: Pinnaflex Press; 1999.\n\nSambamurthy V, Zmud R: Arrangements for information technology governance: a theory of multiple contingencies. MIS Q. 1999; 23(2): 261–290. Publisher Full Text\n\nTransfield D, Denyer D, et al.: Towards a methodology for developing evidenceinformed management knowledge by means of systematic review. Br. J. Manag. 2003; 14: 207–222. Publisher Full Text\n\nDost M, Pahi MH, Magsi HB, et al.: Effects of sources of knowledge on frugal innovation: moderating role of environmental turbulence. J. Knowl. Manag. 2019; 23(7): 1245–1259. Publisher Full Text\n\nBencsik A, Machová R, Tóth Z: Cheap and clever – symbiosis of frugal innovation and knowledge management. Problems and Perspectives in Management. ; Sumy. 2016; 14(1): 85–93. Publisher Full Text\n\nSilva IM, et al.: Antecedents of cost innovation: the combined impact of strategy and organisational culture. International Journal Of Innovation And Learning. 2018; 24: 327–344. Publisher Full Text\n\nAgostini L, Nosella A: Enhancing radical innovation performance through intellectual capital components. J. Intellect. Cap. 2017; 18(4): 789–806. Publisher Full Text\n\nAgostini L, Nosella A, Filippini R: Does intellectual capital allow improving innovation performance? A quantitative analysis in the SME context. J. Intellect. Cap. 2017; 18(2): 400–418. Publisher Full Text\n\nDost M, Badir YF, Ali Z, et al.: The impact of intellectual capital on innovation generation and adoption. J. Intellect. Cap. 2016; 17(4): 675–695. Publisher Full Text\n\nDumay J, Rooney J, Marini L: An intellectual capital-based differentiation theory of innovation practice. J. Intellect. Cap. 2013; 14(4): 608–633. Publisher Full Text\n\nDavenport TH, Prusak L: Working knowledge: How organizations manage what they know. Boston, Mass: Harvard Business School Press; 1998.\n\nStewart T: The New Wealth of Organizations. London: Nicholas Brealey; 1997.\n\nBhatt GD, Grover V: Types of Information Technology Capabilities and Their Role in Competitive Advantage: An Empirical Study. J. Manag. Inf. Syst. 2005; 22: 253–277. Publisher Full Text\n\nKim G, Shin B, Kim KK, et al.: IT Capabilities, Process-Oriented Dynamic Capabilities, and Firm Financial Performance. J. Assoc. Inf. Syst. 2011; 12(7): 487–517. Publisher Full Text\n\nRockart JF, Earl MJ, Ross JW: Eight imperatives for the new IT organization. Sloan Manag. Rev. 1996; 38(1): 43–55. [Google Scholar]\n\nBharadwaj A: A Resource-Based Perspective on Information Technology Capability and Firm Performance: An Empirical Investigation. MIS Q. 2000; 24(1): 169. Publisher Full Text\n\nRoss JW, Beath CM, Goodhue DL: Develop long-term competitiveness through IT assets. Sloan Manag. Rev. 1996; 38(1): 31–42.\n\nWesterman G, Calméjane C, Bonnet D, et al.: Digital transformation: A roadmap for billion-dollar organizations. MIT Center for Digital Business and Capgemini Consulting. 2011; 1–68.\n\nWeill P, Woerner S: Is your business ready for a digital future?. MIT Sloan Manag. Rev. 2018; 59(2): 21–24.\n\nAbbas J, Mahmood S, Hashim A, et al.: The Effects of Corporate Social Responsibility Practices and Environmental Factors through a Moderating Role of Social Media Marketing on Sustainable Performance of Business Firms. Sustainability. ; Basel. 2019; 11(12): Publisher Full Text\n\nArshi TA, Rao V, Islam S, et al.: SECURE – a new business model framework for measuring start-up performance. J. Entrep. Emerg. Econ. 2020; 13: 459–485. Publisher Full Text Vol. ahead-of-print No. ahead-of-print.\n\nBashir M, Farooq R: The synergetic effect of knowledge management and business model innovation on firm competence: A systematic review. Int. J. Innov. Sci. 2018; 11(3): 362–387. Publisher Full Text\n\nBhattacharya S, Momaya KS, Iyer KC: Benchmarking enablers to achieve growth performance: a conceptual framework. BIJ. 2020; 27(4): 1475–1501. Publisher Full Text\n\nBotha AP: A mind model for intelligent machine innovation using future thinking principles. J. Manuf. Technol. Manag. 2019; 30(8): 1250–1264. Publisher Full Text\n\nBrem A, Wolfram P: Research and development from the bottom up - introduction of terminologies for new product development in emerging markets. Journal of Innovation and Entrepreneurship; Heidelberg. 2014; 3(1): 9–22. Publisher Full Text\n\nde Lange DE : Legitimation Strategies for Clean Technology Entrepreneurs Facing Institutional Voids in Emerging Economies. J. Int. Manag. 2016; 22(4): 403–415. 1075-4253.Publisher Full Text\n\nDhamija P, Bag S: Role of artificial intelligence in operations environment: a review and bibliometric analysis. The TQM Journal. 2020; 32(4): 869–896. Publisher Full Text\n\nDiaw D, Lessoua A, Ndione LC: Specialization in Entry-Level Products: A Strategy for Industrial Development in Africa. Manag. Int. 2020; 24(2). 39-53,185,187,189. Montréal.Publisher Full Text\n\nDurst S, Hinteregger C, Temel S, et al.: Insights from the later stage of the new product development process: findings from Turkey. Eur. J. Innov. Manag. 2018; 21(3): 456–477. Publisher Full Text\n\nFarooq R: Developing a conceptual framework of knowledge management. Int. J. Innov. Sci. 2020; 11(1): 139–160. Publisher Full Text\n\nGupta AK, Dey AR, Shinde C, et al.: Theory of open inclusive innovation for reciprocal, responsive and respectful outcomes: coping creatively with climatic and institutional risks. J. open innov. 2016; 2(16). Publisher Full Text\n\nGupta S: Understanding the feasibility and value of grassroots innovation. J. Acad. Mark. Sci. 2019; 48: 941–965. New York. Publisher Full Text\n\nHart S, Sharma S, Halme M: Poverty, Business Strategy, and Sustainable Development. Organ. Environ. 2016; 29(4): 401–415. June 13, 2021.Publisher Full Text Reference Source\n\nHerting AM, Schmidt AL: A Systematic Analysis of how Practitioners Articulate BusinessModels across Disruptive Industries. Technol. Innov. Manag. Rev. 2020; 10(10): 29–42. Ottawa.Publisher Full Text\n\nHorn C, Brem A: Strategic directions on innovation management – a conceptual framework. Manag. Res. Rev. 2013; 36(10): 939–954. Publisher Full Text\n\nHossain M: Business model innovation: past research, current debates, and future directions. J. Strateg. Manag. 2017; 10(3): 342–359. Publisher Full Text\n\nHossain M, Islam KMZ, Sayeed MA, et al.: A comprehensive review of open innovation literature. J. Sci. Technol. Policy Manag. 2016; 7(1): 2–25. Publisher Full Text\n\nKaraman Kabadurmus FN: Antecedents to supply chain innovation. Int. J. Logist. Manag. 2020; 31(1): 145–171. Publisher Full Text\n\nKoerich GV, Cancellier ÉLPDL: Frugal Innovation: origins, evolution and future perspectives. Cadernos EBAPE.BR. ; Rio de Janeiro. 2019; 17(4): 1079–1093. Publisher Full Text\n\nWoo KL: How Chinese commercial banks innovate: process and practice. Journal of Innovation Management. 2017; 5(2): 81–110. Porto Portugal.Publisher Full Text\n\nLiotta DC, Nwaka S, Sencer SD, et al.: North-South Collaborations To Promote Health Innovation In Africa. Emory Law Journal. 2018; 67(3): 619–653. Atlanta.\n\nMichelam LD, Córtese TTP, Yigitcanlar T, et al.: Revista de Gestão Ambiental e Sustentabilidade; Sao Paulo.2020; 9(1): 1–19. Publisher Full Text\n\nNag B, Tran J: Blue Ocean Strategy and Operations Management. Am. J. Manag. 2020; 20(2): 33–44. West Palm Beach.\n\nPenco L, Torre T, Scarsi R: Does strategic orientation influence strategy formulation and organisational design in Italian food medium sized enterprises? The role of the family. Br. Food J. 2020; 122(5): 1397–1419. Publisher Full Text\n\nRese A, Kopplin CS, Nielebock C: Factors influencing members’ knowledge sharing and creative performance in coworking spaces. J. Knowl. Manag. 2020; 24(9): 2327–2354. Publisher Full Text\n\nSahay S: Big Data and Public Health: Challenges and Opportunities for Low and Middle Income Countries. Commun. Assoc. Inf. Syst. 2016; 39: 419–438. Atlanta.Publisher Full Text\n\nSnehvrat S, Dutta S: Multi-level ambidexterity in new product introduction at Tata Motors, India: The role of metaroutines. Journal of Organizational Effectiveness: People and Performance. 2018; 5(3): 211–235. Publisher Full Text\n\nSon H, Lee J, Chung Y: Value Creation Mechanism of Social Enterprises in Manufacturing Industry: Empirical Evidence from Korea. Sustainability. 2018; 10(1): 46. Basel.Publisher Full Text\n\nDe Sordi JO, Nelson RE, Meireles M, et al.: Exaptation in management: beyond technological innovations. Eur. Bus. Rev. 2019; 31(1): 64–91. Publisher Full Text\n\nYin X, Chen J, Li J: Rural innovation system: Revitalize the countryside for a sustainable development. J. Rural. Stud. 2019. 0743-0167.Publisher Full Text\n\nShen Z, Siraj A, Jiang H, et al.: Chinese-Style Innovation and Its International Repercussions in the New Economic Times. Sustainability. 2020; 12(5)1859. Basel.Publisher Full Text\n\nDzenopoljac V, Yaacoub C, Elkanj N, et al.: Impact of intellectual capital on corporate performance: evidence from the Arab region. J. Intellect. Cap. 2017; 18(4): 884–903. Publisher Full Text\n\nBontis N, Janošević S, Dženopoljac V: Intellectual capital in Serbia’s hotel industry. Int. J. Contemp. Hosp. Manag. 2015; 27(6): 1365–1384. Publisher Full Text\n\nAtalay M, Anafarta N: Enhancing innovation through intellectual capital: A theoretical overview. Journal of Modern Accounting and Auditing. 2011; 7(2): 202–210.\n\nForsman H: Innovation capacity and innovation development in small enterprises: A comparison between the manufacturing and service sectors. Res. Policy. 2011; 40(5): 739–750. Publisher Full Text\n\nPedro EM, Leitão J, Alves H: The intellectual capital of higher education institutions: Operationalizing measurement through a strategic prospective lens. J. Intellect. Cap. 2019; 20(3): 355–381. Publisher Full Text\n\nLeitner KH, Curaj A, Elena-Perez S, et al.: A Strategic Approach for Intellectual Capital Management in EuropeanUniversities. Guidelines for Implementation, UEFISCDI Blueprint Series, No. 1, Executive Agency for Higher Education, Research, Development and Innovation Funding, Bucharest.2014.\n\nCunha MP, Rego A, Clegg S, et al.: Unpacking the concept of organizational ingenuity: learning from scarcity. Handbook of Organizational and Entrepreneurial Ingenuity. 2014; 34. Publisher Full Text\n\nTiwari R, Fischer L, Kalogerakis K: Frugal Innovation in Scholarly and Social Discourse: An Assessment of Trends and Potential Societal Implications. Joint working paper of Fraunhofer MOEZ Leipzig and Hamburg University of Technology in the BMBF-ITA project, Leipzig/Hamburg. 2016.\n\nJayabalan J, Dorasamy M, Raman M: Data file.xlsx. figshare. Dataset. 2021. Publisher Full Text\n\nJayabalan J, Dorasamy M, Raman M: PRISMA checklist. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "119603",
"date": "03 Feb 2022",
"name": "Fivi Anggraini",
"expertise": [
"Reviewer Expertise management accounting",
"intellectual capital"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral: In general, this research is very interesting. The author has reviewed the literature extensively to produce this paper. However, there are some things that need to be improved so that this paper is more valuable for indexing.\n\nTitle: The title is incomplete because the author did not include information technology capabilities (ITC) variables.\n\nIntroduction: The research problem is not sharp to portray the issues. In fact, the argument is also not clear on why the author uses three variables in this study.\n\nMethod: What is the reason for the authors making statistics in Figures 4, 5, 6, and 7? In my opinion, the data is not related to the research objectives, because this research is a just systematic literature review, not investigational research.\n\nResults and discussion: The discussion is very shallow; the authors have reviewed a lot of literature, but the discussion of the results is less in-depth. The intended research gap (in table 5) is not clear. Need to write down the author's analysis.\n\nSummary: I think the authors failed to conclude significant findings as to the new theory in this study\nWhat is the reason the authors concluded the frugal innovation, intellectual capital, and ITC insufficient? Need justification on the matters.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? No\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? No",
"responses": [
{
"c_id": "8262",
"date": "24 May 2022",
"name": "Jayamalathi Jayabalan",
"role": "Author Response",
"response": "Title: Title is changed according to the suggestion given to include information technology Capabilities Problem statement: included more clear and with contextual detail to establish why it is important Findings: Figure 4,5,6, and 7 is only added for descriptive analysis purposes as it might be useful for future research Results and discussion: Provided more explanations on the major findings Summary: Provided detailed discussion to strengthen the sections"
}
]
},
{
"id": "99071",
"date": "18 Feb 2022",
"name": "Logaiswari Indiran",
"expertise": [
"Reviewer Expertise Intellectual capital"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral Comments: Despite the fact that this is an intriguing study, the authors have obtained a unique dataset through the a comprehensive literature. On the whole, the paper is well-written and well-structured. However, I believe the study has several flaws, particularly on the reason for this research to be conducted, mainly on the importance/need of the relationship between IC, ITC and FI, and how the findings contribute significance contribution to the theoretical gaps.\nIntroduction: The problem statement is too general without any supporting detail. The reason for introducing IC and ITC towards FI is not clear.\nMethod: I would advise removing Figure 4, 5, and 6 as they are not suitable to systematic literature review study. Discussion for Figure 8 is not clear.\nResult and Discussion: The analysis and discussion of the finding is too general and did not demonstrate any contribution to the theoretical gap. Need further discussion on the research gaps derived from Table 5.\nSummary: I would advise adding details on the theoretical and contextual contribution of this study in the summary. Example: how is it significant to the existing knowledge and how it plays its role in context?\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": [
{
"c_id": "8263",
"date": "24 May 2022",
"name": "Jayamalathi Jayabalan",
"role": "Author Response",
"response": "1. Problem statement: included more clear and with contextual detail to establish why it is important to include ITC 2. Findings: Figure 4,5,6, and 7 is only added for descriptive analysis purposes as it might be useful for future research 3. Results and discussion: Provided more explanations on the major findings. Commented more on the significance of the studies and overall interpretation of the results 4. Summary: Provided detailed discussion to strengthen the section"
}
]
}
] | 1
|
https://f1000research.com/articles/10-1109
|
https://f1000research.com/articles/11-549/v1
|
19 May 22
|
{
"type": "Method Article",
"title": "ALL-IN meta-analysis: breathing life into living systematic reviews",
"authors": [
"Judith ter Schure",
"Peter Grünwald",
"Peter Grünwald"
],
"abstract": "Science is justly admired as a cumulative process (“standing on the shoulders of giants”), yet scientific knowledge is typically built on a patchwork of research contributions without much coordination. This lack of efficiency has specifically been addressed in clinical research by recommendations for living systematic reviews and against research waste. We propose to further those recommendations with ALL-IN meta-analysis: Anytime Live and Leading INterim meta-analysis. ALL-IN provides statistical methodology for a meta-analysis that can be updated at any time—reanalyzing after each new observation while retaining type-I error guarantees, live—no need to prespecify the looks, and leading—in the decisions on whether individual studies should be initiated, stopped or expanded, the meta-analysis can be the leading source of information. We illustrate the method for time-to-event data, showing how synthesizing data at interim stages of studies can increase efficiency when studies are slow in themselves to provide the necessary number of events for completion. The meta-analysis can be performed on interim data, but does not have to. The analysis design requires no information about the number of patients in trials or the number of trials eventually included. So it can breathe life into living systematic reviews, through better and simpler statistics, efficiency, collaboration and communication",
"keywords": [
"Anytime",
"Live",
"Leading",
"Interim",
"Meta-analysis",
"Efficiency",
"Collaboration",
"Communication",
"Research Waste"
],
"content": "\n\nThe scientific response to the coronavirus disease 2019 (Covid-19) pandemic constitutes a major gamble. In the United States, for example, the funding program for vaccine development did not put money on a single vaccine, but on six different ones. They purposely took “multiple shots on goal” according to Larry Corey of the National Institutes of Health (NIH) Covid-19 Prevention Network in an interview with STAT (Branswell, 2021). Vaccine development is not a sure thing, and so their strategy needed to be robust enough to just “let the chips fall”. Also in the search for treatments, the scientific community had to hedge its bets. Clinical trials competed for resources and patients, and had to continuously change course when new information arrived. In contrast to vaccines, however, in most countries a strategy to find treatments was lacking. Many clinical trials suffered from “poor questions, poor study design, inefficiency of regulation and conduct, and non or poor reporting of results”: research waste (Glasziou et al., 2020). We believe that more strategic thinking can benefit a future pandemic response as well as non-pandemic evidence-based medicine, as uncertainty is often a given. Honest scientific bets can breathe life into the approach called living systematic reviews that aims to keep the evidence record up-to-date (Elliott et al., 2017) and the medical guidelines current (Akl et al., 2017). We propose to make those bets by using ALL-IN meta-analysis in clinical trial design, monitoring and reporting.\n\nALL-IN meta-analysis stands for Anytime Live and Leading INterim meta-analysis. The Anytime aspect provides analysis that controls type-I error in testing and coverage in interval estimation regardless of the decision making along the way, and so regardless of any stopping rules or accumulation bias processes (Ter Schure & Grünwald, 2019). The Live aspect prevents research waste caused by meta-analyses that are out-of-date, which is often the case in retrospective meta-analysis. The synthesis can be a bottom-up collaboration of trials, as well as a prospective top-down statistical analysis for decision making. The Leading aspect allows the systematically collected evidence included so far to drive the necessity and design of new trials. Finally, the INterim aspect is new in meta-analysis and makes for effortless combination of trials while they are still ongoing. What is more, ALL-IN meta-analysis is also literally ALL-IN since any number of new studies can be included; it has an unlimited horizon. Like the use of the law of iterated logarithm in meta-analysis, proposed by Lan et al., 2003, Hu et al., 2007, this property goes back to early work by Robbins and colleagues (Robbins, 1970). We illustrate this in the setting of time-to-event data, where waiting for new events is an inherent challenge of clinical trials. Combining trials early can prevent delays if studies are slow in themselves to complete the necessary number of events. ALL-IN has advantages in four categories: statistics, efficiency, collaboration and communication. We introduce all four briefly (page 4–5) before we go into more detail, but first illustrate the language of betting for single trials studying a Covid-19 vaccine.\n\nOn June 30th, 2020, the US Food and Drug Administration (FDA) published its guidance document on “Development and Licensure of Vaccines to Prevent Covid-19” (FDA, 2020). This set the goals for any Phase III clinical trial betting on a protective effect of a vaccine against Covid-19. The guidance document advised on the definition of events of confirmed (symptomatic) SARS-CoV-2 infection for the trials to be counting. And in counting those, the document prescribed the two things to achieve: (1) at least a vaccine efficacy (VE) of 50% and (2) evidence against a null hypothesis of ≤ 30% VE (FDA, 2020, p. 14). Most Covid-19 vaccine trials randomized large numbers of participants 50:50 vaccine:placebo such that we can assume that also throughout the trial the participants at risk stayed approximately balanced. According to the definition of SARS-Cov-2 infections, we start counting once a participant has a confirmed infection after being fully vaccinated for at at least a number of days, e.g. 7 days in the Pfizer-BioNTech trial (Polack et al., 2020). This is also when a (virtual) bet could start. In the following we reinterpret the design for the Covid-19 vaccine trials in the language of betting.\n\nEach new event carries evidence that we express by a betting score. We make a (virtual) investment on one of the two outcomes: either the next event occurs in the vaccine group or it occurs in the placebo group. If there is no effect of the vaccine whatsoever, the 50:50 risk set ensures that the infected participant has 0.5 a chance to be vaccinated and 0.5 a chance to be a placebo. Yet, following the FDA, we do not only want to rule out an ineffective vaccine, but also reject the hypothesis that the vaccine has an effect that is too small—set as the null hypothesis of (at most) 30% VE. In that case each newly observed infection has slightly smaller chance to be a vaccinated participant. That probability to be in the vaccine group is 0.41, since each placebo group member has a 100% risk of Covid-19 and a vaccine group member has 100−30 = 70% of the risk, which is a fraction 0.41 of the total risk (70/(100 + 70)). So if the VE is too small to be of interest we expect (at least) a fraction 0.41 of Covid-19 events to occur in the vaccine group and (at most) 0.59 in placebo.\n\nHow do we bet against that and win if the vaccine has a much larger protective effect? We are betting against the probability 0.41 of the next Covid-19 event to occur in the vaccine group. If this probability actually is that large (the vaccine is not very protective; the null hypothesis) we do not want the game to be favorable under any strategy, just like the casino does not want any gambler to earn a salary playing the roulette wheel. On the other hand, we are betting in favor of a much smaller probability for the vaccine group. If this probability is smaller (the vaccine is protective; the alternative hypothesis) we do want to win money, just like a professional poker player who makes a salary out of gambling well. We use the betting scores to decide whether the vaccine is a real deal-breaker (the scores behave like the salary of a professional poker player) or whether it is not effective enough (the scores behave like anyone playing the roulette wheel). To ensure that our betting scores can show either case, we first design the game such that it is fair—under the null hypothesis—and then optimize playing the game with a strategy that is profitable —under the alternative.\n\nDesigning a fair game under the null hypothesis Consider gambling at the roulette table where the vaccine trial analogy is like betting on red (vaccine) or black (placebo). Betting correctly doubles your investment, betting incorrectly loses everything you risked. Assuming no house edge (no 0 or 00 on the roulette wheel) and an initial €100 you do not expect to increase your investment, since you have 0.5 a chance of doubling (2 · €100) and 0.5 a chance of losing all (0 · €100). Whether you bet everything on black or red, in expectation the betting score after one round is (0.5·2+0.5·0)·€100, which is the initial investment €100. To achieve the same thing betting against the 0.41:0.59 probabilities instead of 0.5:0.5, your investment needs to multiply by 2.4 (1/0.41) for vaccine and 1.7 (1/0.59) for placebo. If you bet everything on vaccine you have 0.41 chance of multiplying by 2.4 (2.4 · €100) and 0.59 chance of losing all (0 · €100) and if you bet everything on placebo you have 0.59 chance of multiplying by 1.7 (1.7·€100) and 0.41 chance of losing all (0·€100). The expected betting score after one round is again the initial investment for both: (0.41·1/0.41+0.59·0)·€100 and (0.59 · 1/0.59 +0.41 · 0) · €100. Hence, at either the roulette table or in this FDA game, by design the game is fair and does not favor us. After all, if our observed infections land on the vaccine and control group with the probabilities 0.41:0.59, like a spin of the roulette wheel on black and red with 0.5:0.5, we do not expect to claim an effective vaccine.\n\nOptimize playing the game under the alternative hypothesis How do we win as fast and as much as possible if our observed infections do not behave like a roulette wheel? It has been known since the work of Kelly (1956) and Breiman (1961) that the best way to increase your capital in the long run is to not bet all your (virtual) investment €100 on one of the two possible outcomes (red/vaccine or black/placebo) but to divide it based on the odds that make the game favorable to you. So our focus needs to be on the minimal VE of 50% from the FDA guidance. In the scenario of 50% VE, the probability that the next Covid-19 case is in the vaccine group is 1/3: if we set the risk of Covid-19 for a placebo group member to 100%, a vaccine group member has 100−50 = 50% of that risk, which is 1/3 of the total risk (50/(100 + 50)). Kelly (1956) and Breiman (1961) urge us to invest one-third (1/3 · €100) on observing the next infection in the vaccine group and two-thirds (2/3 · €100) on placebo.\n\nLikelihood ratios If we bet this way we can rewrite our betting scores in terms of a likelihood ratio. We first show this for the red-black roulette game where we double what we had put at risk on either black or red if the spin of the roulette wheel outputs the color we bet on. Just like in our strategy in the FDA game, we put 1/3 · €100 on red and 2/3 · €100 on black, so we win the following if the ball X lands on either red or black:\n\nThe Bernoulli 1/3-likelihood 𝔏(1/3 | X) assigns likelihood 1/3 when is X = red and 2/3 when is X = black. So if our strategy is to invest 1/3-2/3 in roulette, our payout is our initial investment €100 multiplied by the likelihood ratio, whether X is red or black.\n\nThe likelihood for 50% VE (𝔏(50% VE | X)) assigns likelihood 1/3 when is X = vaccine and 2/3 when is X = placebo. Similarly, the likelihood for 30% VE (𝔏(30% VE | X)) assigns likelihood 0.41 when is X = vaccine and 0.59 when is X = placebo. Hence if our strategy is to invest 1/3-2/3 in the FDA game, our payout is also our initial investment €100 multiplied by the likelihood ratio, whether X is vaccine or placebo.\n\nReinvesting We assume now that we start with an initial (virtual) investment of €1 instead of €100, to easily assess our winnings by the factor with which we multiply our initial investment. At the first observation we bet €0.33 on vaccine and €0.66 on placebo. After we observe the event in the placebo group we lose our €0.33 bet on vaccine and multiply our €0.66 on placebo by 1.7 to €1.13. The likelihood ratio between our 30% VE alternative hypothesis and our 50% VE null hypothesis— so 𝔏(50% VE | X )/𝔏(30% VE | X )—is also about 1.13, so multiplying our initial investment of €1 into €1.13. On the other hand, if we observe the event in the vaccine group we lose our €0.66 bet on a placebo event and multiply our €0.33 on vaccine by 2.4 to €0.81. The likelihood ratio of a vaccine event multiplies our investment by 0.81. After each observed event we reinvest what we have left in the new bet, so multiply that with the next likelihood ratio.\n\nA winner The Pfizer/BioNTech trial observed 8 cases of Covid-19 among participants assigned to receive the vaccine and 162 cases among those assigned to placebo (Polack et al., 2020). This totals a betting score of 0.818 · 1.13162· €1, which is about €118 million (note that 1.13 is really 1.13333 . . .). If someone wins that at the poker table, we have good reason to consider her a professional poker player with a favorable strategy, rather than a lucky beginner (Konnikova, 2020).\n\n\nMeta-analysis: bottom-up collaboration\n\nThe Pfizer/BioNTech trial included more than 43 thousand participants (Polack et al., 2020), which is quite unique for a clinical trial. Usually trials are much smaller, and scientific consensus is built through systematic reviews and retrospectively combining trials in a meta-analysis. ALL-IN is a way to do so by collaborating bottom-up in a strategic way that can be live instead of retrospective. It has advantages in four categories that we will first briefly introduce and then further elaborate on in this paper: statistics, efficiency, collaboration and communication.\n\nNot all mRNA vaccines showed such favourable results as the Pfizer/BioNTech vaccine. In a press release CureVac AG (2021) announced that the final analysis of their clinical trial observed 83 events in the vaccinated group and 145 in placebo, so only a 43% VE (our calculations assuming a 50:50 balanced risk set (r = 1 in CureVac AG (2020, p. 124))1). Their protocol states the FDA goal in terms of a confidence interval that excludes a VE of 30%, adjusted for two interim analyses. That adjusted confidence interval at the final analysis is based on Zα/2-statistic for the nominal level α/2 = 0.02281 (CureVac AG, 2020, Table 8). That interval is [25.3%, 57.1% VE] (our calculations; normal approximation interval) and, regrettably, does not exclude 30%. When the chips fell, this trial lost.\n\nStatistical analyses like these are essentially all-or-nothing, just as any other p < α analysis. As soon as all the α is spent—either on a few interims and a final analysis or just on one fixed sample size—we cannot continue the trial and perform subsequent analyses without violating the type-I error rate. This might be a reasonable price to pay in the urgency of a pandemic when multiple vaccines are competing, but it is a very inconvenient property for clinical trials in general. Usually, we do want to reanalyze a clinical trial in combination with other similar trials in a meta-analysis. Yet any p < α procedure is equivalent to setting a rejection region for the test statistic and checking whether the value for the statistic falls within that region. This rejection region is based on a sampling distribution that assumes the number of studies in the meta-analysis, and the number of patients within each study to be fixed in advance. Given such a fixed sample size (but also for any sequential stopping rule that sets a maximum sample size in advance, such as α-spending), there is only one region, and your test statistic is either in it or not. If it is not, you are not allowed to redo the analyses with an increased sample size. This problem is recognized in approaches to control type-I error for living systematic reviews (Simmonds et al., 2017). But also if the meta-analysis is not updated, the α is essentially already spent on the individual trial analyses, since the meta-analysis is an update of the trial analysis that is unscheduled and lacks type-I error control at the same level α. If the individual study analysis would have been conclusive, the meta-analysis might never be performed, and we can recognise that we are dealing with a situation of “meta-optional-stopping”. A different way to see this is by the actual sampling distribution of trials in a meta-analysis: any data-driven decision within the series—whether to accumulate more studies and when to perform the meta-analysis—changes the sampling distribution and invalidates the fixed-sample-size distribution assumed for p < α. Hence hardly any meta-analysis has valid type-I error control, when the accumulation of trials is based on strategic decisions that introduce accumulation bias (Ter Schure & Grünwald, 2019).\n\nALL-IN meta-analysis is not all-or-nothing but can still combine all available studies. In fact, it allows any number of new studies or patients to be included without ever spending all α. In terms of gambling, we can keep betting our virtual investment because we never lose everything. The CureVac AG (2021) results, for example, would have accumulated a betting score of 0.8183 · 1.13145· €1 = €1.84. This single trial is not very profitable, but at least it still preserves some evidence to reinvest in the next trial, such that we can continue to observe evidence and express it by betting on additional observations in a new trial. An ALL-IN meta-analysis can always continue testing the null hypothesis—with type-I error control—and estimating the confidence interval—with coverage guarantees. Importantly, for these tests and intervals the procedures are exactly the same no matter what decisions—so-called stopping rules, or accumulation bias processes (Ter Schure & Grünwald, 2019)—are at play.\n\nLack of efficiency has been addressed in clinical research in many ways. Not only in the proposal of living systematic reviews (Elliott et al., 2017), but also in encouragements to present new studies in the context of existing evidence (Young & Horton, 2005), in advice to design new trials based on systematic reviews and meta-analysis (Chalmers & Lau, 1993; Goudie et al., 2010; Lau et al., 1995; Lund et al., 2016; Sutton et al., 2007) and in pleading to prevent the “scandal” of wasteful research into clinical questions that are already answered or not of primary importance (Altman, 1994; Chalmers & Glasziou, 2009; Ioannidis et al., 2014; Glasziou & Chalmers, 2018; Glasziou et al., 2020, “research waste”). These calls have not been completely ignored, since clinical research has seen an increase in efficiency—e.g. in platform trials or adaptive meta-analysis (Tierney et al., 2021)—whenever collaboration is deemed possible prospectively. Nevertheless, most clinical trial data is synthesized retrospectively, and still deserves all of the above recommendations. ALL-IN meta-analysis enables these data-driven decisions that can make science more efficient. New studies can be easily informed by the synthesis of all data so far such that exactly the right number of patients are randomized to answer a research question, no more and no less. Moreover, an ALL-IN meta-analysis can give an account of the evidence at anytime and therefore facilitate prioritizing new studies, if more than one line of research needs additional data, but not all can be funded.\n\nALL-IN meta-analysis can be a live meta-analysis, since it does not matter how many studies will eventually be combined or which study will contribute most data. Whether it is based on summary statistics (Tierney et al., 2021) or on individual patient data (IPD) (Polanin & Williams, 2016), involvement in the same meta-analysis facilitates discussion between those running trials in the same line of research; especially if the line of research can be concluded early. Trial protocols and statistical analysis plans can be exchanged and scrutinized, to identify discrepancies between the design and the conduct of trials. In an ongoing meta-analysis, trials can be selected for inclusion before investigators are unblinded to the results, which helps to mitigate the problems of publication bias and p-hacking. If IPD analysis is possible, intense collaboration might also prevent mistakes and fraudulent data that would otherwise depreciate the meta-analysis.\n\nA meta-analysis benefits from homogeneity. With too much heterogeneity, it can be very disheartening to update a random-effects meta-analysis, since many trials are needed to precisely estimate the between trial variation and overcome it (Jackson & Turner, 2017; Kulinskaya & Wood, 2014; Sutton et al., 2007). Close collaboration might prevent unnecessary heterogeneity, if trial investigators are involved in the selection of trials in the meta-analysis; especially if they can advise on the design and conduct of new trials and align inclusion criteria and endpoint definitions. A fixed-effects meta-analysis can conclude the research effort early. Sufficient homogeneity may be possible in close collaboration.\n\nThe language of betting The interpretation of evidence in terms of a betting score might help to communicate the uncertainty in statistical results. As Shafer (2021) puts it: “When statistical tests and conclusions are framed as bets, everyone understands their limitations. Great success in betting against probabilities may be the best evidence we can have that the probabilities are wrong, but everyone understands that such success may be mere luck.” Thinking in terms of bets also helps to understand when statistical analyses can be anytime-valid. If they are of the all-or-nothing kind, but reanalyzed in a meta-analysis, they are gambling while broke. (This intuition can be made mathematically precise; see the description of Neyman-Pearson testing in terms of betting Shafer (2021) and Grünwald et al. (2019).) Yet if we add new studies to an ALL-IN meta-analysis, we are reinvesting the betting score that we saved from earlier studies, to evaluate whether the strategy in those earlier studies continues to succeed. Just like when reinvesting your profits in a casino from one slot machine into another, the notion of winning stays the same. Our evidence against the hypothesis of a fair casino does not change when we alternate slot machines. It does not change if we use the score so far to decide on alternating them or to decide when to cash out. If the slot machines are fair, any strategy of playing them is not expected to make money, and our notion of type-I error control holds under any dependency on past results (stopping rules or accumulation bias processes).\n\nOther communication Those uncomfortable with the language of betting can also easily resort to any of three more familiar notions of statistical communication. Firstly, the likelihood ratios/betting scores and their generalizations, so-called e-values (Grünwald et al., 2019; Vovk & Wang, 2021), can be interpreted as conservative p-values by taking their inverse. If we denote any betting score or e-value by €(e.g. € = €1.84 for the CureVac trial data), then p < 1/€ is a conservative p-value (e.g. p = 1/1.84 = 0.54 for the CureVac trial data). If we communicate the p-value p = 1/€ anyone can test by comparing p < α but with the addition that this conservative p-value is anytime valid2 and so p < α can never spend all α (it is never an all-or-nothing test). Secondly, the likelihood ratios have their own notion of evidence in the likelihood paradigm (Royall, 1997). Just as well as stating that the Pfizer/BioNTech trial (Polack et al., 2020) multiplied €1 to almost €118 million and the CureVac AG (2021) trial multiplied €1 to €1.84, we can state that their data was almost 118 million times and 1.84 times more likely if we assume the FDA’s goal of 50% VE in comparison to assuming only 30% VE. For Pfizer, that sounds very good, for CureVac, not so much, and so these numbers have an interpretation of their own without imposing any α level. Thirdly, likelihood ratios can be accepted by the Bayesian paradigm, as Bayes factors, and possibly combined with prior odds. Grünwald et al. (2019) and Grünwald (2021) show that betting scores/e-values and Bayes factors are closely related, although not all Bayes factors are betting scores/e-values. The bottom-line for communication purposes is that the reporting by ALL-IN meta-analysis can be interpreted in many ways—p-values, likelihood ratios, Bayes factors—but regardless of the interpretation provide fully frequentist type-I error control for tests and coverage for confidence sequences.\n\nThe remainder of this paper discusses the four categories of advantages in more detail: Statistics in Section 1, Efficiency in Section 2, Collaboration in Section 3 and Communication in Section 4. We use the Covid-19 vaccine trials as running examples, based on the FDA game described already, but also in terms of the safe/e-value logrank test (Ter Schure et al., 2020b). We also briefly discuss an actual ALL-IN meta-analysis in Section 3.1, that used this safe/e-value logrank test to study whether the Bacillus Calmette–Guérin (BCG) vaccine, originally developed to protect against tuberculosis and named after its inventors, could protect against Covid-19 (Van Werkhoven et al., 2021, ALL-IN-META-BCG-CORONA). In the concluding section we will provide some broader context, with an overview of all the methods already developed—e-values, safe tests (Grünwald et al., 2019) and anytime-valid confidence sequences— methods already available in software—notably safestats R package (Turner et al., 2022)—and future work. R code for all calculations, simulations and plots is available in the software availability statement (Ter Schure, 2021, https://doi.org/10.17605/OSF.IO/U6WTP).\n\n\n1 Statistics\n\nThe language of betting comes with the intuition that winning a large betting score has a small probability if the null hypothesis is generating our observations (e.g. the roulette wheel is fair). We will make this intuition precise and show how to control the type-I error by bounding this probability by Markov’s inequality and Ville’s inequality. Crucial here is that the betting score underlying our test is an e-value. The language of betting also comes with the intuition that when playing a game that is favorable to us in principle, we can use strategies of different quality: even among all strategies under which we expect to get richer, some of them can be expected to earn us much more than others. We will relate the more well known notion of power to such a different notion of optimality. In the following we discuss both e-values and optimality first for a single trial (in the FDA game and more generally) and then for ALL-IN meta-analysis. We conclude by a generalization of optimal e-value tests to confidence sequences.\n\nTo make the FDA game fair we imposed a multiplication by 2.4 (or 170/70) if we observe the event in the vaccine group and 1.7 (or 170/100) if we observe it in the placebo group. This multiplication has expectation 1 (or smaller) if we assume the null hypothesis of a vaccine with negligible VE of 30% (or smaller). In case of 30%, we have probability 0.41 (or 70/170) to observe a vaccine event and probability 0.59 (or 100/170) to observe placebo, so in expectation we multiply our investment by: 70/170 · 170/70 +100/170 ·170/100 = 1. No matter how we invest in the two outcomes, (e.g. putting 1/3 on vaccine and 2/3 on placebo, or something different) in expectation under the null we multiply the initial investment by 1. This means that our betting score is an e-value, since by definition an e-value is the outcome of a nonnegative random variable with expectation (at most) 1 under the null hypothesis (Grünwald, 2021).\n\nOur betting score could also be rewritten as a likelihood ratio, so the expectation of the likelihood ratio (𝔏(50% VE | X)/𝔏(30% VE | X)) is 1 as well. We hence-forth write the likelihood ratio after n rounds of betting (or after observing n events) as LR(n), with for the FDA game\n\nUsing its expectation of 1, Markov’s inequality bounds the probability of observing a large multiplication of our investment € (a large likelihood ratio) by α after n = 170 rounds as follows:\n\nFigure 1 shows at the right side the histogram of betting scores in the FDA game after 170 events when we simulate events under the null hypothesis, with probability 0.41 to occur in the vaccine group, corresponding to 30% VE. A line is shown at 40, and indeed no more than α = 1/40 = 2.5% of the scores seem to be larger than that threshold. In fact, in these 1000 runs of simulation only 0.3% of the runs have a betting score larger than 40; Markov’s inequality is a loose bound. We also have a stronger result because we obtained our betting score over events by multiplying the score of the rounds (see (1), corresponding to reinvesting our winnings), called Ville’s inequality. We get the following from Ville (1939):\n\nThe dashed line is the threshold 1/α = 40 one-sided. The histogram at the right shows the betting score/LR(170) after 170 events. Note that the expectation of 1 of the scores is not the mode of its distribution nor its median and that the y-axis is on a log scale.\n\nVille’s inequality is also illustrated in Figure 1: if we take the sequence of rounds into account, still only a few out of the 1000 simulations ever reach a betting score larger than 40. In fact, in these 1000 runs of simulation only 1.1% of the runs have a betting score that is larger at any round in the game, such that our type-I error is controlled at α = 2.5% at any time. Moreover, this type-I error control is not tied to this maximum number of 170 events, but continues to hold with an unlimited horizon. Making a large profit in such a fair game casts doubt on the null hypothesis and is captured by a likelihood ratio that grows away from 1: a large betting profit is obtained if the null likelihood is performing worse than alternative.\n\nWhen trials can be summarized as bets Before they can be combined in a meta-analysis, individual trials are often characterized by the summary statistics from trial publications. Conventional meta-analysis combines these statistics (e.g. mean differences and standard deviations) in a Z-statistic (Borenstein et al., 2009). Unlike the vaccine/placebo outcomes that we have seen so far, such a Z-statistic has a continuous density and cannot be summarized by separately dealing with all possible outcomes. Fortunately, Shafer (2021) shows that any likelihood ratio of distributions can be viewed as a betting score in a game with initial investment €1. This is possible because likelihood ratios have expectation 1 in general if we assume the null hypothesis in the denominator of the ratio. For a Z-statistic we have two normal distributions with variance 1, one with mean µ0 under the null hypothesis, and one with µ1 under the alternative. If the data is generated by the null model, the expectation of the likelihood ratio is\n\nsince ϕµ1(z) is a probability density that integrates to 1. This means that any such likelihood ratio for a Z-statistic is an e-value and can be used to construct tests by betting.\n\nNot all summary statistics can be assumed to form a Z-statistic with a normal distribution. Fortunately for the logrank statistic this is reasonable (Ter Schure et al., 2020b) if studies are large and the effect size not too extreme (hazard ratios not too far away from 1). We will use the logrank Z-statistic as a running example for meta-analysis on summary statistics. For an IPD meta-analysis (on individual patient data), however, we recommend to use the exact safe/e-value logrank test from Ter Schure et al. (2020b) that is valid regardless of the randomization (e.g. 1:1 balanced or 1:2 unbalanced), the number of participants at risk, the number of events or the size of the effect—so also for a hazard ratio 0.05 that corresponds to a VE of 95%.\n\nAssume we want to perform a meta-analysis and we collect a Z-statistic Zi from each trial i, e.g. a logrank statistic. Before observing Zi we construct an honest bet LRi = ϕµ1(Zi)/ϕµ0(Zi) for each trial that is an e-value and thus has type-I error control under the null hypothesis ϕµ0—for a default logrank statistic this is always µ0 = 0 corresponding to hazard ratio of 1. If we think of the betting score from the first study and invest it in the second study, we are in fact multiplying likelihood ratios. We need to have a notion of time t, such that at each time we know the number of studies k〈t〉 so far and the number of observations ni〈t〉 in each study i. If we assume that all studies are completed at time t with n1, n2,...,ni events summarized by logrank Z-statistics z1(n1),z2(n2),…,zk(nk) we can construct our ALL-IN bet as follows:\n\nThe global null hypothesis Each trial bet is testing the same null hypothesis µ0 = 0 in (3), such that the ALL-IN meta-analysis bet tests a global null hypothesis of no effect (0% VE) in all trials. Such a global null hypothesis can be rejected with a contribution from each trial, but also in case only one trial observes a large score betting against the hypothesis and no other trial observes a very small betting score that loses those winnings again. After all, the null in each trial is rejected as soon as the null is rejected in one of the trials.\n\nMeta-analysis on interim data We can generalize this ALL-IN meta-analysis bet of completed trials to bets on interim data by assuming that we only have an interim logrank Z-statistic z1〈t〉,z2〈t〉,..., zk〈t〉 for the n1〈t〉, n2〈t〉,..., nk〈t〉 events observed so far at time t; k〈t〉 still represents the number of studies so far at time t, but now these studies are not (all) completed. We construct our ALL-IN bet in a similar way:\n\nFrom the perspective of Ville’s inequality, the analysis on completed trials and the one on interim data are indistinguishable. The only thing that matters is that we include all the data we have so far at time t, such that we have type-I error control\n\nfor the global null hypothesis probability P0 with an unlimited horizon over time t.\n\nA power analysis sets a very specific goal for a trial, usually to detect an effect of minimal clinical relevance. This is the effect we would not like to miss if it were there, although we hope that the real effect is larger. We nevertheless use this smallest effect of interest to decide on the sample size of the trial, otherwise we risk a futile trial. The FDA was clear on what this minimal effect should be for the Covid-19 vaccine trials: a VE of 50% (FDA, 2020). This is the effect we used to bet in the FDA game.\n\nOur strategy in the FDA game, however, was not trying to achieve optimal power. If we compare the all-or-nothing confidence interval for CureVac AG (2021) from the introduction—the final analysis on 83+145 events—we notice that this confidence interval [25.3%, 57.1% VE] is smaller than the final anytime valid interval we show in Figure 3 in Section 1.5, which is [20.2%, 60.3% VE]. Note that we are comparing a Zα/2-confidence interval for α/2 = 0.02281 with α/2 = 0.05, so the wider interval cannot be attributed to the level of α. The difference is that the former one is optimized to have spent all α at the final analysis, while the latter one is optimized to continue data collection. Power is the probability of finding the desired result using the specified analysis at a sample size or stopping rule. So for an analysis that is intended to have unlimited horizon, power is not a well-defined concept. Instead Grünwald et al. (2019) introduced the concept of growth-rate optimality in the worst case, or GROW. Here, the goal is to optimize the expected rate at which the evidence grows (or the interval shrinks) for each new data point, not at a specific sample size. The worst case here is the 50% VE for a one-sided alternative hypothesis H1 = {PVE : 50% ≤ VE ≤ 100%}. We optimized the FDA bet in the introduction by putting this 50% VE in the alternative likelihood. This can be rewritten in terms of a likelihood ratio for the logrank statistic Z as follows:\n\nwith µmin = log(0.5)/4 and µ0 = log(0.7)/4 with 0.5 and 0.7 the hazard ratios corresponding to VE of 50% and 30% respectively (see Ter Schure et al. (2020b)). So our one-sided alternative hypothesis for the logrank Z-statistic is a Z-distribution with a mean representing an effect that is at least µmin:\n\n(since positive VE corresponds to a negative µ1). Our choice of the parameter of the alternative likelihood µmin follows directly from the minimal effect set by the FDA. Kelly (1956) already showed that this way of betting optimizes the way our betting score grows if the true VE is 50% (our worst-case scenario). Breiman (1961) showed that this approach also minimizes the number of events we need to reach a given betting score set in advance (e.g. €1/α), for which some intuition is given in Figure 2. Grünwald et al. (2019), Shafer (2021) and the appendix to Ter Schure et al. (2020b) give various other reasons why this is the best way to bet, relating it to data compression, information theory, Neyman-Pearson testing, Gibb’s inequality, and Wald’s identity. The most crucial property for the purposes of ALL-IN meta-analysis is that the alternative likelihood puts some money on each possible outcome, such that no matter what outcome we observe, we keep some of the money we risk. This contrasts the approach with a classic p < α test that essentially puts all money on the rejection region, such that if the outcome is not in it, we we lose all and cannot continue betting. A thorough interpretation of Neyman-Pearson testing and p-values in terms of betting is given by both Grünwald et al. (2019) and Shafer (2021).\n\nThe number of events we need decreases if the true VE underlying the data increases (the true difference in risk between vaccine and control is larger). The smallest number of events for a true VE of 40% is reached by betting VE1 of 40% (blue solid line), the smallest number of events for a true vaccine efficacy (VE) of 50% by betting VE1 of 50% (orange dotted line) and the smallest number for true VE of 60% by betting VE1 of 60% (grey dashed line). Note that for the alternative in the FDA game H1 = {PVE : 50% ≤ VE ≤ 100%} we are only interested in playing the game well if the true VE is 50% or larger. Since for larger true VE, taking VE1 = 50% performs quite well, our strategy is to optimize for the worst case of 50% VE itself and use the bet with VE1 = 50% in the FDA game.\n\nNote that the y-axis is on the log scale.\n\nALL-IN meta-analysis allows for a retrospective meta-analysis that is bottom-up. The betting score that we accumulate by reinvesting from one trial into the other (which is multiplying betting scores) has an interpretation without enforcing a common design or stopping rule on all included trials. This is especially important if trials have their own stopping rules, or if meta-accumulation processes are at play that influence the existence of trials based on earlier (trial) results in the same meta-analysis. While a meta-analysis can be bottom-up and each have its own design and effect of minimal interest, it can be advisable to agree on a µmin for the meta-analysis. However, the meta-analysis betting score can also allow each trial i to have its own alternative likelihood with parameter µmin(i). Then the following multiplication of those betting scores is still a valid meta score with type-I guarantees:\n\nAs long as ϕμmin(i)ni is a probability density that integrates to 1, we have that each likelihood ratio integrates to 1 under the global null hypothesis, such that (5) holds. This means that trials can also learn their parameter µmin(i) from already completed trials. This is sometimes the case if trials are not powered to detect an effect of minimal interest, but an effect that is plausibly true based on earlier research. Kulinskaya et al. (2016) shows that such use of existing studies to power new trials can actually bias conventional meta-analysis since it introduces yet another dependency between sample size and results that is unaccounted for in any analysis that assumes a fixed sample size. For ALL-IN meta-analysis this is no problem at all, and trials can learn from each other as long as the parameter µmin(i) is fixed before seeing new data that is evaluated using that parameter in (7). In Ter Schure et al. (2020b) we discuss the advantages of even learning the parameter within one trial using prequential plugins or Bayesian posteriors. In a game like the FDA game with a clear goal, this is inferior to the GROW approach, but in other situations it could be preferred.\n\nThe CureVac AG (2021) trial reached their final interim analysis but was not able to reject the null hypothesis of 30%VE. The trial had been too optimistic and powered for 60% instead of 50% VE (CureVac AG, 2020). If a trial is underpowered but still has a large number of participants in follow-up, there is good reason to continue the trial, or combine the trial with results from a new trial in a meta-analysis. However, with a total of 227 events this trial was not underpowered to reject the null hypothesis with an effect in the same ballpark as the Pfizer/BioNTech trial that reported 95% VE. In such a case it is very interesting to zoom in on the estimate for the effect, instead of its test.\n\nA standard confidence interval can be seen as an inversion of a hypothesis test: if the null falls outside a two-sided 90%-confidence interval it can be rejected with a one-sided type-I error level of α/2 = 0.05. In general, the interval excludes all the values for the parameter that can be rejected. Similarly, in our context, an anytime-valid confidence interval excludes all values of the parameter that can be rejected by the e-value test that corresponds to the betting strategy at hand. So the interval is essentially tracking a whole range of bets, each against a different null hypothesis. Figure 3 gives a sequence of anytime-valid confidence intervals for a random ordering of the CureVac AG (2021) data, one for each new observed event or betting round. It shows that the more events we observe, the more parameters (hazard ratios, or their corresponding VEs) we can exclude from the interval. Because these intervals are valid at any time, once we can exclude a value, we never have to include it again. So we also show a sequence of intervals that is the running intersection of all the previous intervals. This of course crucially depends on the ordering, so the one shown for the CureVac AG (2021) data is just an example, since the ordering is not real. Since these intervals are anytime valid, it is possible to further shrink the intervals by continuing follow-up and observing more events. The coverage of an anytime-valid confidence sequence—like an e-value test—has an unlimited horizon.\n\nAn ALL-IN meta-analysis confidence interval that is based on a running intersection is of course only possible in an IPD meta-analysis, and cannot be based on summary statistics. The confidence interval shown in Figure 3 is based on the logrank Z-statistic (by repeatedly calculating it after each event), which can also be a summary statistic to achieve a single interval that is anytime-valid. The interval follows from the likelihood ratio of normal densities from (6) and follows a general recipe for constructing confidence sequences from Howard et al. (2021) where the hazard ratio is obtained by means of the Peto estimator (Peto, 1987). The same approach can be used to obtain an ALL-IN meta-analysis confidence interval. A fixed-effects meta-analysis Z-statistic corresponds to a logrank statistic stratified by trial, and an estimate can be obtained from such a logrank statistic that Peto (1987) calls a typical hazard ratio. We discuss this approach a bit further in the final section.\n\n\n2 Efficiency\n\nTrials often suffer from recruitment difficulties, with estimates of 35% (between 1994 and 2002) and 56% (between 2004 and 2016) not reaching the goal set in advance (McDonald et al., 2006; Walters et al., 2017). These trials find themselves underpowered according to their own protocol: when they decide the stop the recruitment and obtain the final sample size for analysis, they have a high probability for their test statistic to fall outside the rejection region they set in advance. This is exactly the scenario where meta-analysis could rescue the line of research by combining multiple underpowered trials. However, the literature on research waste (Chalmers & Glasziou, 2009) and Evidence-Based Research (Lund et al., 2016) shows that we are not using the existing evidence base well to design the new trials needed for conclusion or to interpret new research. ALL-IN meta-analysis makes this very easy to do. It comes with a simple notion of the evidence already collected and what is still needed, and a notion of a new trial’s ability to provide that: the implied target. The combination of the two has the capacity to make study design more honest, showing what a trial can add to the existing evidence base instead of just evaluating a misguided goal to single-handedly answer a research question.\n\nAn ALL-IN meta-analysis can set a prospective goal for conclusion, e.g. α = 0.0025 = 0.052 corresponding to the level of α required by authorities like the FDA that ask for two trials at the α = 0.05 level. Following Ville’s inequality (5) we need a betting score of 1/α = €400 if we start with €1 to reach a conclusion. Because an ALL-IN meta-analysis combines trials by reinvesting or multiplying betting scores, a very simple calculation gives the betting score we still need at any given point. If an initial trial is able to reach a score of €8, any new trial can be designed to multiply that by 50. So on its own, starting with €1 instead of €8, it would need a betting score of €50 to help the meta-analysis reach €400. We could evaluate the sample size of the new trial on its ability to reach 50, which for a fixed sample size gives the conditional power of the meta-analysis once the new trial is added. However, if this second trial also foresees recruitment issues, it is more difficult to evaluate its planned contribution since it will probably not be the final trial in the meta-analysis. For this, Shafer (2021) proposed a new notion for the ability of a study, not to reach a specific target betting score, but as a continuous notion of how profitable it can be: the implied target.\n\nThe likelihood ratio summarizes the data not in just two categories—statistical significant or not statistical significant—but captures the evidence so far on its way to a certain threshold. Similarly we propose to not evaluate experimental design as all-or-nothing, but summarize its ability to build on what is already there and facilitate future research. To capture a study’s expected contribution to a series of studies, we formulate the implied target from Shafer (2021) as the multiplicative amount with which the combined evidence is expected to grow if the study—designed with a certain µmin and sample size n—is added. In general, the implied target E* is defined as:\n\nThe logarithm appears in equation (8) because the distribution of a likelihood ratio based on n events is very non-symmetric and heavy tailed, with extremely large likelihood ratios occurring with not so small probability (see Figure 4). So the expectation of the likelihood ratio is drawn very far from its typical values by these large likelihood ratios and is not a good expression of what to expect. The logarithm makes the distribution more symmetric (asymptotically (for large n) and for normal likelihood ratios even normally distributed), such that the expectation is a more meaningful summary of the evidence promised by the study. By exponentiation (exp()) we bring this expectation back to the scale of the likelihood ratio, such that it can be interpreted as a betting score or e-value.\n\nThis is the alternative hypothesis of 60% vaccine efficacy (VE) used to power the CureVac AG (2020) trial at a number of events of 160. The dashed line is the threshold 1/α = 40 one-sided and the solid line is the implied target of €104. Note that the x-axis is on a log scale.\n\nThe histogram for the final betting scores at the right shows the larger scores above and the smaller ones at the bottom, which means that if we turn it, it is the mirror image of the histogram in Figure 4. The dashed line is the threshold 1/α = 40 one-sided. The increase in the solid line per additional event/betting round shows the contribution to the implied target of each event, up until the implied target at n = 160 of 104. In this figure, the design has an approximate 79% power to observe a betting score/e-value larger than 1/α = 40 before 160 events and 72% power at exactly 160 events (better visible in Figure 4). Note that the y-axis is on a log scale.\n\nIn the FDA game the expected growth rate per new event in the CureVac trial, assuming their effect of minimal interest of 60% VE, is the following:\n\nThe cumulative contribution of each new event is shown as the linear line on the log scale in Figure 5. The CureVac AG (2020, Table 8) design planned a final analysis at n = 160 events, so their implied target was 1.029454160 ≈ 104. In comparison to the target score of €104 at 160 events, the actual betting score €1.84 after 83 + 145 = 228 events in the press release is quite disappointing. Shafer (2021) gives more examples of how betting scores and implied target help to interpret study results in the context of study design.\n\nAn implied target does require an honest proposal of the effect of minimal clinical interest µmin, to evaluate the merits of the study. In regular power analysis, this parameter might be tweaked—e.g. setting an unrealistically large effect—to still argue for the study’s advancement with only small sample size. Or the smallest effect size of interest analysis is set after data is observed (Wang et al., 2018). This behavior is incentivized by the all-or-nothing character of Neyman-Pearson tests that also make the power analysis all-or-nothing. If your desired sample size does not meet the power hoped-for, you need to either increase it or abandon the study. This aspect of traditional analyses fully ignores the ideal of cumulative science in which one study is not expected to single-handedly answer a research question and small increments in knowledge are valuable, as long as they build towards a common goal. If they use e-values and the ALL-IN framework, researchers do not have to view their analysis as the final one, which helps them to evaluate their study more honestly (Lakens, 2021).\n\n\n3. Collaboration\n\nThe Evidence-Based Research Network (Lund et al., 2016) aims to always inform new research by past results and to reduce research waste by separating research ideas that are necessary from those that are wasteful. This is not easy to do, however. Different communities might have different notions of necessity or even of what is ethical (a state of so-called clinical equipoise (Shamy et al., 2020)). It might therefore be very beneficial to have all those running new clinical trials in a field collaborate together in an ALL-IN meta-analysis.\n\nWe ran two ALL-IN meta-analyses during the Covid-19 pandemic with the involvement of seven trials in one and four in the other. All were designed to study whether the BCG vaccine, originally developed to protect against tuberculosis, could protect against Covid-19 (based on a theory of non-specific immune effects and innate immunity (Netea et al., 2020)). The two meta-analyses study different populations (healthcare workers and the elderly) and two questions each: the effect of the BCG vaccine on Covid-19 infection (not necessarily symptomatic) and the effect on severe Covid-19 (indicated by hospitalizations). In the following description we will focus on the analysis of Covid-19 infections in the healthcare workers population.\n\nALL-IN-META-BCG-CORONA followed many of the steps also outlined by Tierney et al. (2021), that we will briefly discuss here: (1) Meta-analysis design, (2) Systematic search for trials, (3) Systematic review for trial inclusion (4) Data upload, and (5) Disseminating results.\n\n(1) Meta-analysis design Early in the project we decided to aim for an IPD meta-analysis on interim data and wrote our protocols and statistical analysis plans. This timestamped two important decisions on the meta-analysis design: the hazard ratio of minimal interest of 0.8 (20% VE) for events of Covid-19 and the level of α set at 0.0025 so the threshold for the e-value was at 1/α = 400. For these decisions we set up a meta-analysis Steering Committee that was still fully blinded to any results at the time. The design was preregistered (Van Werkhoven et al., 2021) and all documentation and a webinar explaining the methodology were made available on a project website (Ter Schure et al., 2020a).\n\n(2) Systematic search for trials We continuously searched for trials to include in the meta-analysis. Some were already known to our Steering committee before we started. They initiated a BCG trial of their own very early in the pandemic and shared their protocol with many of their contacts in the BCG research community. Other trials were found by a repeated systematic search of trial registries. The trials that agreed to join the meta-analysis were each represented by a member in the Advisory Committee. Meetings of the Advisory committee were scheduled regularly and the trials involved could point us to any new developments. A major advantage of ALL-IN meta-analysis here is that the number of trials does not need to be specified in advance.\n\n(3) Systematic review for trial inclusion We received external advice from Cochrane Netherlands on trial inclusion based on a thorough risk-of-bias assessment. For this assessment, each trial shared their protocols, and subsequently all Cochrane’s evaluations were shared and discussed with the Steering committee and Advisory committee (where trials were usually represented by their PI’s who were blinded to any trial results). Trials had multiple opportunities to answer questions—from Cochrane Netherlands as well as other trials involved—explain their trial and express other concerns about differences between the trials included. The Steering Committee made the final decision on including a trial, before any of that trial’s results were known to anyone part of the discussion. The decision of the Steering committee explicitly incorporated both trial quality and meta-analysis homogeneity.\n\n(4) Data upload Parallel to the discussions on trial inclusion, data transfer agreements were signed and data was shared through a secure upload. Each trial had a data uploader that was in close contact with the ALL-IN metatrial statistician (the first author of this paper) about data quality. The ALL-IN statistician did not attend the discussion meetings and kept the Steering committee and Advisory committee blinded to any results before each trial inclusion decision.\n\n(5) Disseminating results Each data-uploader received a dashboard account with permissions to inspect the meta-analysis e-value and their own trial contribution. Their access of interim meta-analysis results in the dashboard served as a motivator to keep their own trial data upload up-to-date and to check the sequence of e-values for errors. Figure 6 shows this dashboard based on a demo login with synthetic data (this demo was available for everyone involved to get an impression). After an initial period where the data-uploaders could only inspect their own trial results, they granted each other permission to inspect all the individual trial contributions. When the first trials were completed and the meta-analysis was approaching its conclusion, the results were also presented to the Advisory and Steering committees. Any interim decisions were planned based on the ALL-IN meta-analysis e-values, but results were also presented in the context of power, implied target per trial and confidence sequences.\n\nThe involved trials were performed in the Netherlands (NL), Denmark (DK), the United States (US), Hungary (HU), Brazil (BR), France (FR) and Guinea-Bissau/Mozambique (AF). The dashboard is in demo mode and shows synthetic (“fake”) data. The option to (de)select trials is for plotting purposes of individual trial e-values; all trials in the dashboard stay included in the meta e-value, following the decision from the Steering committee on trial inclusion. Note that the y-axis is on the log scale.\n\nIn many aspects, our approach agrees with the framework for prospective, adaptive meta-analysis (FAME) proposal from Tierney et al. (2021). FAME argues for prospective meta-analyses in close collaboration with ongoing trials to achieve the same advantages outlined in this paper, such as aligning trial characteristics (“minimize heterogeneity”) and reducing publication bias and “bias [in] both review and meta-analysis methods” introduced by “prior knowledge of trial results” (e.g. accumulation bias (Ter Schure & Grünwald, 2019)). In alignment with the FAME recommendations, ALL-IN-META-BCG-CORONA was prospectively designed by preregistering an overall effect size of minimal interest and an α-level. However, ALL-IN meta-analysis in general also allows for a more bottom-up approach when each trial’s e-value is based on that trial’s own design (effect size of minimal interest, see Section 1.4) and trial evidence is synthesized more loosely without a strict decision rule. In comparison to FAME, ALL-IN meta-analysis is much more adaptive. FAME proposes to use conventional meta-analysis (with a fixed sample size) and optimize the timing of the meta-analysis “to anticipate the earliest opportunity for a potentially definitive meta-analysis”. In that sense, FAME can only adapt to the speed of recruitment, while ALL-IN allows to adapt to any information so far including the evidence in the trials and the synthesis of the meta-analysis itself. There is also a statistical inconsistency in the FAME approach that is concerned with “striking a balance between maximising the absolute and relative information size and producing a sufficiently timely review” but does explicitly state that the last step of the meta-analysis is to “assess the value of updating the systematic review and meta-analysis”. A fixed sample-size statistical analysis should not be reanalyzed using the same statistical methodology. Any proposal to use conventional meta-analysis for efficiency purposes risks accumulation bias (Ter Schure & Grünwald, 2019) because the timing of the meta-analysis might be driven by some of the results part of that same analysis. Hence the best approach is to combine the recommendations from FAME (Tierney et al., 2021) with statistical approach from ALL-IN meta-analysis and the spirit of living systematic reviews.\n\nCollaboration using a dashboard A dashboard for ALL-IN meta-analysis allows us to spot trends in the accumulating evidence, or allow other stakeholders to monitor. A dashboard like Figure 6 can give access to the accumulating e-values to those that need to prepare for crossing a threshold in the near future, e.g. for independent data monitoring committees of ongoing trials or for those considering new trials or preparing to update medical guidelines. On a log-scale, the increase in e-values is linear (in expectation) and the observed trends can be estimated, e.g. in Figure 6 as an increase in evidence per additional calendar day.\n\nFor ALL-IN-META-BCG-CORONA, the time unit t in the definition of LR〈t〉 from (4) was set to calendar days and the e-values were updated at each calendar day with an event. The dashboard plots in Figure 6 horizontal lines at 1 for trials that do not observe any events yet: they have not started betting and are still at their initial investment of €1 contributing a neutral amount to the multiplication meta-e-value. ALL-IN meta-analysis monitors e-values as events come in, also when they do so from multiple trials simultaneously. In the language of betting, even the analysis of simultaneous events is considered a sequential bet. If the bet on the events from one trial pays out €4, it multiplies our initial capital by 4, and if the events from another trial pay out €5, it does so by a factor 5. Yet if we actually consider those trials to be consecutive bets, we reinvest the €4 from the first into the second, and obtain €1 ⋅ 4 ⋅ 5 = €20, as follows from the definition of the meta-analysis e-value on interim data in (4).\n\nFigure 6 illustrates what going ALL-IN means: the evidence in all studies can be monitored and compared to the required threshold at any time. The hypothesis test is carried out by comparing the meta e-value in blue to the threshold 1/α of 400, plotted as a dotted line. Because the meta-analysis is anytime and live a conclusion is reached whenever the e-value sequence passes that threshold. The synthesis of studies can efficiently lead the decision to stop recruiting, treat the placebo group or discourage new trials to start, while encouraging inspection of each individual trial’s contribution to the meta-analysis. Since each trial’s contribution is a simple multiplication, their components can often be conveniently spotted in the agreement of the shape of the meta-analysis and individual trial lines in a dashboard like Figure 6 (as long as not too many trials are contributing simultaneously).\n\nCollaboration in a competitive field or a pandemic ALL-IN meta-analysis also prevents losing type-I error control when many trials compete for answers on the same research question, e.g. in an uncoordinated scientific response to a pandemic. If trials are only evaluated in isolation and a response follows the first positive result of a single trial, serious multiple testing issues arise that inflate the type-I error and result in unreliable inference and, subsequently, poor decisions. This happens especially if all trials perform interim analyses on their own, and a type-I error occurs at an interim analyses before any other trial results are published to refute it. The example dashboard also clearly demonstrates decreased type-II errors: synthesizing the evidence in a meta-analysis at interim stages of the trials, and not after trials are completed, improves the ability to find an effect early. Collaboration is indeed much more efficient.\n\nSutton et al. (2007, p. 2491) note that “in a meta-analysis with considerable heterogeneity, the impact of a new (large) study will be (much) less in a random compared to fixed effect model”. This is due the incorporation of a parameter in the model that represents the between-study variation. Also Kulinskaya & Wood (2014) find that the goal of sequentially updating a random-effect meta-analysis might involve planning a large number of small trials to estimate the between-study variance well. Even if that is considered advisable, a random-effects model result might still be very difficult to interpret (Riley et al., 2011). Hence there are various reasons to prefer the fixed-effects model to monitor evidence efficiently and to ensure that the trials are sufficiently homogeneous.\n\nAlongside ALL-IN-META-BCG-CORONA we initiated a second ALL-IN meta-analysis. While the first included trials on healthcare workers, the second included trials in the elderly. Early in the process, before seeing any data, our Steering committee noticed that the two groups could be very different. Based on a theory of innate and trained immunity, they expected a different effect of the BCG vaccine on the younger immune system of healthcare workers than on the older immune system in the elderly. It could even be that the BCG vaccine effect was beneficial in the ability to fight off Covid-19 in one population but harmful in the other. In general, the differences between trials can be in three categories: heterogeneous effects, conflicting effect and multiple testing.\n\nHeterogeneous effects Our Steering committee decided that to declare success, all included trials in health-care workers should observe an effect of 20% VE or larger. If they indeed do, heterogeneity in their effect sizes (e.g. one 20%, one 50%, one 25%) does not matter for their joint ability to reject the global null hypothesis of no effect in all trials. So for testing the global null, trials are allowed to be heterogeneous in where they are in the space of the alternative hypothesis H1 = {VE: 20% ≤ VE ≤ 100%}. For estimation, however, it is not clear what the ALL-IN confidence interval is estimating if we assume that the effects in the trials are very different. Still, as a first summary, a typical effect size (Peto, 1987) might be useful if we are unable to estimate a random effects model. The development of confidence sequences for random-effects meta-analysis is a major goal for future work. We do not, however, believe that the evidence in a line of research should be monitored based on whether this interval excludes the null hypothesis, or whether the e-value corresponding to the random-effects null model does: for testing, the global null is much more natural. Waiting for a random-effect model to reach a certain threshold is counter-intuitive, since it might require many small trials to estimate the between-trial variability instead of focusing on testing the treatment effect. Moreover, the goal of rejecting the null hypothesis corresponding to this model can be quite strange. When testing a zero-effect null hypothesis, it assumes that there are true effects of harm and true effects of benefit among the trials and that their mean is exactly zero.\n\nConflicting effects If one of the trials has an effect smaller than 20% or even a harmful effect, we should anticipate betting scores or e-values that are smaller than 1. So a meta-analysis multiplication of those e-values would reduce the evidence available from other trials. If we can identify groups for which we expect that the trials in each group have an effect in the same direction and of at least the minimal size, we can perform separate meta-analyses. This was the rationale behind grouping healthcare workers and the elderly each in their own ALL-IN-META-BCG-CORONA analysis.\n\nMultiple testing When our analysis is exploratory, and we really have no idea how to group the various trials, we are faced with a multiple testing problem. Note that in this situation also no conventional meta-analysis method would be used to test a common null-hypothesis. We wonder whether any of the trials has the ability to reject the null hypothesis. In that case, we can divide our initial investment over the trials, and see if the totality of their bet achieves a high betting score. Research into this use of e-values has shown that indeed averaging e-values is the optimal way to have type-I error control in a standard multiple testing setting (Vovk & Wang, 2021). We return to the notion of hedging bets and averaging e-values in Section 4.\n\nProblems with heterogeneity in meta-analysis are not tied to the ALL-IN approach and familiar to anyone working with meta-analysis methods. ALL-IN-META-BCG-CORONA had the advantage that many of the trials that started later had drawn inspiration from the protocol of the first trial. The same sort of alignment of inclusion criteria and outcome definitions might be achieved in other lines of research as well. Hence close collaboration can be very important and the promise of an early conclusion of the research effort might keep a research field motivated to keep the goals aligned.\n\n\n4. Communication\n\nWe have illustrated that the language of betting can be useful in interpreting results from an ALL-IN meta-analysis. Here we argue this further by giving extensions of our method that are very easily explained in terms of betting.\n\nOur examples so far covered one-sided tests, but those can be easily extended to two-sided tests, e.g. by taking\n\nto represent a two-sided alternative hypothesis\n\nSuch a two-sided test is easy to interpret in the language of betting. We essentially split our initial investment (e.g. €1) between the two sides of the alternative hypothesis (e.g. by betting €0.50 on one side and €0.50 on the other). Any other weighting of the two sides is also possible and corresponds to a different division of the initial investment. The crucial thing is that each side tests the same null hypothesis H0 = {ϕµ0} and has expectation 1 under the null hypothesis, such that any weighted average also has expectation 1 and is an e-value. Note that for a meta-analysis at time t with k〈t〉 studies this becomes:\n\nUsually one side of the bet is losing and the other is winning such that we do not want to reinvest (multiply) across sides but keep them separate for all trials. In our ALL-IN-META-BCG-CORONA dashboard we also visualized these two sides of the meta-analysis test separately; in Figure 6 we show only the left-sided test (for benefit) of the two.\n\nAnother way to hedge our bets is by considering multiple primary outcomes. In ALL-IN-META-BCG-CORONA, for example, not only were the Covid-19 events counted, but Covid-19 hospitalizations as well, as an indicator for severe disease. We started with α = 0.05 and put 10% on Covid-19 (α = 0.0025 on each of the two sides of a two-sided test) and 90% on hospitalisations (α = 0.0225 on each of the two sides of a two-sided test). So the thresholds to achieve with the e-value for Covid-19 was set at 1/α = 400 and the one for hospitalization at 1/α = 44.44. A different way to formulate this is that each had to achieve 1/α = 20, but that the sequence of e-values for Covid-19 started with an initial investment of €0.05 for each side of the two-sided test (and had to multiply by 400 to reach €20) and that the e-value for hospitalization started with an initial investment of €0.45 for each side (and had to multiply by 44.44 to reach €20).\n\nThere are two ways to consider such a bet on two co-primary outcomes: separately and combined. If we evaluate the e-values for each primary outcome separately and reach the threshold with either of the two, we are rejecting the null for that outcome. We are doing two separate tests. If we evaluate the e-values combined, we average them weighted by their α, just as for the two sides of the two-sided test. In that case we have similar type-I error control, but reject the null hypothesis that both are a null effects in favor of the alternative hypothesis that one of them is not. Yet we cannot conclude which one is non-null with the same type-I error since our α level applies to the combined bet and the individual components to the averaged bet are essentially lost.\n\n\nConcluding remarks\n\nThe novelty of this paper lies in a new method for meta-analysis. We do not claim any novelty for the underlying mathematics, though. The basic methods we describe can be viewed as relatively minor variations of the anytime-valid tests that are designed to preserve type-I error under optional stopping, as designed by H. Robbins and his students (Darling & Robbins, 1968; Robbins, 1970). Unfortunately and surprisingly, these tests have not caught on in statistics until a few years ago—right now they are thriving in work on so-called safe tests, anytime-valid confidence sequences and e-values e.g. Grünwald et al. (2019); Henzi & Ziegel (2021); Howard & Ramdas (2019); Howard et al. (2021); Johari et al. (2021); Pace & Salvan (2019); Ramdas et al. (2020); Shafer et al. (2011); Shafer (2021); Turner et al. (2021); Vovk & Wang (2021). As far as we know, it has never before been suggested to use such methods in a meta-analysis context. (Group sequential methods, which have originally also been inspired by the anytime-valid tests, have in turn spurred developments in meta-analysis, but these are substantially different from ALL-IN.) Also, the fact that the logrank test can give a likelihood ratio of the type needed for an anytime-valid test/an ALL-IN meta-analysis is a new finding described by Ter Schure et al. (2020b).\n\nIn this paper we presented betting scores/e-values that are equivalent to likelihood ratios. In general though, betting scores and e-values are really generalizations of likelihood ratios that preserve the properties of likelihood ratios that give them a prominent role in statistics. Entire books have been written to advocate for summarizing evidence in observed data by a likelihood ratio (Edwards, 1974; Royall, 1997) and to separate the goal of measuring evidence from expressing posterior beliefs and making decisions. Likelihood ratios have the property that they can “favor a true hypothesis over a false one more and more strongly” and while a likelihood ratio can be misleading, “strong evidence cannot be misleading very often” (Royall, 1997, p. 14). This latter type-I error control is also referred to as a universal bound by Royall (1997) and, by recognizing Ville’s inequality, can be generalized to other betting scores and e-values.\n\nA betting score € is a random outcome of a bet and its random variable is an E-variable if it is nonnegative and for all P ∈ H0, EP [€] ≤ 1. For a given outcome of the bet, the value of such a random variable is the e-value. Ville’s inequality relies on the multiplication of E-variables—forming a test martingale—which also has expectation smaller than 1 and thus is itself an E-variable. For the example e-values in this paper, the requirement on the expectation E0[LR] ≤ 1 holds for a simple null hypothesis, e.g. H0 = {ϕ0}.\n\nApart from likelihood ratios of two simple hypotheses, e-values can also be defined for more complicated tests—e.g. a t-test with a nuisance parameter for the variance—in which case the unit expectation needs to hold not for a single mean-0-normal distribution with known variance, but for all mean-0-distributions with any variance. Grünwald et al. (2019) shows that it often is possible to construct E-variables for such composite testing problems, which is why we consider the e-value the right generalization of the likelihood ratio.\n\nIn this paper we briefly presented a confidence sequence (in Figure 3) for the hazard ratio or VE that was based on the Gaussian approximation to the logrank statistic and the Peto (1987) estimator. This estimator can be derived from summary statistics and is therefore still quite common in meta-analysis as a so-called two-stage method, although it is advised against for extreme hazard ratios (Simmonds et al., 2011). Research into other confidence sequences for the hazard ratio is still ongoing. For other estimation problems, confidence sequences already have been thoroughly studied, for example for medians and other quantiles (Howard & Ramdas, 2019), and odds ratios (Turner et al., 2021). These have not, however, been extended to meta-analysis, and especially for the random-effects meta-analysis model, research into confidence sequences is a major goal of future work.\n\n\nData availability\n\nNo data are associated with this article.\n\n\nSoftware availability\n\nThe safestats R package (Turner et al., 2022) provides software to do an e-value analysis for the t-test, Z-test, logrank test and 2x2-tables. Also functions are available to calculate the power and implied target for these study designs. Confidence sequences can be calculated for the odds ratio in 2x2-tables and the hazard ratio in time-to-event data.\n\nR code for the calculations, simulations and plots in this paper can be found on the Open Science Framework (Ter Schure, 2021, https://doi.org/10.17605/OSF.IO/U6WTP).\n\nThese were produced using the GitHub version of the safestats R package accessed 22 September 2021 (Ly et al., 2021).\n\nThis code is available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).\n\nThe code that produces the dashboard in Figure 6 is not publicly available since it mainly deals with logins and permissions that concern those involved in the particular ALL-IN meta-analysis that is described there as an example.",
"appendix": "Acknowledgements\n\nWe acknowledge Henri van Werkhoven for his confidence and nerve. Amid the chaos of the initial Covid-19 pandemic months, he quickly grasped the subtleties and benefits of our ideas and committed to intensify a network of Covid-19 research to implement ALL-IN-META-BCG-CORONA. In this partnership, he structured our thinking for this paper. We further acknowledge Marc Bonten and Mihai Netea for the atmosphere of collaboration they put in place in BCG vaccine research and their public stance against “each-small-study-on-its-own” research culture. We also thank Glenn Shafer, Daniël Lakens, Muriel Pérez and Alexander Ly for feedback and extensive discussions. We are especially grateful to Alexander for being the lead developer of the safe/e-value logrank test software and co-meta-statistician on ALL-IN-META-BCG-CORONA.\n\n\nFootnotes\n\n1The CureVac AG (2021) press release reports a VE of 48%, so uses a different r (ratio of follow-up time in the two groups). In such large trials r can often be assumed to stay close to 1, so we set it to 1 to make all calculations simpler. All our calculations are available as R code in the software availability statement. (Ter Schure, 2021, https: //doi.org/10.17605/OSF.IO/U6WTP).\n\n2Such conservative p-values cannot be pictured as the tails of a sampling distribution since such a picture needs a sample size. The Introduction chapter and the appendix to Chapter 1 in the Ph.D. dissertation Ter Schure (2022) give more details.\n\n\nReferences\n\nAkl EA, Meerpohl JJ, Elliott J, et al.: Living systematic reviews: 4. living guideline recommendations. J Clin Epidemiol. 2017; 91: 47–53. PubMed Abstract | Publisher Full Text\n\nAltman DG: The scandal of poor medical research. BMJ. 1994; 308(6924): 283–284. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBorenstein M, Hedges LV, Higgins JPT, et al.: Introduction to Meta-Analysis. John Wiley & Sons, Ltd. 2009. Publisher Full Text\n\nBranswell H: 12 lessons covid-19 taught us about developing vaccines during a pandemic. 2021; Accessed: 12 July 2021. Reference Source\n\nBreiman L: Optimal gambling systems for favorable games. Fourth Berkeley Symposium. 1961. Reference Source\n\nChalmers I, Glasziou P: Avoidable waste in the production and reporting of research evidence. Lancet. 2009; 374(9683): 86–89. PubMed Abstract | Publisher Full Text\n\nChalmers TC, Lau J: Meta-analytic stimulus for changes in clinical trials. Stat Methods Med Res. 1993; 2(2): 161–172. PubMed Abstract | Publisher Full Text\n\nCureVac AG: Clinical trial protocol a phase 2b/3, randomized, observer-blinded, placebo-controlled, multicenter clinical study evaluating the efficacy and safety of investigational sars-cov-2 mrna vaccine cvncov in adults 18 years of age and older. 2020; Accessed: 16 July 2021. Reference Source\n\nCureVac AG: Curevac final data from phase 2b/3 trial of first-generation covid-19 vaccine candidate, cvncov, demonstrates protection in age group of 18 to. 2021; Accessed: 16 July 2021. Reference Source\n\nDarling DA, Robbins H: Some nonparametric sequential tests with power one. Proc Natl Acad Sci U S A. 1968; 61(3): 804–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEdwards AWF: Likelihood: An account of the statistical concept of likelihood and its application to scientific inference. Cambridge University Press, New York, 1974; 41(4): 427–429. Reference Source\n\nElliott JH, Synnot A, Turner T, et al.: Living systematic review: 1. introduction—the why what, when, and how. J Clin Epidemiol. 2017; 91: 23–30. Publisher Full Text\n\nFDA: Development and Licensure of Vaccines to Prevent COVID19. 2020; Accessed: 12 July 2021. Reference Source\n\nGlasziou P, Chalmers I: Research waste is still a scandal—an essay by Paul Glasziou and Iain Chalmers. BMJ. 2018; 363: 1756–1833. Publisher Full Text\n\nGlasziou PP, Sanders S, Hoffmann T: Waste in covid-19 research. BMJ. 2020; 369: m1847. PubMed Abstract | Publisher Full Text\n\nGoudie AC, Sutton AJ, Jones DA, et al.: Empirical assessment suggests that existing evidence could be used more fully in designing randomized controlled trials. J Clin Epidemiol. 2010; 63(9): 983–991. PubMed Abstract | Publisher Full Text\n\nGrünwald P: Peter D. Grünwald’s contribution to the Discussion of ‘Testing by betting: A strategy for statistical and scientific communication’ by Glenn Shafer. J R Stat Soc Series A. 2021; 184(2): 440–441. Publisher Full Text\n\nGrünwald P, de Heide R, Koolen W: Safe Testing. arXiv: 1906.07801 [cs, math, stat]. 2019. Publisher Full Text\n\nHenzi A, Ziegel JF: Valid sequential inference on probability forecast performance. arXiv preprint arXiv: 2103.08402. 2021. Publisher Full Text\n\nHoward SR, Ramdas A: Sequential estimation of quantiles with applications to a/b-testing and best-arm identification. arXiv preprint arXiv: 1906.09712. 2019. Publisher Full Text\n\nHoward SR, Ramdas A, McAuliffe J, et al.: Time-uniform, nonparametric, nonasymptotic confidence sequences. The Annals of Statistics. 2021; 49(2): 1055–1080. Publisher Full Text\n\nHu M, Cappelleri JC, Lan KKG: Applying the law of iterated logarithm to control type I error in cumulative meta-analysis of binary outcomes. Clin Trials. 2007; 4(4): 329–40. PubMed Abstract | Publisher Full Text\n\nIoannidis JPA, Greenland S, Hlatky MA, et al.: Increasing value and reducing waste in research design, conduct, and analysis. Lancet. 2014; 383(9912): 166–175. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJackson D, Turner R: Power analysis for random-effects meta-analysis. Res Synth Methods. 2017; 8(3): 290–302. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJohari R, Koomen P, Pekelis L, et al.: Always valid inference: Continuous monitoring of a/b tests. Oper Res. 2021. Publisher Full Text\n\nKelly JL: A new interpretation of information rate. Bell System Technical Journal. 1956; 35(4): 917–926. Publisher Full Text\n\nKonnikova M: The Biggest Bluff: How I Learned to Pay Attention, Master Myself, and Win. Penguin, 2020. Publisher Full Text\n\nKulinskaya E, Huggins R, Henry Dogo S: Sequential biases in accumulating evidence. Res Synth Methods. 2016; 7(3): 294–305. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKulinskaya E, Wood J: Trial sequential methods for meta-analysis. Res Synth Methods. 2014; 5(3): 212–220. PubMed Abstract | Publisher Full Text\n\nLakens D: Sample size justification. 2021. Publisher Full Text\n\nLan KG, Hu M, Cappelleri JC: Applying the law of iterated logarithm to cumulative meta-analysis of a continuous endpoint. Statistica Sinica. 2003; 13(4): 1135–1145. Reference Source\n\nLau J, Schmid CH, Chalmers TC: Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care. J Clin Epidemiol. 1995; 48(1): 45–57. PubMed Abstract | Publisher Full Text\n\nLund H, Brunnhuber K, Juhl C, et al.: Towards evidence based research. BMJ. 2016; 355: i5440. PubMed Abstract | Publisher Full Text\n\nLy A, Turner R, Pérez-Ortiz MF, et al.: R-package safestats. 2021; Maintainer: Alexander Ly <a.ly@jasp-stats.org>, install in R by devtools::install_github(\"AlexanderLyNL/safestats\",ref=\"logrank\",build_vignettes=TRUE), accessed 22 September 2021.\n\nMcDonald AM, Knight RC, Campbell MK, et al.: What influences recruitment to randomised controlled trials? a review of trials funded by two UK funding agencies. Trials. 2006; 7: 9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNetea MG, Giamarellos-Bourboulis EJ, Domínguez-Andrés J, et al.: Trained immunity: a tool for reducing susceptibility to and the severity of sars-cov-2 infection. Cell. 2020; 181(5): 969–977. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPace L, Salvan A: Likelihood, replicability and Robbins’ confidence sequences. Int Stat Rev. 2019. Publisher Full Text\n\nPeto R: Why do we need systematic overviews of randomized trials? (transcript of an oral presentation, modified by the editors). Stat Med. 1987; 6(3): 233–244. PubMed Abstract | Publisher Full Text\n\nPolack FP, Thomas SJ, Kitchin N, et al.: Safety and efficacy of the bnt162b2 mrna covid-19 vaccine. N Engl J Med. 2020; 383(27): 2603–2615. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPolanin JR, Williams RT: Overcoming obstacles in obtaining individual participant data for meta-analysis. Res Synth Methods. 2016; 7(3): 333–341. PubMed Abstract | Publisher Full Text\n\nRamdas A, Ruf J, Larsson M, et al.: Admissible anytime-valid sequential inference must rely on nonnegative martingales. arXiv preprint arXiv: 2009.03167. 2020. Reference Source\n\nRiley RD, Higgins JPT, Deeks JJ: Interpretation of random effects meta-analyses. BMJ. 2011; 342: d549. PubMed Abstract | Publisher Full Text\n\nRobbins H: Statistical methods related to the law of the iterated logarithm. Ann Math Statist. 1970; 41(5): 1397–1409. Publisher Full Text\n\nRoyall R: Statistical evidence: a likelihood paradigm. CRC press, 1997; 71. Reference Source\n\nShafer G: Testing by betting: A strategy for statistical and scientific communication. J R Stat Soc Ser A Stat Soc. 2021; 184(2): 407–431. Publisher Full Text\n\nShafer G, Shen A, Vereshchagin N, et al.: Test martingales, Bayes factors and p-values. Statist Sci. 2011; 26(1): 84–101. Publisher Full Text\n\nShamy M, Dewar B, Fedyk M: Different meanings of equipoise and the four quadrants of uncertainty. J Clin Epidemiol. 2020; 127: 248–249. PubMed Abstract | Publisher Full Text\n\nSimmonds M, Salanti G, McKenzie J, et al.: Living systematic reviews: 3. statistical methods for updating meta-analyses. J Clin Epidemiol. 2017; 91: 38–46. PubMed Abstract | Publisher Full Text\n\nSimmonds MC, Tierney J, Bowden J, et al.: Meta-analysis of time-to-event data: a comparison of two-stage methods. Res Synth Methods. 2011; 2(3): 139–149. PubMed Abstract | Publisher Full Text\n\nSutton AJ, Cooper NJ, Jones DR, et al.: Evidence-based sample size calculations based upon updated meta-analysis. Stat Med. 2007; 26(12): 2479–2500. PubMed Abstract | Publisher Full Text\n\nter Schure J: Code for paper ALL-IN meta-analysis: breathing life into living systematic reviews. 2021. http://www.doi.org/10.17605/OSF.IO/U6WTP\n\nter Schure J: ALL-IN meta-analysis. PhD thesis, Leiden University, 2022. Reference Source\n\nter Schure J, Grünwald P: Accumulation Bias in meta-analysis: the need to consider time in error control [version 1; peer review: 2 approved]. F1000Res. 2019; 8: 962. PubMed Abstract | Publisher Full Text | Free Full Text\n\nter Schure J, Ly A, Grünwald P: Safes-tats and ALL-IN meta-analysis project page. 2020a. Reference Source\n\nter Schure J, Pérez-Ortiz MF, Ly A, et al.: The safe logrank test: Error control under continuous monitoring with unlimited horizon. arXiv preprint arXiv: 2011.06931. 2020b. Publisher Full Text\n\nTierney JF, Fisher DJ, Vale CL, et al.: A framework for prospective, adaptive meta-analysis (FAME) of aggregate data from randomised trials. PLoS Med. 2021; 18(5): e1003629. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTurner R, Ly A, Grünwald P: Safe tests and always-valid confidence intervals for contingency tables and beyond. arXiv preprint arXiv: 2106.02693, 2021. Reference Source\n\nTurner R, Ly A, Pérez-Ortiz MF, et al.: R-package safestats. R package version 0.8.6, Maintainer: Alexander Ly <a.ly@jasp-stats.org>, 2022. Reference Source\n\nvan Werkhoven CH, ter Schure J, Bon-ten M, et al.: Anytime Live and Leading Interim meta-analysis of the impact of Bacillus Calmette-Guérin vaccination in health care workers and elderly during the sars-cov-2 pandemic (ALL-IN-META-BCG-CORONA). 2021. Reference Source\n\nVille J: Etude critique de la notion de collectif. Bull Amer Math Soc. 1939; 45(11): 824. Reference Source\n\nVovk V, Wang R: E-values: Calibration, combination, and applications. Ann Stat. 2021. Publisher Full Text\n\nWalters SJ, Bonacho Dos Anjos Henriques-Cadby I, Bortolami O, et al.: Recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the United Kingdom Health Technology Assessment Programme. BMJ Open. 2017;7(3): e015276. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang MQ, Yan AF, Katz RV: Researcher requests for inappropriate analysis and reporting: A U.S. survey of consulting biostatisticians. Ann Intern Med. 2018; 169(8): 554–558. PubMed Abstract | Publisher Full Text\n\nYoung C, Horton R: Putting clinical trials into context. Lancet. 2005; 366(9480): 107–108. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "145459",
"date": "19 Aug 2022",
"name": "Junfeng Wang",
"expertise": [
"Reviewer Expertise DTA meta-analysis",
"Clinical prediction models",
"Health Technology Assessment"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this manuscript, ter Schure and Grünwald proposed a new form of meta-analysis, namely ALL-IN meta-analysis, which can facilitate living systematic reviews.\nThe authors provided a different understanding of evidence synthesis, and a novel way of performing meta-analyses.\nThe new method is illustrated in the language of betting, which is complement with the acronym of ALL-IN.\nMajor comments:\nThe calculation of probability of next event in group X (e.g. in page 3, the fraction of 0.41 of COVID-19 events to occur in the vaccine group, 0.41=70/(100+70)), is only valid when the number of participants is infinite in each group.\nWhen the number of participants still at risk in one group decreases, the probability of next event occurring in this group will also decrease. So the constant probability assumption may not be valid in real practice.\n\nIn page 14 and 15, the authors mentioned heterogeneity several times, however, the authors avoid giving a direct answer or solution to heterogeneous results from primary studies. This should be addressed or at least extensively discussed (as a limitation).\n\nThe COVID-19 vaccine trials are used as an example. However, all these trials are conducted recently and in a short time period (compared to other treatment). How is the generalizability of this new methods in other treatments?\n\nThe method is easily extended to IPD meta-analysis. How well this method can be extended to network meta-analysis of multiple treatments?\n\nHow can covariates, both on study level and individual level, be adjusted in this new framework?\n\nMinor comments:\nIn Page 7, section 1.1, the equation “70/170*170/70 + 100/170*170/100 = 1”, seems not correct, the right side should be 2. But I assume the authors forget adding something in the left side of the equation. Please check.\n\n“Betting on vaccine” in this paper actually means betting on the next event will occur in the vaccine group (which means vaccine is not effective). It can be a bit misleading, since in common sense, reader may think betting on vaccine means betting on vaccine can protect participants.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
},
{
"id": "146413",
"date": "16 Sep 2022",
"name": "Ewelina Rogozinska",
"expertise": [
"Reviewer Expertise Conduct of systematic reviews and methodological reviews",
"IPD meta-analysis",
"bias in evidence synthesis",
"use of evidence synthesis in clinical practice guidelines"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe work by ter Schure and Grünwald outlines an alternative approach to evidence synthesis, aiming to include emerging evidence in real time without increasing type-1 error. The authors suggest that their ALL-IN method can “breathe life into living systematic reviews, through better and simpler statistics, efficiency, collaboration and communication”. As much as I agree with the three final points and fully support this notion, I have some doubts regarding the professed ‘simplicity’ of the proposed statistical approach, implementation, and generalizability of the method.\nFirstly, the approach has been developed and tested only in one very unusual setting (Covid-19 pandemic), in which the accumulation of evidence over a short space of time was extreme and sharing of data and collaboration was greater than witnessed in previous years. According to Heinze et al. (manuscript in submission) and their proposed framework of four phases of methodological research in biostatistics, the ALL-IN method would be classified as a method in a second phase of its development. Consequently, it requires further evaluation in a range of settings and refinement before it could be considered as a viable alternative to other available methods. This should be discussed in their paper, with declarations more balanced to reflect the single setting in which their method was applied.\nSecondly, contrary to the authors' claim that the introduction of terminology from game theory makes it easier to communicate the uncertainties, I am finding the sections using betting language difficult to follow. The evidence synthesis community still to some extent grapples with more standard methods of advanced evidence synthesis (Wang et al. BMJ 2021; 373: n736).1 Thus, the introduction of new concepts (or their reintroduction) should be carefully thought through. Overall, I feel the manuscript would benefit from limiting the use of references to betting and investments to an essential minimum.\nFinally, the authors present a real-life example of their method using BCG vaccines trials for Covid-19. The presented example resembles an approach more akin to prospective individual participant data (IPD) meta-analysis than a living systematic review or also the referenced FAME approach - both relying on aggregate rather than individual participant data. The challenges associated with accessing IPD, the non-standard approach to data analysis and lack of clear proof of its benefits push this method toward “interesting” developments rather than “a new way forward”. The authors should explain more clearly how their method could help aggregate-level evidence synthesis or refocus the scope to IPD based projects. Furthermore, it would be interesting to learn how the ALL-IN compares to commonly used methods in terms of efficiency and reliability of obtained results.\nConcluding, the presented method is an interesting approach to evidence synthesis; however, at the current stage of its development, it requires further evaluation of its utility for the evidence synthesis to be able to bet on it.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Partly\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
},
{
"id": "146412",
"date": "21 Oct 2022",
"name": "Shubhendu Trivedi",
"expertise": [
"Reviewer Expertise Machine Learning",
"Statistics",
"Conformal Prediction",
"Sequential Testing",
"Drug Discovery."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper presents a new method for meta-analysis, motivated partly by (and for \"breathing life\" into) living systematic reviews that are used in the clinical domain which provide recommendations to prevent research waste. The authors christen their method to be ALL-IN meta-analysis, which is Anytime Live and Learning Interim Meta-Analysis. \"Anytime\" meaning analysis can be updated at any time and can control for type I error irrespective of any other decision making along the way. \"Live\" allows for a bottomup collaboration of different trials; a trial can be initiated in any way, and we can include data from the meta-analysis itself. \"Interim\" permits for a combination of data from trials that are still ongoing.\n\nThe paper begins with a topical motivation from the covid19 pandemic, while emphasizing that the methodology could help better evidence combination, collaboration, and communication during later pandemics, or even smaller clinical trials. Using a single trial and specifications issues by the FDA for the covid19 vaccine trails (regarding vaccine efficiency and evidence against a null hypothesis say 30% VE) , the general betting game that is the language central to much of the contribution of the paper is introduced. It is shown that the same can also be written in terms of likelihood ratios and examples for scores are calculated for a Pfizer trial and a CuraVac trial.\n\nThe betting based methodology allows the statistical analysis to not simply be all or nothing (like p testing). In the all or nothing setting, we can not continue from one trial to another without violating type I error rates, while in the betting (ALL-IN) setting one can simply update patients later on. This also permits for better efficiency (we can understand the number of participants needed to answer a research question) and collaboration (since we can combine analysis as data becomes available). The language of betting also can be interpreted in various equivalent ways (likelihood ratios, conservative p values, e values) that also allow for easy and crisp communication about the analysis.\n\nThe intuitions of the language of betting are made more precise using standard tools in the literature (Markov's inequality, and Ville's inequality). Further, the betting score underlying the test is an e-value which further permits statistical analysis (using the tools cited). logrank Z statistics are used as a running example for meta-analysis on the summary statistics -- we can simply collect the Z statistics Z_i from each trial, which can easily be combined (as shown in equation 3). Notably if we add in interim data, then from the perspective of Ville's inequality, they are indistinguishable for testing. The methodology also allows for combining data from trials without requiring a common design -- this can easily done by deciding upon a min mu parameter for each trial, using which one can still get a valid combination of different trials with valid type I guarantees. Further, method not only captures whether an effect is statistically significant or not, it also captures evidence up till now. The language of the \"implied target\" of Shafer is used to make this precise, which in turn can also be used to quantify how much will the evidence change if a new study with some mu and N is added.\n\nThe paper also reports testing the methodology during the covid19 pandemic in two meta-analysis. One involving 7 trials, and the other involving 4 trials - considering different populations (healthcare workers, and the elderly). The trials involved testing if BCG could help with COVID19 immunity. The results are discussed while discussing issues (and recommendations) for meta-analysis design, systematic search for trials, systematic reviews for trial inclusion, data upload, and disseminating results.\n\nIn general, I found the paper very well written. The methodology is described very clearly, along with a glimpse of the underlying statistical tools available. The advantages and recommendations that the methodology has/implies are also discussed in detail. The underlying mathematics for testing is standard, but as far as I understand this is the first application for it in the setting considered in the paper. I would recommend the paper for acceptance.\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-549
|
https://f1000research.com/articles/10-1106/v1
|
02 Nov 21
|
{
"type": "Study Protocol",
"title": "Post-pandemic e-learning: a pre-protocol to assess the integration of mobile VR and its effect on VARK learning styles",
"authors": [
"Shahida Raihan Manzoor",
"Wan-Noorshahida Mohd-Isa",
"Khairi Shazwan Dollmat"
],
"abstract": "Background: The Covid-19 pandemic has resulted in an abrupt but accelerated shift to e-learning worldwide. Education in a post-pandemic world has to amalgamate the advantages of e-learning with important pedagogical goals associated with in-person teaching. Although various advanced technologies are present at our fingertips today, we are still unable to use their full potential in teaching and learning. In this regard, mobile VR technology is both cost-efficient, versatile and engaging for students. Developing countries have more smartphone users than developed countries, implying that developing countries, like Malaysia, should utilize mobile or cellphones more significantly. With that in mind, we propose here a pre-protocol to investigate learner motivation and levels of engagement for e-learning with smartphone-integrated VR, based on their VARK (Visual, Auditory, Read/Write, Kinesthetic) learning styles. Proposed methodology: This study intends to use a minimum sample of 30 students from the same age group under the K-12 (particularly grade 9-12) belonging to STEM curriculum. The Google Cardboard VR set will be used as the prime technology for its affordability, easy build feature and variety of available vendors. A mixed-method (survey and activity log/tracking) for data collection is suggested to find the degree of engagement and motivation of the learners’ learning in the mobile VR-assisted e-learning context. The students will be taught a topic using the mobile VR and then be assessed through simple classroom quizzes to assess how well they grasped the concept. The data collected through activity logs (while teaching the topic in mobile VR) and questionnaires will be mapped to each individual learner and organized in a data repository. Further visualization, analysis and investigation will be performed using Smart PLS, Python or R language.\nConclusions: The study aims to provide context for smartphone and software companies to develop technologies that could facilitate learner engagement during the post-pandemic state.",
"keywords": [
"E-Learning",
"Mobile VR",
"Learning Style",
"Post- pandemic Education"
],
"content": "Introduction\n\nSince the Covid-19 pandemic broke out in 2020, e-learning has become a new standard worldwide. A staggering number of educational institution closures took place in 192 countries, as reported by the International Labour Organization (ILO), resulting in 91.4% of enrolled learners being affected.1 To tackle these circumstances, a number of educational institutions had been forced to abruptly adopt full online learning measures.\n\nOne of the sectors that is being heavily affected by these measures is the education sector, particularly school students. According to a survey conducted by RAND Corporation, teachers of virtual classrooms need more overall instructional support compared to teachers teaching in physical classrooms, in terms of tailoring content, engaging students, academically advancing them and measuring their progress.2 Access to digital devices and the internet was a concern too.2\n\nNumerous educators often use smartphones for e-learning in many parts of the world. Because of the perceived utility of mobile phones, learners in such contexts may suffice without a computer to access e-learning materials.3,4 Yet, uses of mobiles for learning are mostly limited among tertiary-level students. According to Darko-Adjei,5 learners were not prepared for the integration of mobile phones in the learning context, especially in Malaysian schools. Moreover, there is a lack of awareness of its potential power of innovation in the education system.5\n\nIn addition to that, traditional e-learning tends to face challenges in retaining learner motivation and keeping them engaged, as well as certain limitations in explaining abstract scientific concepts to different types of learners. According to Stovall,6 in the context of web-based learning systems, “a student’s degree of engagement in educational learning is lower than that in traditional education systems”. As cited in Hartnetter,17 e-learners are frequently expected to be further naturally motivated as the learning environment depends heavily on their interest, self-drive, and intrinsic motivation to evoke student engagement.\n\nIn reality, some regard the technology used as intrinsically motivating since it offers a range of properties acknowledged as essential in the development of intrinsic motivation, notably, novelty, challenge, fantasy and curiosity.7 The study proposed here intends to investigate learners’ motivation and levels of engagement for e-learning with smartphone-integrated VR for the K-12 student cohort in Malaysian schools. Accordingly, it will provide recommendations for smartphone and software companies to develop technologies integrating various learning styles that could facilitate learning engagement during the post-pandemic state.\n\n\nLiterature review\n\nThe learning styles of an individual pertain to his or her ability to effectively understand and absorb information.8 In terms of student-centric learning, it is essential to accommodate all students with different learning preferences. Many teachers believe that teaching according to individual style can help improve learners’ performance.24 Mirza and Khurshid8 identified the learning modalities of health professional students and suggested that student motivation is positively enhanced when students recognized their learning styles. The study by Good et al.24 also suggested that VARK (Visual, Aural, Read/write, Kinesthetic) is a significant teaching tool and also helps enhance performance.\n\nMirza and Khurshid8 have stated that VARK (Visual, Auditory, Reader/Writer and Kinesthetic) is the most accepted teaching model that categorizes learners with respect to their sensory characteristics. It is one of the earliest and most popular learner style tools developed by Fleming and Mills.19 According to these researchers, the success of the model stems from its authenticity, usability, and the array of learning resources available to complement it.\n\nThe term e-learning or electronic learning originated in the mid-1990s when the Internet began to gather momentum.20 The two core elements of e-learning include computer-based learning as well as web-based learning.9\n\nResearchers have developed a number of models to guide e-learning research and e-learning effectiveness. By studying and synthesizing previous models of e-learning research from management, information systems, education, sociology and psychology, Johnson and Brown10 concluded that e-learning outcomes are influenced by multiple processes and inputs. They proposed a model to summarize the literature consisting of five inputs: organizational context, technology, design/pedagogy, instructions and trainee or learner traits. The study by Johnson and Brown focuses more on technology as an input and influencing factor in the learning process. The sub focuses under technology are reliability, usefulness, ease of use and media richness (Figure 1).\n\nMobile learning is an integral part of e-learning. As cited by Basak et al.,9 Behera stated that mobile learning or m-learning is correlated with mobile computing and e-learning. According to Sanchez-Prieto et al.,18 mobile learning is a learning environment that is closely related to e-learning, belonging to a separate typology, where the process of teaching, as well as learning, would have a digital dimension (Figure 2).\n\nVirtual reality (VR) is a computer-generated rendering of a 3D world or image that can be communicated in a relatively natural or tactile manner by a human wearing special electronic devices (headgear with an incorporated display inside or accessories equipped with sensors). VR provides 3D digital worlds featuring sophisticated ways of interaction that can motivate students to understand more completely. Its truly interactive learning environment has the power to improve the learning process and skill acquisition.12 Previous research has shown that the use of VR technologies will help to motivate the learning process by allowing students to experience ‘natural phenomena’ while being safe from the real-world consequences.12 In other words, the incorporation of VR allows new educational opportunities to emerge.\n\nTeachers frequently encounter issues concerning student engagement with teaching materials.22 Higher levels of engagement with learning activities can be achieved if the virtual world is more interactive. For instance, debates are typically effective at involving learners in subjects needing critical thinking,21 but they are less suitable for learning factual science subjects like physics or chemistry. VR may be particularly useful for those subjects where a spatial arrangement is important or there are dynamic changes.\n\nVR can enhance engagement and improve retention, as students get to learn through experience, which is necessary for STEM subjects. VR also influences the students’ spatial ability for real-time visualization, which are crucial skills in the engineering field. Students can explore “the use of advanced holographic technologies to bring virtual 3D building components to life” [11, para 3]. The implications of VR require investment in resources and technical equipment. Hence there is a need for educational institutions to start with “cheaper alternatives and small mobile devices first” [11, para 5].\n\nVR and learner motivation\n\nMany professions, including medical science, engineering, architecture, product development, and geology, have used VR to study and visualize abstract concepts.25 According to previous research, utilizing VR technology as a teaching tool enhances learners' grasp on the concept, test scores as well as learning motivation while lowering training costs and experimental risks. Employing VR in instruction can potentially increase student learning motivation and positively enhance student performance.26 However, there is a paucity of studies on the impact of mobile VR on student motivation in STEM courses.\n\nMobile VR\n\nAlthough VR has been available for a long time, the associated technology required to access it has been prohibitively expensive, heavy and high battery/power consumption. VR apps have been able to proliferate into the general market because of mobile VR headsets, which are essentially eyewear that can support a smartphone.13\n\nWith a number of available ways to experiment with VR content, headsets, video and apps, this tool has the potential to become yet another method in an educator's repertoire for assisting learners in understanding critical theories and mastering a range of concepts. As smartphones with integrated video capability became widely available, the influence of what could be shared and generated in the classroom has improved significantly. VR technology is essentially the first phase leading to the advancement of interactive learning,1 and mobile VR adds accessibility and cost-efficiency to that advancement.\n\n\nProposed methodology\n\nBased on the above review of literature, the following hypotheses are proposed for this study:\n\nVisual learners have the highest level of engagement in a mobile VR environment.\n\nAuditory learners have the highest level of engagement in a mobile VR environment.\n\nKinesthetic learners have the highest level of engagement in a mobile VR environment.\n\nReader/Writer has the least engagement in a mobile VR environment.\n\nVisual learners have the highest level of motivation in a mobile VR environment.\n\nAuditory learners have the highest level of motivation in a mobile VR environment.\n\nKinesthetic learners have the highest level of motivation in a mobile VR environment.\n\nReader/Writer learners are least motivated to learn in a mobile VR environment.\n\nThe literature review shows that VR is swiftly becoming a household word, thanks to the recent boom of VR-compatible devices. Despite having a significant impact on student engagement and performance, mobile VR is greatly neglected in education. The proposed framework considers factors such as learning styles of learners and technology used to teach in order to measure the motivation and engagement of students belonging to the K-12 group (Figure 3).\n\nA minimum cluster of 30 students from the same age group under the K-12 curriculum should be selected for the pilot study to be statistically significant. It is very important that the students be selected from a definite age group, preferably high schoolers (grade 9-12), and course, preferably STEM curriculum, as different age groups may produce different results. In addition, the study includes surveys in multiple levels; it’s desired that they be filled in with proper understanding of the questions being asked. High schoolers are young adults that fit the mentioned criteria. During the sample selection, diverse VARK learner types should be included in an even ratio to avoid a biased outcome and a healthy ratio of male to female should be considered to avoid skewing the results. This could be ensured with the “VARK LS Questionnaire” stage mentioned in Figure 3.\n\nThe most appropriate device for this study is Google Cardboard, as it is affordable, easy-to-build and has numerous vendors. It also supports both Android and iOS-based mobile devices. The VR devices (Google Cardboard) are to be acquired and distributed by the research team whereas the mobile devices can be the students’ own devices. A list of students’ existing mobile phones can be produced before initiating the test to ensure a smooth execution.\n\nAlthough most young learners are familiar with VR and can rapidly pick up technology usage or its trends, the teachers or instructors may need to get a better understanding of the possible uses and integration of the existing mobile VR software in the curriculum. Coming up with suitable educational content may require some training or professional help. This can be ensured by allowing time to the educators to explore the technology first and look though the manuals and tutorials available online. Then they can communicate their concerns or areas of difficulty and training/troubleshooting with the help of Google cardboard community can be arranged. For activity logs to be tracked, students will be taught a topic (in line with their study curriculum) using mobile VR technology which will be accompanied by a simple quiz to gauge how well the students understood the topic and how well they retained that information. This process should be repeated several times over the period of one semester to investigate the patterns over a decent time span. The design of the content should be appropriate for the age group, relevant to the topic, and have the ability to be supported by existing mobile VR software such as Expeditions, InCell VR, Titans of space, and Google Daydream. These VR software are some of the most well-established and widely used platforms for educational purposes with a variety of existing materials.\n\nA mixed-method for data collection will be conducted to find the degree of engagement and motivation the learners learning in the mobile VR-assisted e-learning context.\n\nA questionnaire method will be utilized as the first method to collect learner motivation and engagement-related data.\n\n• Measuring motivation: the questionnaire developed by Vallerand et al.15 known as EME [(Échelle de Motivation en Éducation (Measure of Motivation towards Education)], which comprises seven subscales measuring “three different kinds of intrinsic motivation and three different kinds of extrinsic motivation”.16\n\n• Measuring engagement: the Student Engagement (SE) survey developed by Ahlfeldt et al.23 will be used that emphasizes the concepts of “cooperative learning, cognitive-level, and personal skills development, encompassing four, five, and five items respectively”. The three concepts are answerable on a four-point Likert scale, with 4 – very often, 3 – often, 2 – occasionally, and 1 – never. The aim of SE was to build an instrument that would be fast and easy to administer in class and which would measure student engagement.\n\nA system log or activity log tracking will be used as the second method to collect data regarding engagement. Some of the system logs parameters proposed to be collected in this study are shown in Table 1.\n\nThe data collected through activity logs and questionnaires will be mapped to each individual learner correctly. Further visualization, analysis and investigation will be performed using Smart PLS, Python or R language to summarize the main characteristics of the data collected. Various methods of clustering, regression and correlation heatmaps will be applied to have an improved understanding of the relationships of the variables, detect patterns, spot anomalies, and test the hypothesis and other assumptions. Principal component analysis (PCA) will be explored to understand which attributes contribute most to the variance of each model. The Panda and Seaborn libraries in Python are very powerful in terms of data visualization and assessing correlation.\n\n\nDiscussion\n\nMany studies related to the use of mobile VR in the context of education have been carried out in recent years. These studies vary in terms of education level, course type, teaching environment, level of immersion, and more. There is however a lack of work that includes learning style frameworks in terms of using mobile VR for e-learning.\n\nPauschenwein et al. researched game-based learning elements that are economically priced and highly mobile VR systems with an enhanced feeling of immersion in the virtual environment and sound didactical scenarios.27 The study focused on the method of making VR more affordable and widely used in practical studies but not so much on its potential in the field of e-learning. A pilot study carried out by Raya et al. compared mobile VR technology with conventional video content on a tablet device for teaching. The study was done on 56 high school learners looking into the effects of immersion and the induction of positive emotion while learning social science courses. The findings indicated that while delivering educational content, knowledge retention is heavily influenced by the immersive condition. Also, short-term participants of the study exhibited better retention when there were positive emotional induction and high immersion. Unlike our proposed study that integrates learning style element into the mobile VR and analyses its influences, this research focused on manipulating emotions, its impacts on knowledge retention, and high immersion as a potential technology in enhancing the influence of emotions.28\n\nGüray and Kısmet29 proposed a model to integrate VR or AR (Augmented Reality) technologies in building construction education. Their proposed model highlighted the advantages of the creative use of VR/AR tools through integrating the Building Information Modelling tools in distance learning particularly during the Covid-19 pandemic conditions, but the VR/AR technology mentioned was not mobile supported and rather desktop based. One of the latest works done by Sprenger and Schwaninger30 shed light on the technology acceptance of e-learning and mobile VR based on a three months usage. The voluntary participants were 94 students from a university in Northwestern Switzerland, studying the course “General Psychology 1”. The results suggested that the acceptance of mobile VR was very low compared to technologies like classroom response system, e-lectures, and classroom chat. Based on the theory of course alignment and examinations, the study revealed that students focused more on exam preparation rather than enjoying the process of learning. Apart from oversimplified VR content causing an underwhelming experience for some learners, the VR technology not having much relevance with the exam questions was also noted as one of the reasons for mobile VR having a low score on the spectrum of technology acceptance. The findings of the study re-emphasize the importance of selecting a proper learner age group and study level as well as an understanding of learner motivation and learning style while deploying a learning technology, which our conceptual model is greatly focusing on.\n\n\nConclusion\n\nPast research highlights the relationship between different learning styles and VR but there is very little research on the latter’s subbranch known as mobile VR and its usage in terms of e-learning. The conceptual framework is expected to bring the required focus on mobile VR and its potential usage in e-learning which is expected to greatly aid K-12 students belonging to more practical-oriented disciplines of study or those with a more visual or kinesthetic learning style. The framework allows an integration between e-learning and mobile VR supported by the principles of VARK learning styles. Its purpose is to enhance the motivation and engagement of e-learners by better understanding multiple learning styles in a mobile VR environment.\n\nVR is considered one of the technology pillars of industry 4.0 or the fourth industrial revolution.13 To introduce this fascinating innovation into classrooms, educators and facilitators should investigate the training needed to make it into a regularly used learning instrument. Although the idea of VR to some may appear as very advanced, in reality, it is quite similar to technology used in common social media apps, such as Instagram and Snapchat, home decor apps, such as Ikea Place, and gaming apps, such as Pokémon Go. Learning about mobile VR and its impact is a perfect place to start for educators who want to make their online teaching space VR-friendly.\n\nAlthough the advantages of VR in teaching and learning are universal for a broad range of courses and learner types, the best integration approach differs from institution to institution as well as from class to class. Integrating mobile VR in terms of e-learning, on the other hand, is certainly achievable with the proper resources and knowledge on how VR will improve students' understanding and enthusiasm for learning. While the incorporation of VR technology in education is certain to enhance learning in almost every educational setting, the implementation approach does not demand to be radical.14\n\nThere are challenges on traditional VR to pedagogical practice and theories such as cost, equipment usability, and fear of technology,11 hence the education administrators need to jointly work together with the smartphone companies and VR product developers for its personalized, cost-effective implication at the post-pandemic stage to facilitate the process of e-learning.\n\n\nData availability\n\nNo data is associated with this article.\n\n\nGrant information\n\nThis work was supported by TM R&D Grant [Grant ID MMUE/190022].",
"appendix": "References\n\nILO (International Labour Organisation): COVID-19 and the Education Sector.2020. Reference Source\n\nSchwartz S: Survey: Teachers and Students Are Struggling With Online Learning. Educ. Week. 2020. Accessed on 14 June 2021. Reference Source\n\nPullen D, Swabey K, Abadooz M, et al.: Malaysian university students’ use of mobile phones for study. Australian Educ. Com. 2020; 30(1).\n\nIsmail I, Bokhare S, Azizan S, et al.: Teaching via mobile phone: A case study on Malaysian teachers’ technology acceptance and readiness. J. Educ. Online. 2013; 10(1): 1–38. Publisher Full Text\n\nDarko-Adjei N: The use and effect of smartphones in students' learning activities: Evidence from the University of Ghana, Legon.2019.\n\nStovall: Engagement and online learning. UIS community of practice for e-learning.2016. Reference Source\n\nLepper MR, Malone TW: Intrinsic motivation and instructional effectiveness in computer-based education. Snow RE, Farr MJ, editors. Aptitude, learning, and instruction: Vol. 3. Conative and affective process analyses. Hillsdale, NJ: Lawrence Erlbaum; 1987; pp. 255–286.\n\nMirza MA, Khurshid K: Impact of VARK Learning Model at Tertiary Level Education. Int. J. Educa. Pedagogical Sci. 2020; 14(5): 359–366.\n\nBasak KS, Wotto M, Belanger P: E-learning, M-learning and D-learning: Conceptual definition and comparative analysis. E-Learning and Digital Media. 2018; 15(4): 191–216. Publisher Full Text\n\nJohnson RD, Brown KG: E-learning.2017.\n\nOigara JN: Integrating virtual reality tools into classroom instruction. Handbook of research on mobile technology, constructivism, and meaningful learning. IGI Global; 2018; pp. 147–159.\n\nRafidi R: Bringing Learning to Life. New Straits Times.2020, February. Accessed on 12 June 2021. Reference Source\n\nTechTarget Contributor: VR headset (virtual reality headset).2016. Accessed on 12 June 2021. Reference Source\n\nBrodheim T: The Pathway to Integrating Virtual Reality in Education.2017, March. Accessed on 10 June 2021. Reference Source\n\nVallerand RJ, Blais MR, Brière NM, et al.: Construction et validation de l’échelle de motivation en éducation (EME) (Construction and validation of the Motivation towards Education Scale). Revue canadienne des sciences du comportement/Canadian Journal of Behavioural Science. 1989; 21(3): 323–349. Publisher Full Text\n\nKubischta F: Engagement and Motivation: Questioning students on study-motivation, engagement and study strategies.2014.\n\nHartnetter M: The importance of motivation in online learning. Motivation in online education. SingaporeSpringer; 2016; pp. 5–32.\n\nSánchez-Prieto JC, Olmos-Migueláñez S, García-Peñalvo FJ: Informal tools in formal contexts: Development of a model to assess the acceptance of mobile technologies among teachers. Comput. Hum. Behav. 2016; 55: 519–528. Publisher Full Text\n\nFleming ND, Mills CE: Not Another Inventory, Rather a Catalyst for Reflection.1992.\n\nGarrison DR: E-Learning in the 21st Century: A Framework for Research and Practice. Taylor & Francis; 2011.\n\nAllcoat D, von Mühlenen A : Learning in virtual reality: Effects on performance, emotion and engagement. Res. Learn. Technol. 2018; 26. Publisher Full Text\n\nChristopoulos A, Conrad M, Shukla M: Increasing student engagement through virtual interactions: How? Virtual Reality. 2018; 22: 353–369. Publisher Full Text\n\nAhlfeldt S, Mehta S, Sellnow T: Measurement and analysis of student engagement in university classes where varying levels of PBL methods of instruction are in use. High. Educ. Res. Dev. 2005; 24(1): 5–20. Publisher Full Text\n\nGood JP, Ramos D, D'Amore DC: Learning style preferences and academic success of preclinical allied health students. J. Allied Health. 2013 Winter; 42(4): 81–90.\n\nTudor AD, Minocha S, Collins M, et al.: Mobile virtual reality for environmental education. Journal of Virtual Studies. 2018; 9(2): 25–36.\n\nLund BD, Wang T: Effect of Virtual Reality on Learning Motivation and Academic Performance: What Value May VR Have for Library Instruction?. Kansas Library Association College and University Libraries Section Proceedings. 2019; 9(1): 4. Publisher Full Text\n\nPauschenwein J, Sandtner H, Behmel A, et al.: VR-Simulation in education From Full mission to Mobile VR-Simulators. Mobile Game-Based Simulator for welding training. Proceedings of the International Workshop for Interactive Computer Aided Learning, Villach. 2006; pp. 1–11.\n\nOlmos-Raya E, Ferreira-Cavalcanti J, Contero M, et al.: Mobile virtual reality as an educational platform: A pilot study on the impact of immersion and positive emotion induction in the learning process. EURASIA Journal of Mathematics, Science and Technology Education. 2018; 14(6): 2045–2057.\n\nGüray TS, Kısmet B: Model Proposal for Integrating VR/AR Technologies in Building Construction Project in Architecture Education During Covid-19.\n\nSprenger DA, Schwaninger A: Technology acceptance of four digital learning technologies (classroom response system, classroom chat, e-lectures, and mobile virtual reality) after three months’ usage. Int. J. Educ. Technol. High. Educ. 2021; 18(1): 1–17. Publisher Full Text"
}
|
[
{
"id": "115777",
"date": "02 Feb 2022",
"name": "Aslina Baharum",
"expertise": [
"Reviewer Expertise User experience"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper proposed a pre-protocol to investigate learner motivation and levels of engagement for e-learning with smartphone-integrated VR, based on their VARK (Visual, Auditory, Read/Write, Kinesthetic) learning styles. However, the paper needs to be improved for better presentation:\nThe findings of the paper should be added to the abstract.\n\nFurthermore, no method is given. Authors should tell the reader how and what method(s) were used to get their findings. What was the proposed methodology, the authors should also give examples, and explain what systematic review has been used etc.\n\nNo data has been collected since this paper only provides the proposed method, but using method such as systematic review, data from the Literature Review can be extracted. Justification for the proposed method should included as well.\n\nIn the conclusion, authors should suggest future works they recommend for further examination, for example, the process for verifying and validating the proposed instrument or method, or data collection, based on the limitations of the study.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? No",
"responses": [
{
"c_id": "8243",
"date": "19 May 2022",
"name": "Shahida Manzoor",
"role": "Author Response",
"response": "Thank you, Dr. Aslina Baharum for taking out the time to review the article. The suggestions/comments have been addressed as follows: 1. As this is a conceptual study/Study protocol, only what kind of results are expected have been discussed and mentioned in the abstract. 2. Narrative review has been used for this study, which synthesizes primary studies and explores this through description rather than statistics. (mentioned in the literature review) 3. The methodology suggested for the proposed framework is derived and synthesized from the literature review. (mentioned in discussion section + literature review section) 4. Future work has been added (newly) in the conclusion section."
}
]
},
{
"id": "98843",
"date": "03 Feb 2022",
"name": "Tunku Badariah Tunku Ahmad",
"expertise": [
"Reviewer Expertise Pedagogical Studies",
"Web 2.0 tools",
"technology acceptance"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary of Feedback\n1. The researchers/authors need to align the title with the research objectives and the constructs of interest (learner engagement and motivation). How do the authors define engagement and motivation?\n2. The present hypotheses appear to contradict one another, and should instead appear as follows:\nH1: The effect of the VR intervention on learner engagement will vary significantly by learning style. H2: The effect of the VR intervention on learner motivation will vary significantly by learning style.\n3. VARK learning styles are the moderator variable because the research aims to examine if the VR effects on learner engagement and motivation would vary significantly by the respondents' style of learning (i.e. whether they have a visual, auditory, reader/writer and kinesthetic learning style). In other words, you may find the results as such: The VR application increased students' learning engagement significantly for all groups, but its impact on students with visual and auditory learning styles was significantly greater, as an example, at Cohen's d = 0.87 and d = 0.91, respectively.\n4. A sample of 30 respondents is too small to test the hypotheses or run PCA/SEM on the data. The general rule is to have 5 to 10 respondents for every questionnaire item. For example, if the questionnaires have a total of 20 items, so the minimum sample needed is 20 x 5 = 100 (at least) or 20 x 10 = 200 respondents. PCA will not run if the minimum sample requirement is not met.\n5. Revisit the techniques of data analysis. SEM appears to be most appropriate for addressing the research objectives (while treating VARK as the moderator variable), on the condition that the sample size is large enough.\nSee Annotated Manuscript for Further Remarks. https://f1000researchdata.s3.amazonaws.com/supplementary/73311/8047b5da-7165-4c21-9a47-177351dd26a9.pdf.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "122923",
"date": "14 Feb 2022",
"name": "Kenneth Y. T. Lim",
"expertise": [
"Reviewer Expertise the learning sciences",
"learning with VR / AR / XR",
"learning with mobile technology",
"learning during the COVID-19 pandemic",
"curriculum design and development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript is a study protocol and will be reviewed as such.\nThe rationale for the protocol is justified in terms of current socio-economic contexts and the review of literature emerges from the rationale. I also find coherence between the review of literature, research questions, and the proposed methodology.\nThe protocol proposed essentially seeks to investigate learner engagement and motivation with mobile VR from a theoretically-grounded perspective in the context of (a) the on-going pandemic and (b) the high prevalence of mobile technological penetration in relatively less economically developed countries.\nIn this regard, I offer only the following suggestions for improvement:\n(a) In the review of literature, you refer to VARK variously as a \"model\" and a \"tool\". Please be consistent in how you perceive and refer to it.\n(b) I feel that such the outcomes of such a study - once carried out - would be only as strong as the curricular materials developed for the chosen technology (Google Cardboard). I would therefore like the authors to elaborate more on this, and not just content themselves to the three sentences beginning respectively with \"Coming up with suitable...\", \"This can be ensured by...\", and \"Then they can communicate their concerns...\".\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "8244",
"date": "19 May 2022",
"name": "Shahida Manzoor",
"role": "Author Response",
"response": "Thank you, Dr. Kenneth Y. T. Lim for taking out the time to review the article. The suggestions/comments have been addressed as follows: a) Changed VARK framework/tool>model for consistency. b) The current study is to be carried out by utilizing existing VR software and study curriculum to understand its (current software's + curriculums') influence better and aims to later aid in the development of curriculum (new) based on the findings. Suggestions made for this article have been added in the Future Work (section)."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1106
|
https://f1000research.com/articles/11-545/v1
|
19 May 22
|
{
"type": "Opinion Article",
"title": "On the essence of cardiopulmonary resuscitation",
"authors": [
"Xiang Li"
],
"abstract": "This article discusses that the essence of cardiopulmonary resuscitation (CPR) is energy transfer. The concept of occult cardiac arrest is proposed, and cardioversion after cardiac arrest is divided into spontaneous cardioversion and CPR according to the principle of energy transfer: the internal energy transmission of the body makes the cardioversion that is known as spontaneous cardioversion, and energy is mainly transfers from the outside leads to cardioversion, that is, CPR. The concept of domain energy in CPR is proposed, and it is argued that only energy transfer beyond the domain energy can lead to cardioversion in both spontaneous cardioversion and CPR. The principle of energy transfer is used to explain the common clinical electrocardiographic phenomena: dysrhythmia can occur when the energy required for the cardiac functions is insufficient, it is a manifestation of self-protection of the heart and the body, and the mechanism is further argued. It is demonstrated that serious cardiac events, such as ventricular fibrillation and cardiac arrest, are special types of cardiac self-protection. The mechanisms, general rules, and energy properties of modern CPR energy transfer are described, and the influence and interaction of energy transfer principle on the three states of time, space, and energy transfer during CPR are assessed, which will be significant for future research on CPR.",
"keywords": [
"cardioversion",
"cardiopulmonary resuscitation",
"energy transfer",
"domain energy",
"three states"
],
"content": "1. The concept of CA and the essence of CPR\n\nThe concept of CA in modern medicine is the sudden cessation of cardiac pumping function.4 The concept of CA can be extended as a group of syndromes with a short asystole time and no obvious clinical manifestations, accompanied by actual pathophysiological changes in the body, which is called occult CA. As a result, CA includes a larger group of cardiac emergencies with different pathophysiological or clinical manifestations depending on the duration of asystole, which can be divided into two types: ordinary CA (clinical manifestations and pathophysiological changes) and occult CA (with no or mild clinical manifestations and some pathophysiological changes).\n\nAfter CA, the patient’s body is depleted due to the gradual transfer of energy (bioenergy, kinetic energy, thermal energy, electrical energy, etc.) to the external environment over time, and the longer the asystole time, the more energy is lost from the body.\n\nIf the heart is to be re-paced, sufficient energy must be delivered to the heart. Cardiac resuscitation can be defined as the process of energy transfer and utilization. Depending on the type of CA (as mentioned above) and the different ways of energy transfer, cardiac resuscitation is divided into cardiac self-resuscitation and artificial resuscitation (i.e., CPR).\n\nCardiac self-resuscitation relies on the body’s energy transfer to the heart, making the heart cardioversion or re-pacing (hereinafter, cardioversion is used, rather than all forms of heart rhythm after re-pacing). CPR is the transfer of external energy to the body, which then transfers it to the heart and leads the heart to cardioversion. Excluding other influential factors, if energy transfer is effective, the heart is able to undergo cardioversion, and cardiac self-resuscitation or CPR is effective.\n\nTherefore, whether it is cardiac self-resuscitation or CPR, the essence is energy transfer.\n\n\n2. Cardiac self-resuscitation—transfer of energy from the body\n\nRegardless of the type of CA, cardiac resuscitation is achieved in some patients by spontaneous cardioversion. This includes pure spontaneous cardioversion and the Lazarus phenomenon.5 The Lazarus phenomenon confirms the objective of spontaneous cardioversion/resuscitation.\n\nWhether the cause of CA is ventricular fibrillation, ventricular tachycardia, or ventricular arrest, when the heart is under the status of cardioversion, the first heartbeat that appears, the first QRS wave group on the electrocardiogram, such as after ventricular fibrillation, appears to be the automatic depolarization of a pacing point and eventually depolarizes the heart, while the essence is energy transfer. Without energy transfer, there would be no automatic depolarization of the pacing point, accompanying by less self-cardioversion after several minutes of asystole.6 This energy is generated by the body during asystole and transmitted to the heart, and with the intervention of energy regulation mechanisms, it selectively acts on a specific area of the heart, such as a pacing point, rather than the whole heart, in order to depolarize the pacing point, eventually manifesting as the first cardiac depolarization after asystole. Thus, limited energy is used rationally and efficiently to successfully complete cardioversion/resuscitation.\n\nEnergy is the driving force behind cardioversion, which originates from the body and restarts the heart in form of cardiac depolarization. During this time, the body, especially the heart, undergoes a series of electrophysiological and pathophysiological changes, whereas the essence is the change of energy and energy transfer.\n\nThe process of cardioversion or re-pacing by heart using energy is called cardiac self-resuscitation.\n\nWithout energy transmission, the heart will not be able to undergo cardioversion. The Lazarus phenomenon is not only a consequence of energy transfer, but also further proves that energy transfer is the only driving force for cardioversion.\n\nWhen the heart stops, how much energy is stored in the body for cardioversion of the heart through internal transmission? The authors proposed the concept of “critical energy or domain energy (hereinafter referred to “domain energy”)”: the domain energy is the minimum amount of energy that the body can survive on, which is greater than the energy that the body can survive, and less than the energy that the body rapidly declines.\n\nIn an emergency, the body can supply the heart with special energy production (energy production of non-lethal organs, such as muscle or visceral organs) and energy transfer to maintain the cardiac function. The sum of the energy produced and the energy present in the body must exceed the domain energy for the heart to have enough energy to cardioversion. Presumably, the Adams–Stokes (cardio-cerebral ischemia) syndrome or the generalized convulsions during a grand mal seizure are examples that the body mobilizes the muscles of the whole body to generate energy to supply important organs (e.g., heart and brain).\n\nAs the body is associated with a large number of self-protection mechanisms,7,8 the heart itself has self-protection mechanisms.9,10 It can protect the body and perpetuate life through multiple forms of energy transfer from primary to advanced levels, including the heart itself, from the body to the heart, and by mobilizing energy transfer from tissues and organs throughout the body to the heart.\n\nEscape beats and escaped rhythms are self-protective phenomena of the heart, and ventricular tachycardia or ventricular fibrillation may also be a self-protective measure of the heart. When an emergency event that endangers the cardiac function occurs, the energy required for a normal cardiac function is seriously insufficient and can induce CA, and the heart extends the myocardium contract in form of ventricular tachycardia or ventricular fibrillation. At the same time, the body also participates in the productivity (such as Adams–Stokes syndrome) and, when the generated energy is greater than the domain energy, cardioversion may occur.\n\nVentricular fibrillation is therefore a self-protective measure, resulting from the activation of protective mechanisms by the heart after CA. Ventricular fibrillation is not the cause of CA, and it is a self-protective electrophysiological and mechanical response triggered after CA.\n\nSeveral other severe dysrhythmias, such as sinus arrest, ventricular arrest, and pulseless electrical activity are associated with the occurrence of CA, while they, similar to ventricular fibrillation, are a consequence rather than a cause of CA and are electrophysiological manifestations after CA.\n\nAfter CA, the heart can pace itself if the heart/body passes its own energy production and exceeds the domain energy; when the heart/body’s own energy is lower than the domain energy, it cannot start its own self-rescue mechanism, and it needs an external energy transfer to make the heart possible to pace again, such as CPR, ICD, pacemaker, etc.\n\nVentricular fibrillation is a protective mechanism triggered by heart and generates energy; when the energy produced is greater than the domain energy, the heart can automatically implement cardioversion. Numerous other dysrhythmias after CA suggested that the heart does not have enough energy to start ventricular fibrillation to generate energy, while it can only rely on the body to generate energy (e.g., Adams–Stokes syndrome) or other currently undiscovered forms of energy production in the heart, or the protection of external energy, whereas they are also embodiment of cardiac self-protection. The difference between them and ventricular fibrillation lies in the energy difference in CA. The greater the energy, the greater the possibility of cardioversion.\n\nConsequently, it seems that all dysrhythmias are manifestations of cardiac self-protection mechanisms after CA.\n\nFrom the point of view of mechanical movement, the heart is undoubtedly the organ with a large amount of body movement. Due to the regulation of nerves and body fluids, the body can ensure the degree of relaxation of the heart by adjusting myocardial tension, arteriovenous tension, and even heart rate within a certain range. However, when the physiological range is exceeded, the heart needs to rest for a period of time to restore energy reserves and myocardial function. dysrhythmias may be a form of cardiac resting, a reflection of self-protection mechanism. There are two types of dysrhythmias: slow dysrhythmias and compensatory intervals of tachydysrhythmias are ways in which the heart regulates rest; tachydysrhythmias, including tachycardia, heart flutter, and fibrillation are the need for the heart to generate energy, which are more urgent than the first type, suggesting that the heart is also not physiologically in a resting state. When the energy produced by heart exceeds the domain energy, tachydysrhythmia will be recovered, otherwise, dysrhythmia will be further deteriorated. Ventricular flutter and ventricular fibrillation suggest that the heart is in severe energy failure and needs to produce more energy.\n\nCompared with a normal heart, the pathological heart requires more rest and is more prone to CA. It is inferred that, similar to dysrhythmias, CA is a manifestation of the self-regulatory mechanism of the heart, which essentially regulates the cardiac resting and the gathering of energy to restart it.\n\nThese cardiac functions can be summarized as the cardiac self-regulatory–resting–resuscitation mechanism.\n\nThe electrocardiogram (EKG) at the time of the patient’s moribund death is a special form of energy in asystole with a straight EKG and very few ventricular fibrillation waves. The main reason for this is that the energy of the moribund body has been severely attenuated, which is markedly lower than the domain energy, and both the body and the heart have no energy transfer and initiate self-rescue mechanisms; thus, no ventricular fibrillation occurs or mild ventricular fibrillation with almost no vital information can be found.\n\nHowever, there are several special circumstances that suggest the presence of energy in the body or heart: (1) sinus arrest or sinus quiescence in sick sinus syndrome mainly has a long interval when there is no pacing; (2) a linear EKG between defibrillation and rhythm recovery in patients with ventricular fibrillation; (3) the Lazarus phenomenon; (4) a proportion of patients with successful CPR who have a linear EKG during resuscitation or may change from a non-shockable to a shockable heart rhythm.11–13\n\nCA or asystole is the result and expression of the primary force of cardiac functions (i.e., cardiac energy depletion, and cardioversion or re-pacing), requires a new energy transfer.\n\nThe cardiac self-resuscitation mechanism can be summarized as follows: body energy is transferred to the heart, the pacing point, the conduction system and myocardium are successively depolarized, and the cardioversion is finally performed.\n\nWhen the body energy is greater than the domain energy, the next stage of physiological function is completed by the energy transfer from the previous stage; when the body energy is less than the domain energy, within a certain range, the body can start the self-protection mechanism to generate energy and transmit it to the heart for cardioversion.\n\nThe essence of cardiac cardioversion and resuscitation is energy transmission.\n\n\n3. CPR (the transfer of external energy of the body)\n\nWhen the asystole is prolonged and its own energy decays below the domain energy,14 the body cannot perform cardioversion by its own energy transfer, and when the energy decays to a lower degree, the body shows an irreversible tendency to decay. At this time, external energy will become the key to saving life.\n\nThere are several relationships between external energy transfer to the body and the body’s own energy: first, the sum of external energy and the body’s own energy is greater than the domain energy; second, the more the body’s energy decays, the more the external energy transfer is required; third, when the body’s own energy decays to a certain level, no matter how much external energy there is, cardioversion cannot be performed.\n\nModern CPR techniques, such as chest compressions, artificial respiration, and electroshock defibrillation all deliver energy to the body. The magnitude, essence, and mode of energy transfer are unique: chest compressions (kinetic and biological energy), artificial respiration (biological and kinetic energy), and electroshock defibrillation (electrical energy). The common precordial tapping in CPR was previously a type of kinetic energy transmission.\n\n3.2.1 Defibrillation by electric shock (transmission of electrical energy)\n\nAs electroshock defibrillation is the direct transfer of electrical energy to the body, it theoretically seems to be more in line with the energy transfer principle, whereas the electrical energy transferred to the body is not directly utilized, and it requires the involvement of the energy conversion mechanisms of the body to regulate it.\n\nHowever, the energy form of defibrillation is not only electrical energy, but also kinetic energy can sometimes achieve the purpose of defibrillation or cardioversion, such as precordial percussion and chest compressions. Therefore, defibrillation or cardioversion is only a phenomenon, and their essence is the transfer and effect of energy.\n\nAs defibrillation by electric shock is only a form of energy transfer and substitution (ventricular fibrillation itself can also generate energy) and is influenced by several factors, the energy received by the body after electric shock must be greater than the energy produced by ventricular fibrillation. Thus, defibrillation will not be fully effective, or even if it is effective, it may not be able to bring the heart back into rhythm. The energy transfer principle can be analyzed as follows: first, at the same ventricular fibrillation, coarse fibrillation suggests that the body or the heart has more energy than fine fibrillation, which is lower than, while it is close to the domain energy, and the external transfer of a less amount of energy can effectively defibrillate the heart, and even a percussion to the precordial area may defibrillate the heart, while fine fibrillation is the opposite;15,16 second, the shorter the defibrillation interval, the closer the energy gathered by the body is to the domain energy, and the better the defibrillation effect;17 third, defibrillation is effective, whereas the sum of the energy provided by defibrillation and the body’s own energy does not exceed the domain energy, therefore, the cardioversion cannot be performed; fourth, early defibrillation is better,18 the longer the asystole time, the more the body energy decays, and the defibrillation effect is always getting worse no matter how much electrical energy is used.\n\nVentricular fibrillation and defibrillation are not contradictory, and they are both forms of energy production or energy transfer: ventricular fibrillation is the form of the body’s own energy production, and defibrillation is the form of external energy transfer, which is an important complement to ventricular fibrillation to generate energy.\n\n3.2.2 Chest compressions and artificial respiration (kinetic energy and bioenergy transfer)\n\nChest compressions include the direct transfer of kinetic energy to the body, which is the driving force of modern CPR mechanisms, such as the so-called “heart pump” and “chest pump”, promoting blood flow and cardioversion in the heart and aorta. Early chest compressions can even make ATP of myocardial fibers to reach the level before asystole,14 while cardioversion can be still performed with difficulties at this time. Cardioversion is possible only when the amplitude and frequency of the compression reach a certain degree, and the energy transferred to the body and heart continuously increases and exceeds the domain energy.\n\nBioenergy is the most basic energy of the body and heart. For instance, in cases of in-hospital CA in COVID-19, the main clinical manifestations are asystole and pulseless electrical activity, while very few exhibit a shockable rhythm.19,20 This phenomenon suggests that severe hypoxia indicates a lack of bioenergy in the body and heart, which is the basis for the action of other forms of energy. Secondly, the biological energy of the body is consumed due to severe hypoxia, while the cardiac energy originates from the body. At this time, the heart has no energy for cardioversion even the heart itself is not seriously damaged.\n\nArtificial ventilation delivers oxygen and other substances that are required for the body and energy metabolism; therefore, oxygen and other substances carry the bioenergy transfer of artificial ventilation. A growing body of evidence proved that the success rate of CPR with artificial ventilation alone is very low, or the simple transmission of bioenergy can rarely lead to cardioversion, which may be related to the high requirements for the utilization of bioenergy.\n\nAlthough it is not still possible to precisely measure the energy delivered to the body by chest compressions and artificial ventilation, after more than half a century of practice, the main parameters of these two techniques, such as depth, frequency, duration of chest compressions,21,22 respiratory rate, time per ventilation, and ventilation volume, have been repeatedly studied and revised to explore the most appropriate energy properties and energy transfer methods.\n\n3.2.3 Summary\n\nThe essence of modern CPR is energy transmission of various properties. Unassisted chest compressions, mechanical CPR,23–27 electroconvulsive defibrillation, and manual ventilation can all generate and deliver energy to the heart in pathways that are difficult to achieve with the drug therapy alone.28 The heart seems to be more receptive to kinetic and electrical energy, as well as to biological energy, which requires to be performed under specific conditions. It is hypothesized that if the pathway is correct, the heart can receive any form of externally transmitted energy, while it must be converted into an energy property that the heart can utilize through an energy conversion mechanism within the body.\n\n\n4. Three states of CPR (time, space, and energy transfer)\n\nTime, space, and energy transfer are the three states of CPR. These three states are interdependent and interact with each other: time and energy transfer throughout the space of CPR, space and energy transfer exist in any time period of CPR, and there is always energy and energy transfer in any time and space, including CPR. Their interactions can be summarized as follows: time–space, space–energy, energy–time, time and space–energy, space and energy–time, energy and time–space, and time–space–energy interactions, forming complex and mutually integrated mechanisms of action.29\n\nModern CPR and the possible future creation of novel CPR theories and practices based on the principle of energy transfer will be inseparable from these three states.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "References\n\nMcNally B, Robb R, Mehta M, et al.: Out-of-hospital cardiac arrest surveillance --- Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005--December 31, 2010. MMWR Surveill. Summ. 2011; 60(8): 1–19.\n\nRadeschi G, Mina A, Berta G, et al.: Incidence and outcome of in-hospital cardiac arrest in Italy: a multicentre observational study in the Piedmont Region. Resuscitation. 2017; 119: 48–55. PubMed Abstract | Publisher Full Text\n\nHo AMH, Mizubuti GB, Ho AK, et al.: Success rate of resuscitation after out-of-hospital cardiac arrest. Hong Kong Med. J. 2019; 25(3): 254–256. PubMed Abstract | Publisher Full Text\n\nHaozhu C, Guowei L, Jiyao W: Practical Internal Medicine. 14th ed.Beijing: People’s Medical Publishing House; 2013; 1419.\n\nSahni V: The Lazarus phenomenon. JRSMOpen. 2016; 7(8): 205427041665352. Publisher Full Text\n\nSprenkeler DJ, van Hout GPJ , Chamuleau SAJ: Lazarus in asystole: a case report of autoresuscitation after prolonged cardiac arrest. Eur. Heart J. Case Rep. 2019; 3(3): ytz134. PubMed Abstract | Publisher Full Text\n\nZhang K, Song F, Lu X, et al.: MicroRNA-322 inhibits inflammatory cytokine expression and promotes cell proliferation in LPS-stimulated murine macrophages by targeting NF-κB1 (p50). Biosci. Rep. 2017; 37(1): BSR20160239. PubMed Abstract | Publisher Full Text\n\nFan J, Lv H, Li J, et al.: Roles of Nrf2/HO-1 and HIF-1α/VEGF in lung tissue injury and repair following cerebral ischemia/reperfusion injury. J. Cell. Physiol. 2019; 234(6): 7695–7707. PubMed Abstract | Publisher Full Text\n\nWinegrad S, Henrion D, Rappaport L, et al.: Self-protection by cardiac myocytes against hypoxia and hyperoxia. Circ. Res. 1999; 85(8): 690–698. Publisher Full Text\n\nWei J, Lin J, Zhang J, et al.: TRPV1 activation mitigates hypoxic injury in mouse cardiomyocytes by inducing autophagy through the AMPK signaling pathway. Am. J. Physiol. Cell Physiol. 2020; 318(5): C1018–C1029. PubMed Abstract | Publisher Full Text\n\nZheng R, Luo S, Liao J, et al.: Conversion to shockable rhythms is associated with better outcomes in out-of-hospital cardiac arrest patients with initial asystole but not in those with pulseless electrical activity. Resuscitation. 2016; 107: 88–93. Publisher Full Text\n\nLuo S, Zhang Y, Zhang W, et al.: Prognostic significance of spontaneous shockable rhythm conversion in adult out-of-hospital cardiac arrest patients with initial non-shockable heart rhythms: A systematic review and meta-analysis. Resuscitation. 2017; 121: 1–8. PubMed Abstract | Publisher Full Text\n\nWah W, Wai KL, Pek PP, et al.: Conversion to shockable rhythms during resuscitation and survival for out-of hospital cardiac arrest. Am. J. Emerg. Med. 2017; 35(2): 206–213. PubMed Abstract | Publisher Full Text\n\nChoi HJ, Nguyen T, Park KS, et al.: Effect ofcardiopulmonary resuscitation on restoration of myocardial ATP in prolonged ventricularfibrillation. Resuscitation. 2013; 84(1): 108–113. PubMed Abstract | Publisher Full Text\n\nZonghua S, Lingang L, Chuanyu G: Influence of frequency and amplitude of ventricular fibrillation on defibrillation. Chinese Journal of Practical Diagnosis and Therapy. 2015; 29(9): 908–909. Publisher Full Text\n\nYegui Y, Nuo L, Jiaxin S, et al.: Effect of potassium chloride on rat ventricular fibrillation model during cardiopulmonary resuscitation. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2016; 28(12): 1095–1098. Publisher Full Text\n\nRoh YI, Jung WJ, Hwang SO, et al.: Shorter defibrillation interval promotes successful defibrillation and resuscitation outcomes. Resuscitation. 2019; 143: 100–105. PubMed Abstract | Publisher Full Text\n\nOng MEH, Perkins GD, Cariou A: Out-of-hospital cardiac arrest: prehospital management. Lancet. 2018; 391(10124): 980–988. Publisher Full Text\n\nHayek SS, Brenner SK, Azam TU, et al.: In-hospital cardiac arrest in critically ill patients with covid-19: multicenter cohort study. BMJ. 2020; 371: m3513. PubMed Abstract | Publisher Full Text\n\nShao F, Xu S, Ma X, et al.: In-hospital cardiac arrest outcomes among patients with COVID-19 pneumonia in Wuhan, China. Resuscitation. 2020; 151: 18–23. PubMed Abstract | Publisher Full Text\n\nRohlin O, Taeri T, Netzereab S, et al.: Duration of CPR and impact on 30-day survival after ROSC for in-hospital cardiac arrest-A Swedish cohortstudy. Resuscitation. 2018; 132: 1–5. PubMed Abstract | Publisher Full Text\n\nDuval S, Pepe PE, Aufderheide TP, et al.: Optimal Combination of Compression Rate and DepthDuring Cardiopulmonary Resuscitation for Functionally Favorable Survival. JAMA Cardiol. 2019; 4(9): 900–908. Publisher Full Text\n\nLixiang W, Wei S, Sisen Z: Chest compression on CPR and active abdominal on CPR. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2017; 29(12): 1057–1061. PubMed Abstract | Publisher Full Text\n\nXiang L, Hui H, Jindong F, et al.: Improvement of cardiopulmonary resuscitation by bending and pressing the lower extremities. Am. J. Emerg. Med. 2013; 31(2): 436–437. PubMed Abstract | Publisher Full Text\n\nHolmberg MJ, Geri G, Wiberg S, et al.: Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review. Resuscitation. 2018; 131: 91–100. PubMed Abstract | Publisher Full Text\n\nRubertsson S, Lindgren E, Smekal D, et al.: Mechanical chest compressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest: the LINC randomized trial. JAMA. 2014; 311(1): 53–61. PubMed Abstract | Publisher Full Text\n\nHardig BM, Lindgren E, Östlund O, et al.: Outcome among VF/VT patients in the LINC (LUCAS IN cardiac arrest) trial-A randomised, controlledtrial. Resuscitation. 2017; 115: 155–162. Publisher Full Text\n\nHaanschoten DM, Elvan A, Ramdat Misier AR, et al.: Long-Term Outcome of the Randomized DAPA Trial. Circ. Arrhythm. Electrophysiol. 2020; 13(11): e008484. PubMed Abstract | Publisher Full Text\n\nHong S: The significance of space-time conversion in cardiopulmonaryresuscitation. Zhong Guo Wei Zhong Bing Ji Jiu Yi Xue. 2008; 20(12): 705. Publisher Full Text"
}
|
[
{
"id": "203392",
"date": "12 Oct 2023",
"name": "Jana Smalcova",
"expertise": [
"Reviewer Expertise refactory cardiac arrest",
"cardiac arrest",
"postresuscitation syndrome",
"cardiology",
"intensive care"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe author presents an article where he discusses the existence of different types of energy in the body, which are intertwined during cardiac arrest and contribute to the restoration of circulation.\nThe existence of different types of energy in the body cannot be denied, and it is certainly an interesting concept.\nHowever, unfortunately, in my opinion, the presentation of the concept itself contains many inaccuracies and speculations.\nFor the explained concept of the transfer of different types of energy in the case of cardiac arrest to be acceptable, I would expect a description of the physical, physiological and pathophysiological basis for the assertion of energy transfer between the different compartments and their relationship to the restoration of myocardial contractility and circulation.\nUnfortunately, for example, one cannot agree that ventricular fibrillation is a protective mechanism that generates energy and can trigger a spontaneous version.\nVentricular fibrillation cannot be described as an autoregulatory mechanism.\nAutoregulatory mechanisms lead to the stabilization of pathological deflections in order to restore balance; malignant arrhythmias cannot be described as autoregulatory mechanisms.\nMalignant arrhythmias are a sign of pathology, impairment of physiological mechanisms, and organism failure.\n\nThe Lazarus phenomenon, mentioned several times in the article, is rather an isolated event. Its occurrence is related to some specific situations such as catalepsy, CO intoxication, hypnotics, hypothermia or electric shock, which is an absolute minority proportion of the causes of cardiac arrests, which are usually acute coronary syndrome or hypoxia.\n\nFurthermore, the article raises many other questions, e.g.\n\n- What exactly do you mean by occult CA - what is the definition, and what causes can be listed under this term?\n\n- that ventricular fibrillation or asystole will become self-inflicted without external intervention is at least plausible.\n\n- what would be the impulse to depolarize spontaneously?\n\nIn the sentences: \"During this time, the body, especially the heart, undergoes a series of electrophysiological and pathophysiological changes, whereas the essence is the change of energy and energy transfer. The process of cardioversion or re-pacing by the heart using energy is called cardiac self-resuscitation.\"\n\n- what exactly does the author imagine? What are electrophysiological and pathophysiological phenomena?\n\nEtc.\n\nThe treatise presented gives more the impression of a philosophical reflection on the existence of different types of energy and their contribution to the occurrence and progression of cardiac arrest than a scientific article dealing with the pathological condition of cardiac arrest.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nAre arguments sufficiently supported by evidence from the published literature? No\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly",
"responses": [
{
"c_id": "10405",
"date": "30 Nov 2023",
"name": "Xiang Li",
"role": "Author Response",
"response": "We are very grateful to the reviewers for their review of this paper. The authors tried to answer the reviewers' opinions: The so-called self-protection mechanism in this paper is based on the assumption that all arrhythmias are a form of self-protection. Secondly, some patients with ventricular fibrillation can self-cardioversion, suggesting that this part of patients with ventricular fibrillation, the heart produces energy, and this energy causes the heart to cardiovert itself. Therefore, it is considered that ventricular fibrillation is one of the mechanisms of cardiac self-protection. Although we know this conclusion is contrary to common sense. Agree with The reviewers on The description of “The Lazarus phenomenon”. There's a bit of confusion when we think about this phenomenon, and that's why the heart can pump again after stopping electrical and mechanical activity for a while? This means that during this period of time there is still energy in the body or heart, and make the heart energy accumulation, when the energy increased to the domain energy, it is possible to re-pacing the heart. Although other factors may play a role, it is impossible to restart the heart without energy. Because some patients develop ventricular fibrillation or other serious arrhythmias that are not clinically detected, cardioversion occurs. Cardioversion occurs because of energy. The concept of “Occult cardiac arrest” was put forward. This concept divides the clinical manifestation of cardiac arrest into two stages, namely clinical stage and preclinical stage. The author thinks this is objective existence."
}
]
}
] | 1
|
https://f1000research.com/articles/11-545
|
https://f1000research.com/articles/11-231/v1
|
24 Feb 22
|
{
"type": "Opinion Article",
"title": "Recommendations for the formatting of Variant Call Format (VCF) files to make plant genotyping data FAIR",
"authors": [
"Sebastian Beier",
"Anne Fiebig",
"Cyril Pommier",
"Isuru Liyanage",
"Matthias Lange",
"Paul J. Kersey",
"Stephan Weise",
"Richard Finkers",
"Baron Koylass",
"Timothee Cezard",
"Mélanie Courtot",
"Bruno Contreras-Moreira",
"Guy Naamati",
"Sarah Dyer",
"Uwe Scholz",
"Anne Fiebig",
"Cyril Pommier",
"Isuru Liyanage",
"Matthias Lange",
"Paul J. Kersey",
"Stephan Weise",
"Richard Finkers",
"Baron Koylass",
"Timothee Cezard",
"Mélanie Courtot",
"Bruno Contreras-Moreira",
"Guy Naamati",
"Sarah Dyer",
"Uwe Scholz"
],
"abstract": "In this opinion article, we discuss the formatting of files from (plant) genotyping studies, in particular the formatting of (meta-) data in Variant Call Format (VCF) files. The flexibility of the VCF format specification facilitates its use as a generic interchange format across domains but can lead to inconsistency between files in the presentation of metadata. To enable fully autonomous machine actionable data flow, generic elements need to be further specified. We strongly support the merits of the FAIR principles and see the need to facilitate them also through technical implementation specifications. VCF files are an established standard for the exchange and publication of genotyping data. Other data formats are also used to capture variant call data (for example, the HapMap format and the gVCF format), but none currently have the reach of VCF. In VCF, only the sites of variation are described, whereas in gVCF, all positions are listed, and confidence values are also provided. For the sake of simplicity, we will only discuss VCF and our recommendations for its use. However, the part of the VCF standard relating to metadata (as opposed to the actual variant calls) defines a syntactic format but no vocabulary, unique identifier or recommended content. In practice, often only sparse (if any) descriptive metadata is included. When descriptive metadata is provided, proprietary metadata fields are frequently added that have not been agreed upon within the community which may limit long-term and comprehensive interoperability. To address this, we propose recommendations for supplying and encoding metadata, focusing on use cases from the plant sciences. We expect there to be overlap, but also divergence, with the needs of other domains.",
"keywords": [
"FAIR",
"plant",
"genotyping",
"snp",
"vcf",
"data management",
"phenotyping",
"ELIXIR"
],
"content": "Introduction\n\nAs of today, there are several public repositories for genetic and genomic variation data. However, most of these repositories are exclusive to humans and do not include other organisms (NCBI Insights, 2017), such as dbSNP (Sherry et al., 2001), dbGaP (Mailman et al., 2007) and dbVar (Lappalainen et al., 2013). There are two main resources for non-human variation data: The European Variation Archive (EVA) (Cezard et al., 2021), hosted by EMBL-EBI, and the Genome Variation Map (GVM) (Song et al., 2018), hosted by CNCB-NGDC. Submitting datasets to these two repositories works very similarly, but we will focus on the submission of genotyping datasets to EVA. Data and metadata are submitted to a File Transfer Protocol (FTP) file server and, after a quality check, are added to the database and displayed on their respective websites or kept hidden until a user-specified release date. Data are only checked for a few critical points: first, the VCF file must comply with the Variant Call Format (VCF) (Danecek et al., 2011) specifications, second, the genome assembly used as reference must be registered with one of the databases of the International Nucleotide Sequence Database Collaboration (INSDC) (Cochrane et al., 2011), i.e., GenBank (Benson et al., 2013), the European Nucleotide Archive (ENA) (Leinonen et al., 2011) or the DNA Data Bank of Japan (DDBJ) (Mashima et al., 2017), respectively, and an accession number is available, and third, the VCF file must contain either allele frequencies and/or genotype information.\n\nWhen a data submission is made to the EVA, samples are automatically registered in the associated BioSamples database (Courtot et al., 2022), unless this has been explicitly done previously by the data submitter. Such automatically created samples possess only the minimum necessary attributes (name, domain, release date) and no other descriptive metadata. If pre-registering samples in BioSamples, metadata can be specified as key-value pairs. For some specific use cases, there are already predefined checklists that list which metadata should be supplied on sample registration, against which the metadata can be validated. Additional information, which is not yet available in a defined attribute, can also be submitted under a free text key. We recommend the manual registration of samples at BioSamples as this gives the greatest flexibility when editing and adding information.\n\nAnother useful resource for the analysis of plant variation data is Ensembl Plants (Howe et al., 2020). This database, also hosted by EMBL-EBI, is a platform for displaying and visualising plant genomes. If the reference genome associated with the data submitted to EVA is supported in Ensembl, then it is possible to display genetic variants in their genomic context in the Ensembl browser, each linked to its sample. Data submitters should contact Ensembl helpdesk to request it. VCFs in EVA should be available as browsable files, as seen for example in soybean.\n\n\nLessons learned from studies on plant phenotyping and its application to metadata information in genotyping\n\nThe standardisation of plant variation data is still in its infancy. Therefore, it is beneficial to look to other data types for guidance and improvement. One particular data type where a lot of standardisation work has been done in recent years is plant phenotyping. Plant phenotyping has developed rapidly with the introduction of high-throughput technologies such as fully automated greenhouses, full-time sensor recording and aerial observation drones. The need to record data points and the method of observation has led the community to implement a standard for describing such experiments: MIAPPE (Papoutsoglou et al., 2020) (Minimal Information About a Plant Phenotyping Experiment). Since its introduction in 2014, the standard has been extended to describe sample material (including the anatomical part sampled) through the use of specialised ontologies. MIAPPE-compliant data can be represented in the Investigation-Study-Assay (ISA) framework for structured data representation (Rocca-Serra et al., 2010) and exposed programmatically via the Breeding API (BrAPI) (Selby et al., 2019). The format is maintained and regularly updated by an active community. Fully MIAPPE-compliant data is rich in metadata that describes and identifies in detail both the sample material and the experiment performed. One aim is to allow machine access to the data via application programming interfaces (APIs). Therefore, the use of controlled vocabularies is encouraged by supporting different ontologies, with AgroPortal (Jonquet et al., 2018) serving as a reference repository.\n\nIn contrast, genotyping data is often published and shared without sufficient metadata to ensure interoperability and reuse, as seen with other data formats (Bernstein et al., 2017). Current automated tools do not fill in the metadata fields very well, leaving the user to take care of it. Some information that should be recorded cannot be easily retrieved from the analysis results, such as the identification of biological material studied, or the reference genome assembly and version used. Depending on who is handling the data and what skills are associated with the role, the difficulty of providing well-formatted metadata will vary. Bioinformaticians who have directly performed the genotyping analyses and thus the creation of the VCF files will consider it a comparatively simple task to enter metadata directly into the file. Similarly, a data steward who may not have previously been directly familiar with the data but with the structure itself should have no problems. Gathering experimental data from conversations with wet lab colleagues or in a laboratory information management system (LIMS) search will be the more laborious activity for individuals in either role. However, experimentalists who have little or no experience with the required metadata formats are most likely to be overwhelmed without a simple GUI or input template. Principal investigators who want to submit the data at the end of an experiment may have similar difficulties. From these observations, we recommend performing both metadata and data validation. For the validation of VCF files, we recommend EBI's VCF validator.\n\n\nData and metadata formatting\n\nThe de facto standard data format for genotyping studies is the Variant Call Format (VCF). The following statements are based on the current version 4.3. A VCF file comprises a single text file that consists of three parts: (i) one or more meta-information lines, initiating with a ## describing the settings, samples and general experimental design of the genotyping study. File meta-information is included after the ## string and must be key=value pairs. There are currently no guidelines on how these are used or what they may contain (ii) a header line initiating with a single #, and (iii) one or more data lines, each recording the genotype calls at each varying position in the reference genome for a single sample. Both the header and data lines use tab stops to delineate separate fields. Meta-information lines are considered optional; however, they need to be well-formed if present. All structured lines that have their value enclosed within “<>” require an ID which must be unique within their type (Figure 1).\n\nA critical aspect of VCF specifications is that sample naming within the VCF file does not follow any standard specifications, i.e. the user can name their samples without reference to any real biological material. Even worse, phenotyping and genotyping data from the same experimental setup often use different sample identifiers even when the same biological material has been used, which makes it difficult to reconstruct later which datasets were derived from a common sample. To be able to represent such relationships, descriptive metadata is required that relates these different sample identifiers to each other.\n\nIn response to the points discussed previously, we propose a minimal list of metadata fields, recommend an identifier schema and guidelines for vocabulary and data format within a VCF file. Our suggestions are divided into recommended and optional changes. Although, we are primarily addressing data submissions to the EMBL-EBI repositories BioSamples and EVA (and implicitly ENA through the submission of sequence information), subsequent formatting guidelines should be applied regardless of the specific deposition repository and should also be considered when designing databases and APIs.\n\nIn our view, these additional fields should be required for a valid VCF:\n\nOne meta-information line, ##fileformat, is obligatory in VCF. We also recommend using the additional lines ##filedate, ##bioinformatics_source, ##reference_ac, ##reference_url, ##contig and ##SAMPLE. To ensure permanent unique and stable IDs for samples and genotypes, we recommend the registration of used genotypes and samples in the BioSamples database. This enables the publishing of biological material used in variation studies, and we explicitly recommend the use of long-term stable BioSamples identifiers as primary IDs for material description in VCF files (Table 1).\n\nThe creation date of the VCF should be specified in the metadata via the field ##fileDate, the notation corresponds to ISO 8601 (Kuhn, 1995) (in the basic form without separator: YYYYMMDD).\n\n##fileDate=date\n\nExample:\n\nDescription of a VCF file that was created on September 21st in 2012.\n\nThe analytic approach (usually consisting of chains of bioinformatics tools) for creating the VCF file is specified in the ##bioinformatics_source field. Such approaches often involve several steps, like read mapping, variant calling and imputation, each carried out using a different program. Every component of this process should be clearly described, including all the parameter values.\n\n##bioinformatics_source=url\n\nThis is ideally specified as the DOI of a publication, or more generally as URL/URI (like a public repository for the scripts and parameters used).\n\nExamples:\n\n1) Description of a GBS experiment in barley and subsequent read alignment and variant calling using a bioinformatics analysis pipeline consisting of cutadapt, BWA-MEM, SAMtools, NovoSort, Picard, BCFtools and seqArray.\n\n2) Modified version of Tassel4 (v.4.3.7) for running the Tassel-GBS pipeline modified for polyploid species with high read depths used in (Pereira et al., 2018).\n\nThis field contains the accession number (including the version) of the reference sequence on which the variation data of the present VCF is based.\n\n##reference_ac=assembly_accession\n\nThe NCBI page on the Genome Assembly Model states (NCBI, 2002): “The assembly accession starts with a three letter prefix, GCA for GenBank assemblies […]. This is followed by an underscore and 9 digits. A version is then added to the accession. For example, the assembly accession for the GenBank version of the public human reference assembly (GRCh38.p11) is GCA_000001405.26”. Note these accessions are shared by all INSDC archives.\n\nExample:\n\nReference genome assembly for barley (Hordeum vulgare) cultivar Morex version 2.\n\n\n\nWhile the ##reference_ac field contains the accession number of the reference genome, the ##reference_url field contains a URL (or URI/DOI) for downloading of this reference genome, preferably from one INSDC archive.\n\n##reference_url=url\n\nThe reference genome should be in FASTA format; the user is free to provide a packed or unpacked publicly available version of the genome.\n\nExample:\n\nReference genome assembly for barley (Hordeum vulgare) cultivar Morex version 2 download link on NCBI FTP.\n\n\n\nThe individual sequence(s) of the reference genome are described in more detail in the #contig field(s).\n\n##contig=<ID=ctg1, length=sequence_length, assembly=gca_accession, md5=md5_hash, species=NCBI Taxon ID>\n\nEach contig contains at least the attribute ID, and typically also include length, assembly, md5 and species. The ID is the identifier of the sequence contig used in the reference genome assembly. Length contains the base pair length of the sequence contig in the reference genome. The assembly is the accession number of the reference genome. If the md5 parameter is given, please note that the individual sequence contigs MD5 checksum is expected, not the MD5 sum of the complete reference genome. The species is the taxonomic name of the species of the reference genome.\n\nExamples:\n\n1) Chromosome 1H of barley (Hordeum vulgare) cultivar Morex version 2.\n\n2) Chromosome 1 of maize (Zea mays) cultivar B73 version 3.\n\nThe ##SAMPLE fields describe the material whose variants are given in the genotype call columns in greater detail and can be extended using the specifications of the VCF format.\n\n##SAMPLE=<ID=BioSample_accession, DOI=doi, ext_ID=registry:identifier>\n\nGenotyped samples are indicated in the VCF by the BioSample accession, which is formed as follows (based on information from the BioSamples documentation): “BioSample accessions always begin with SAM. The next letter is either E or N or D depending if the sample information was originally submitted to EMBL-EBI or NCBI or DDBJ, respectively. After that, there may be an A or a G to denote an Assay sample or a Group of samples. Finally, there is a numeric component that may or may not be zero-padded.” Additional information (like complete Multi-Crop Passport Descriptor (Alercia et al., 2015) records) on the sample material is provided under the DOI (Alercia et al., 2018). In case no DOI exists and the material is held by a FAO-WIEWS recognised institution, the external ID consists of the FAO-WIEWS instcode, the genus and the accession number (see example 2). If the database is not registered with FAO-WIEWS and is not available under a DOI, the DNS of the holding institution, the database identifier, the identifier scheme and the identifier value should be provided (see example 3). For multiple external IDs the field should be used multiple times (delimited by commas).\n\nExamples (Please note that all examples here represent the same genotype. To avoid misunderstandings, if available, the preferred method of describing the data is by DOI.):\n\n1) One genotype from the barley (Hordeum vulgare) GBS experiment with a DOI registered.\n\n2) One genotype from the barley (Hordeum vulgare) GBS experiment with the FAO-WIEWS code available but no DOI.\n\n3) One genotype from the barley (Hordeum vulgare) GBS experiment with no DOI and no FAO-WIEWS code available.\n\nIn order to allow the highest degree of interoperability, we suggest using BioSamples IDs as the column headers for each sample. In the header line, they should be provided after the 9 mandatory column headings (#CHROM, POS, ID, REF, ALT, QUAL, FILTER, INFO, FORMAT).\n\nIn addition, ensure that the genomic positions in the data lines (consisting of the #CHROM and POS tuple) use the same nomenclature as in the reference genome FASTA file and that the positions of the variations are within the start and end positions of the respective chromosome or contig. Watch out for programmes that change these values automatically (especially during imputation).\n\nOn top of the preceding recommendations to improve findability and interoperability, we encourage everyone to describe their data in as much detail as possible in the metainformation lines. Before introducing new fields, please check the official format specifications (in VCFv4.3 this would be under 1.4 Meta-information lines) to avoid redundancy and possible incompatibilities.\n\n\nConclusion\n\nWith the data and metadata recommendations for VCF files presented here, we hope to make a contribution to linking genotypic and other data for plants. In our view, the minimum to achieve this is to have traceable material and sample management. Analytical results should be linked out to the respective sample(s) and defined in the context of the study being reported. One way to ensure this is to generate long-term stable identifiers at an early stage, ideally when the sample is taken, and to document all work steps accurately. Reproducibility is also an important aspect, which has recently been criticised more frequently in various studies (Baker, 2016; Miyakawa, 2020). Technologies such as containers or the provision of the entire data set and the analytical computing pipeline in a cloud environment could be a further step towards overcoming such problems (Grüning et al., 2018).\n\nThe BioSamples database at EMBL-EBI stores samples metadata and allows their pre-registration; it provides unique, stable identifiers for each sample. BioSamples connects to other archives, enabling consistent tracking through time and assays of the samples and derived data. It supports validation of plant phenotypic metadata according to the MIAPPE standard, ensuring data FAIRness (Wilkinson et al., 2016) at submission time as well as keeping metadata on hold pending publication of results. It is recognised by ELIXIR as a recommended Deposition Database for Biomolecular Data. This ensures that comprehensive, validated metadata can be captured at all stages of sample and data generation and that relationships between samples and derived data can be tracked across molecular archives.\n\nThe responsibilities of the people involved may vary from research institution to research institution, but the general tasks for the generation of plant genotyping data and the subsequent publication of these data follow a common pattern. To highlight how the complete data management of a genotyping project could be structured, we have designed an exemplary Unified Modeling Language (UML) diagram (Figure 2) as a best practice proposal. We assume that the research institution has a LIMS and that sample collection, sample preparation, sequencing and all bioinformatic analyses are carried out in house. Even if one or more of these activities are outsourced, most data management activities (indicated in the figure by the actor “Data Steward”) and thus also the primary communication with public repositories remain the scientific responsibility of the research institution. It is relatively obvious that the timing of interaction with public repositories varies greatly depending on the purpose (registration of datasets, retrieval of identifiers, or updating of datasets) and is recommended to occur at the earliest possible date in order to use the persistent identifiers of the datasets in the further course of the analyses and thus avoid errors due to the use of short-lived internal identifiers.\n\nDNA samples are collected by an Experimentalist and their metadata are stored in a Laboratory Information Management System (LIMS). The Data Steward then registers these samples with BioSamples and in return receives unique BioSamples IDs back, which he adds to the created samples in the LIMS. The sequencing and quality control of these samples is then carried out by the Sequencing Staff and the primary sequence data is fed into the LIMS and linked to the sample data by the Data Steward. The sequencing results are then registered and submitted to the European Nucleotide Archive (ENA) using the BioSamples IDs to link the initially submitted samples to the generated sequencing reads. The study identifiers (ENA IDs) are assigned by ENA and added to the samples by the Data Steward in LIMS. The Bioinformatician then analyses the data and produces the genotyping results. Afterwards, the Data Steward prepares these data for transmission by linking them to the already created sample data from the LIMS and extracting the required metadata and adding it to the header of the Variant Call Format (VCF) file. If the reference genome used for genotyping is not yet available in public repositories, it will now be transferred by the Data Steward to one of the International Nucleotide Sequence Database Collaboration (INSDC) databases. Otherwise, the metadata-enriched VCF file can be registered and submitted to the European Variation Archive (EVA). The identifiers assigned by EVA are then transmitted back and the Principal Investigator can approve the publication of the data.\n\nThis approach to data management facilitates the submission of data for publication or at the end of the research project. Here, the situation often arises that the data steward, under time pressure, fails to submit the necessary (meta-)information to the public repositories. The submitted dataset therefore only consists of very generic and not meaningful metadata (Toczydlowski et al., 2021). Such behaviour is the lesser evil compared to not publishing the dataset but can hinder its interoperability and reusability. During the peer review process, large and complex datasets often cannot be checked in depth by the reviewers. A wider use of automatic validations or checklists (such as those supported by BioSamples) that the metadata adhere to would enable reviewers and users to identify well-annotated datasets suitable for re-use.\n\nOnce well-defined metadata is submitted, it can be used by search engines. For example, plant material and sample identifications, as recommended here, are used as germplasm filters in the FAIDARE search portal, allowing discovery of genotyping and phenotyping data containing the same plant material. Adoption of these guidelines and best practices will help make plant genotyping data FAIR and provide new opportunities to advance our understanding of relationships between genotypic and phenotypic data.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "References\n\nAlercia A, Diulgheroff S, Mackay M: FAO/bioversity multi-crop passport descriptors V. 2.1 [MCPD V. 2.1]. Rome (Italy): Food and Agriculture Organization of the United Nations (FAO); Bioversity International; 2015.\n\nAlercia A, López FM, Sackville Hamilton NR, et al.: Digital Object Identifiers for food crops - Descriptors and guidelines of the Global Information System. Rome: Food and Agriculture Organization of the United Nations; 2018.\n\nBaker M: 1,500 scientists lift the lid on reproducibility. Nature. 2016; 533: 452–454. PubMed Abstract | Publisher Full Text\n\nBernstein MN, Doan A, Dewey CN: MetaSRA: normalized human sample-specific metadata for the Sequence Read Archive. Bioinformatics. 2017; 33: 2914–2923. Publisher Full Text\n\nBenson DA, Cavanaugh M, Clark K, et al.: GenBank. Nucleic Acids Res. 2013; 41: D36–D42. PubMed Abstract | Publisher Full Text\n\nCezard T, Cunningham F, Hunt SE, et al.: The European Variation Archive: a FAIR resource of genomic variation for all species. Nucleic Acids Res. 2021; 50: D1216–D1220. PubMed Abstract | Publisher Full Text\n\nCochrane G, Karsch-Mizrachi I, Nakamura Y, et al.: The International Nucleotide Sequence Database Collaboration. Nucleic Acids Res. 2011; 39: D15–D18. PubMed Abstract | Publisher Full Text\n\nCourtot M, Gupta D, Liyanage I, et al.: BioSamples database: FAIRer samples metadata to accelerate research data management. Nucleic Acids Res. 2022; 50: D1500–D1507. PubMed Abstract | Publisher Full Text\n\nDanecek P, Auton A, Abecasis G, et al.: The variant call format and VCFtools. Bioinformatics. 2011; 27: 2156–2158. PubMed Abstract | Publisher Full Text\n\nGrüning B, Chilton J, Köster J, et al.: Practical Computational Reproducibility in the Life Sciences. Cell Syst. 2018; 6: 631–635. PubMed Abstract | Publisher Full Text\n\nHowe KL, Contreras-Moreira B, De Silva N, et al.: Ensembl Genomes 2020—enabling non-vertebrate genomic research. Nucleic Acids Res. 2020; 48: D689–D695. PubMed Abstract | Publisher Full Text\n\nJonquet C, Toulet A, Arnaud E, et al.: AgroPortal: A vocabulary and ontology repository for agronomy. Comput. Electron. Agric. 2018; 144: 126–143. Publisher Full Text\n\nKuhn M: A summary of the international standard date and time notation.1995. (accessed 9.1.21). Reference Source\n\nLappalainen I, Lopez J, Skipper L, et al.: dbVar and DGVa: public archives for genomic structural variation. Nucleic Acids Res. 2013; 41: D936–D941. PubMed Abstract | Publisher Full Text\n\nLeinonen R, Akhtar R, Birney E, et al.: The European Nucleotide Archive. Nucleic Acids Res. 2011; 39: D28–D31. PubMed Abstract | Publisher Full Text\n\nMailman MD, Feolo M, Jin Y, et al.: The NCBI dbGaP database of genotypes and phenotypes. Nat. Genet. 2007; 39: 1181–1186. PubMed Abstract | Publisher Full Text\n\nMashima J, Kodama Y, Fujisawa T, et al.: DNA Data Bank of Japan. Nucleic Acids Res. 2017; 45: D25–D31. PubMed Abstract | Publisher Full Text\n\nMiyakawa T: No raw data, no science: another possible source of the reproducibility crisis. Mol. Brain. 2020; 13: 24. PubMed Abstract | Publisher Full Text\n\nNCBI: NCBI Genome Assembly Model.2002. (accessed 9.1.21). Reference Source\n\nNCBI Insights: NCBI Insights: Phasing out support for non-human genome organism data in dbSNP and dbVar. NCBI Insights. 2017. (accessed 8.31.21). Reference Source\n\nPapoutsoglou EA, Faria D, Arend D, et al.: Enabling reusability of plant phenomic datasets with MIAPPE 1.1. New Phytol. 2020; 227: 260–273. PubMed Abstract | Publisher Full Text\n\nPereira GS, Garcia AAF, Margarido GRA: A fully automated pipeline for quantitative genotype calling from next generation sequencing data in autopolyploids. BMC Bioinformatics. 2018; 19: 398. PubMed Abstract | Publisher Full Text\n\nRocca-Serra P, Brandizi M, Maguire E, et al.: ISA software suite: supporting standards-compliant experimental annotation and enabling curation at the community level. Bioinformatics. 2010; 26: 2354–2356. PubMed Abstract | Publisher Full Text\n\nSelby P, Abbeloos R, Backlund JE, et al.: BrAPI—an application programming interface for plant breeding applications. Bioinformatics. 2019; 35: 4147–4155. PubMed Abstract | Publisher Full Text\n\nSherry ST, Ward M-H, Kholodov M, et al.: dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001; 29: 308–311. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSong S, Tian D, Li C, et al.: Genome Variation Map: a data repository of genome variations in BIG Data Center. Nucleic Acids Res. 2018; 46: D944–D949. PubMed Abstract | Publisher Full Text\n\nToczydlowski RH, Liggins L, Gaither MR, et al.: Poor data stewardship will hinder global genetic diversity surveillance. Proc. Natl. Acad. Sci. 2021; 118: e2107934118. PubMed Abstract | Publisher Full Text\n\nWilkinson MD, Dumontier M, Aalbersberg IjJ, et al.: The FAIR Guiding Principles for scientific data management and stewardship. Sci. Data. 2016; 3: 160018. Publisher Full Text"
}
|
[
{
"id": "125389",
"date": "02 Mar 2022",
"name": "Boas Pucker",
"expertise": [
"Reviewer Expertise Plant genomics",
"plant specialized metabolism"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nBeier et al. present their recommendations for the inclusion of metadata in VCF files. A defined structure is proposed to make VCF files more suitable for re-use. Suggested fields include file date, bioinformatics source, reference URL, contig, and sample. This opinion paper adds a novel perspective to the area. It is important for advancing FAIR and reproducibility in general if individual formats are analysed in this manner. The suggested metadata standards for VCF seem appropriate for users, with some clarification/additions (see comments). The paper is well and clearly written. The figures help the narrative and provide a quick overview.\n\nSpecific comments:\nFAIR principles are not directly discussed in the text despite the abstract/key word emphasis. The term is only mentioned twice in the manuscript. The recommendations presented in this paper would improve many aspects of FAIR in VCF but this is not explicitly discussed. There is mention of individual components but a more direct discussion would be beneficial.\n\nWhy is gVCF excluded? Are there reasons that prevent the direct transfer of this VCF standard to gVCF?\n\nThe introduction mentions a few variant calling databases. What about 1001 genomes GMI-MPI vcf (https://1001genomes.org/data-center.html)? Several variant datasets for Arabidopsis thaliana are also hosted on\nhttps://jbrowse.arabidopsis.org/. It is only for Arabidopsis but considering the importance of this model it should be mentioned that genomic variation data is often hosted on organism-specific databases (which is in itself a problem of format unification). GVM, for example, does not host Arabidopsis VCFs presumably because they are found in their own database.\n\nThe introduction assumes that the reference genome sequence is supported by Ensembl, but what to do if it is not available?\n\nConsidering that phenotype standards are the only provided example, it does not seem like the most useful comparison. The data type/collection/prevalence etc. is very different to VCF. More examples would be needed to emphasize shared elements of various standards (for example, SAM/BAM flags).\n\nOne statement about VCFs should be checked: \"one or more data lines\". It does not make much sense to share such a file, but the VCF file could be empty i.e. no lines with data.\n\n\"well-formed\" could be explained in more detail.\n\nIt might be better to use bioinformatics_source to include a complete description of the data processing in the VCF file. Otherwise, there is the risk that data sets cannot be re-used due to broken links. Some data sets might be the result of unpublished protocols hence it will be impossible to link to a publication. For example, the data set and the workflow might be part of the same paper.\n\nRefSeq instead of GenBank might be preferentially entered by some groups so this needs to be screened/specified. Again, what happens if the reference genome sequence is not publicly available (yet)? Fig. 2 nicely points out that we must also consider a not-yet-published reference used by a lab to adhere to this standard by registering their reference. It would be good to mention this in the description of the respective field as well.\n\nSome assumptions underlying Fig.2 might be too optimistic. The actual sequencing of many projects is conducted by external sequencing providers. Many institutions also lack a LIMS and a \"Data Steward\". Maybe it would be better to adjust the process in Fig.2 or display an alternative scenario. What would happen if, say, an inexperienced PhD student needs to handle the entire process?\n\n\"genome\" should be replaced by \"genome sequence\" at several places in manuscript. This is about different assembly version of the same accession so the genome remains the same, but the quality of the representation improves.\n\nIt would be good to mentioned other examples of VCF containing databases besides EVA and GVM. Even though they are the main ones, one of the biggest issues with metainformation is that you have “straggler” databases in niche fields/organisms that do not adhere to the format.\n\nWith respect to the tools automatically changing information about variant positions: Can this be monitored in any way? It is not reasonable to expect, e.g. EVA to check this and presumably it is databases that would need to enforce these standards. Would a list of common programs that change this help to avoid issues?\n\nAdditional meta-information fields:\na) \"findability and interoperability\": To reiterate a comment above - reusability (at least, if not also accessibility) would be enhanced by these metadata standards. The impact/implications to VCF FAIR would fit the narrative in here and in the conclusion.\nb) \"metainformation lines”: Indeed, and some some suggestions, e.g. from the barley example are needed.\n\n\"genotypic and other data from plants\": What are these other data? Please specify if this would be phenotypic.\n\n\"Analytical results should be linked out to the respective sample(s) and defined in the context of the study being reported.\" ... this could be a bit more specific.\n\nIt does not become clear how the paragraph about BioSample database at EMBL-EBI contributes to the conclusion. Currently, it is only about phenotypic data and a connection to VCF would be helpful.\n\nRe-use is a very important aspect of missing/insufficient metadata consequences. It could be emphasised more as a major benefit of adopting this type of VCF standardisation.\n\nMore specific portals for adoption would be beneficial to mention in the conclusion - should all databases adopt these guidelines, should journals make sure the data referenced in the paper adheres to them, etc.? Enforcement is a major hurdle of adopting metadata (and data) standards that adhere to FAIR (see our paper, Sielemann, Hafner & Pucker, 20201).\n\nThe authors focus on plant VCF and EVA. However, considering these standards are sorely needed in other areas/databases and that VCF formatting should be fairly universal, the authors might want to consider a broader application of these standards. This could be suggested and explored more in the conclusion.\n\nIt could be helpful to include a sample of the improved VCF as supplementary file.\nMinor comments:\nThe link to one reference is not correctly formatted: \"NCBI Insights, 2017\".\n\n'Each contig contains at least the attribute ID, and typically also include length' > \"Each contig entry contains at least the attribute ID, and typically also includes length...\"\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": [
{
"c_id": "8258",
"date": "19 May 2022",
"name": "Sebastian Beier",
"role": "Author Response",
"response": "Dear Boas Pucker and Alenka Hafner, thank you for taking the time to review our article and providing valuable feedback on our project. We would like to address your comments below: 1. FAIR principles are not directly discussed in the text despite the abstract/key word emphasis. The term is only mentioned twice in the manuscript. The recommendations presented in this paper would improve many aspects of FAIR in VCF but this is not explicitly discussed. There is mention of individual components but a more direct discussion would be beneficial. We added explicit FAIR principles discussion in the discussion to clearly state the improved Findability, Reusability and Interoperability. 2. Why is gVCF excluded? Are there reasons that prevent the direct transfer of this VCF standard to gVCF? We added some remarks, showing these recommendations can be directly transferred to gVCF. There is nothing that would exclude the use of our recommendations with gVCF. 3. The introduction mentions a few variant calling databases. What about 1001 genomes GMI-MPI vcf (https://1001genomes.org/data-center.html)? Several variant datasets for Arabidopsis thaliana are also hosted on https://jbrowse.arabidopsis.org/. It is only for Arabidopsis but considering the importance of this model it should be mentioned that genomic variation data is often hosted on organism-specific databases (which is in itself a problem of format unification). GVM, for example, does not host Arabidopsis VCFs presumably because they are found in their own database. We added some remarks regarding this in the manuscript. 4. The introduction assumes that the reference genome sequence is supported by Ensembl, but what to do if it is not available? In the case where the reference genome sequence is not yet in Ensembl the VCF cannot be displayed (within Ensembl). However in such cases Ensembl would try to prioritize adding the missing genome if it is in the public archives. This should not be confused with EVAs requirement of needing a genome assembly supported by INSDC. 5. Considering that phenotype standards are the only provided example, it does not seem like the most useful comparison. The data type/collection/prevalence etc. is very different to VCF. More examples would be needed to emphasize shared elements of various standards (for example, SAM/BAM flags). It is true that MIAPPE, and thus the phenotyping standard, was not intended to characterize genotyping analyses or VCF files. It has been used to enable interoperability with genotyping dataset through shared objects and IDs. It is also true that in order to create a VCF file, there must be one or more mapping files (SAM/BAM) that record the differences and similarities between the genotypes under study and the reference genome assembly. Since there are a large number of different workflows to create a VCF file, our intention was to make the final result FAIR and not necessarily cover all intermediate steps with our suggestions. What all genotyping experiments have in common is that samples are obtained from physical material that is currently poorly described. It is precisely this point that is better addressed and makes it possible to link different experiments and analyses based on the material used with the recommendations presented here. MIAPPE offers a well-designed framework for this and is also ideally suited for the plant domain. 6. One statement about VCFs should be checked: \"one or more data lines\". It does not make much sense to share such a file, but the VCF file could be empty i.e. no lines with data. We agree that sharing such a file would not make much sense, still it would be a perfectly valid VCF file according to the specifications. This wording is taken directly from the specifications. 7. \"well-formed\" could be explained in more detail. We have adjusted the text to make this clearer. 8. It might be better to use bioinformatics_source to include a complete description of the data processing in the VCF file. Otherwise, there is the risk that data sets cannot be re-used due to broken links. Some data sets might be the result of unpublished protocols hence it will be impossible to link to a publication. For example, the data set and the workflow might be part of the same paper. This is a valid concern, but we cannot see that embedded documentation will ensure a sustainable, comprehensive and FAIR documentation of a workflow that enables a re-processing in 10 years. For example, used software needs to be referred to using PUIDs or links. Here, we could also face broken links. If mentioned software or scripts cannot be resolved anymore, VCF embedded documentation could become ambiguous too. To get around this, a container (RO-Crate, Docker, Singularity, etc.) is one of the only solutions that can remedy this and make both the workflow and the data accessible to users. It should be noted here, however, that there are some scenarios where the disclosure of all programmes, scripts or data is not wanted or legally possible. However, until containers are common practice, explaining the workflow in as much detail as possible is a good start. There are some approaches that map this in a more structured way, such as Common Workflow Language (CWL, https://doi.org/10.1038/sdata.2018.118). In general, however, it should be said that here the workflows can also be referenced as DOI, which is fully compliant with our recommendations. 9. RefSeq instead of GenBank might be preferentially entered by some groups so this needs to be screened/specified. Again, what happens if the reference genome sequence is not publicly available (yet)? Fig. 2 nicely points out that we must also consider a not-yet-published reference used by a lab to adhere to this standard by registering their reference. It would be good to mention this in the description of the respective field as well. The complete described pipeline builds upon deposition of genotyping information at EVA, which needs a published genome assembly accession number. That is one of the reasons Fig. 2 also tries to highlight that the genome assembly needs to be deposited and an accession number received before being able to proceed to the next step. We updated the text to make this more clear. In addition, the trend in genome sequencing and assembly is for both the read data and the assembly sequence to be published early, making it less likely in the future that the genome sequence will not be publicly available. 10. Some assumptions underlying Fig.2 might be too optimistic. The actual sequencing of many projects is conducted by external sequencing providers. Many institutions also lack a LIMS and a \"Data Steward\". Maybe it would be better to adjust the process in Fig.2 or display an alternative scenario. What would happen if, say, an inexperienced PhD student needs to handle the entire process? Please have a look at our response to Micha Bayer’s comment referring to Figure 2. As additional clarification and help for more inexperienced scientists we have published a stepwise guide on how to submit data using the recommendations in this manuscript in the FAIR Cookbook under recipe https://w3id.org/faircookbook/FCB061. 11. \"genome\" should be replaced by \"genome sequence\" at several places in manuscript. This is about different assembly version of the same accession so the genome remains the same, but the quality of the representation improves. Indeed, a good catch. We updated the manuscript to be more precise. 12. It would be good to mentioned other examples of VCF containing databases besides EVA and GVM. Even though they are the main ones, one of the biggest issues with metainformation is that you have “straggler” databases in niche fields/organisms that do not adhere to the format. In this paper, we focused on the use case of EMBL-EBI submissions and their use of VCF in collaboration with BioSamples and EVA. We are not aiming at an extensive review of all possible VCF submissions and publishers. We added some remarks in the discussion regarding adoption of the metadata recommendations in the broader community. 13. With respect to the tools automatically changing information about variant positions: Can this be monitored in any way? It is not reasonable to expect, e.g. EVA to check this and presumably it is databases that would need to enforce these standards. Would a list of common programs that change this help to avoid issues? We are not aware of any programs that change the position or other characteristics of variants, but programs such as PLINK are known to define the variant within a genotyping study with the major allele as the reference and the minor allele as the alternative, regardless of the base present in the reference genome assembly. However, PLINK has an option to use the reference allele, and EVA often asks to correct this at the time of submission. EVA also consistently validates each VCF file that is submitted to the archive. Validation compares the reference allele to the reference genome sequence, most likely detecting misplaced variants. It is technically possible for misplaced variants to still match the reference, but in practice this method will detect most of these errors. A list of common programs that work in a similar way to PLINK would be very welcome. However, we do not believe that this would completely avoid this problem, since such a list is not easy to maintain (based on new versions, programs, workflows) and could lull the user into a false sense of security if other programs were used. We would therefore rather urge caution and diligence when using programs that interact with VCF files. 14. Additional meta-information fields: a) \"findability and interoperability\": To reiterate a comment above - reusability (at least, if not also accessibility) would be enhanced by these metadata standards. The impact/implications to VCF FAIR would fit the narrative in here and in the conclusion. b) \"metainformation lines”: Indeed, and some some suggestions, e.g. from the barley example are needed. a) We added reusability in the listing and expanded on the FAIRness of data in the discussion part. b) Information, such as further metadata about the person who analysed the data or collected the plant material and the prevailing environmental conditions (e.g. contact information, tools used, temperature or humidity), would be examples of additional metainformation fields that were not explicitly recommended by us, but in some scenarios make sense to include additionally. 15. \"genotypic and other data from plants\": What are these other data? Please specify if this would be phenotypic. Since the sample description would be uniform, this could be applied to all kinds of different data. This includes phenotypic data but also other -omics layers, like transcriptomic data, metabolomic data and so forth. 16. \"Analytical results should be linked out to the respective sample(s) and defined in the context of the study being reported.\" ... this could be a bit more specific. We have updated the text to be more precise. 17. It does not become clear how the paragraph about BioSample database at EMBL-EBI contributes to the conclusion. Currently, it is only about phenotypic data and a connection to VCF would be helpful. We have updated the wording to clarify that the plant metadata stored at BioSamples does not necessarily have to be of phenotypic origin. 18. Re-use is a very important aspect of missing/insufficient metadata consequences. It could be emphasised more as a major benefit of adopting this type of VCF standardisation. We agree with this statement and have added this throughout the manuscript. 19. More specific portals for adoption would be beneficial to mention in the conclusion - should all databases adopt these guidelines, should journals make sure the data referenced in the paper adheres to them, etc.? Enforcement is a major hurdle of adopting metadata (and data) standards that adhere to FAIR (see our paper, Sielemann, Hafner & Pucker, 2020). We agree with the concerns raised in Sielemann, Hafner & Pucker, 2020, and one of the solutions they offer is improvement of metadata standard which is what this paper tries to accomplish. Enforcing these new metadata standards on many underfunded databases is unlikely. Adoption of new standards is always tricky and takes time but we believe the best way for that is to enforce it in a central point like upon submission to the archives. Alternatively, journals could be approached to enforce compliance with the recommendations. However, one obstacle would be convincing not just one institution but many different publishers to do so, which is very time-consuming. In our view, critical mass is more likely to be achieved through community engagement via larger organisations (such as DivSeek, AgBioData, Australian BioCommons, etc.). We have started to do this and there is overall positive feedback and early signs of acceptance within these organisations. 20. The authors focus on plant VCF and EVA. However, considering these standards are sorely needed in other areas/databases and that VCF formatting should be fairly universal, the authors might want to consider a broader application of these standards. This could be suggested and explored more in the conclusion. Indeed, we are very interested in bringing these ideas and recommendations to other groups. In particular we have been in discussions with scientists in the animal field to work on an adaptation to their field. 21. It could be helpful to include a sample of the improved VCF as supplementary file. We have uploaded an example of this workflow to EVA and highlighted this in the manuscript. The VCF has been validated and accessioned successfully by EVA. The Study is now available on the EVA website at https://www.ebi.ac.uk/eva/?eva-study=PRJEB51851. Minor comments: 1. The link to one reference is not correctly formatted: \"NCBI Insights, 2017\". We have changed the reference to the EVA paper published last year where this was stated. 2. 'Each contig contains at least the attribute ID, and typically also include length' > \"Each contig entry contains at least the attribute ID, and typically also includes length...\" Changed this accordingly in the manuscript."
}
]
},
{
"id": "128674",
"date": "19 Apr 2022",
"name": "Micha M. Bayer",
"expertise": [
"Reviewer Expertise Crop plant bioinformatics",
"variomics",
"genomics",
"transcriptomics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this opinion article, Beier and co-authors review the current procedures for submitting genotypic variation data to public archives and make a number of recommendations to improve the standardisation of submitted data in order to advance the FAIR principles in this area. They show with specific examples how metadata in VCF files could be improved and suggest additional fields that should be included in VCF-based data submissions.\nThis is a very useful paper that should help stimulate further discussion and progress in this area. The presentation is systematic, clear, and thorough. I have a number of suggestions for improvement that should be implemented before indexing, but otherwise, I am very happy to recommend indexing. This will be a very useful contribution to the community.\nWhat are the specific differences between plants and other organisms in this context? What requirements does plant data have that other data doesn’t? It would be good to expand on this a little.\n\nShould a standard such as MIAPPE be established for genotyping experiments/data? This would be a good place to discuss this and perhaps start describing what it could look like.\n\nThe age of pan-genomes is now firmly upon us, and it might be a good idea to add some thoughts on how graph-based genotyping might affect any of the suggestions proposed here - for example, graph-based reference genomes.\n\n“Bioinformaticians who have directly performed the genotyping analyses and thus the creation of the VCF files will consider it a comparatively simple task to enter metadata directly into the file.” It would be helpful to specify what tools can be used (and how) to add metadata to VCF headers and how this can be done with minimal risk of getting things wrong (e.g. mislabelling samples). Is manual editing of a header and replacing it with bcftools the best we have, or are there tools out there that can achieve this in a more foolproof/refined fashion?\n\nIt would be beneficial to mention the ##META header lines for defining phenotype metadata that were introduced in the VCF v4.3 revision and to provide some examples of how they could be used. How do they fit into the existing framework of data in EVA and ENSEMBL?\n\nP.7, section “Sample field format”: Please include some detail on what the “registry” entails – is there a standardised way of creating/naming/referring to registries?\n\nP.9, bottom: Please provide a reference and/or URL for ELIXIR in the text here.\n\nFigure 2 is an idealised scenario that assumes an institution has both a LIMS and a data steward. Neither is a given – this very much depends on the organisational structure and the levels of funding available to an institution. It would be helpful to have – in addition – an alternative workflow that is more realistic/flexible and describes what can be done when these resources aren’t available.\n\nFigure 2: Replace pronouns like “he” with gender-neutral equivalents like “they” or use the passive voice.\n\nFigure 2: The header says “…submission of genotypic data to public databases” but then the legend only mentions the EVA specifically.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": [
{
"c_id": "8259",
"date": "19 May 2022",
"name": "Sebastian Beier",
"role": "Author Response",
"response": "Dear Micha M. Bayer, thank you for taking the time to review our article and providing valuable feedback on our project. We would like to address your comments below: What are the specific differences between plants and other organisms in this context? What requirements does plant data have that other data doesn’t? It would be good to expand on this a little. There are differences with the precise identification, especially for interoperability and genealogy, as well as the chloroplast genome. We have added some clarification in the introduction part of the manuscript. In contrast to plant species other data domains need a different set of metadata, for example animal sciences in particular need information about the breed and gender of the animal that was genotyped. Should a standard such as MIAPPE be established for genotyping experiments/data? This would be a good place to discuss this and perhaps start describing what it could look like. Such an attempt has indeed been made in the past (Huang et al., 2011, 10.4056/sigs.1994602). However, this was apparently not given much attention by the community, so that no critical mass of users could be generated. MIAPPE itself emphasizes phenotyping and is not currently planning to expand into the genotyping domain. If another attempt is made to introduce a standard for genotyping experiments, MIAPPE can serve as an incubator and provide advice and suggestions, as well as interface with other standards or APIs such as BrAPI. The age of pan-genomes is now firmly upon us, and it might be a good idea to add some thoughts on how graph-based genotyping might affect any of the suggestions proposed here - for example, graph-based reference genomes. Thanks a lot for this question, yes there is indeed a need for a better description about both which reference genome was used for genotyping experiments as well as graph-based genotyping when pan-genomes could be utilized. However, the use of VCF has been discussed in various pan-genome contexts, with the conclusion that VCF is not suitable for structural variants, as it is not appropriate for representing nested or complex variants (Hickey et al., 2020, 10.1186/s13059-020-1941-7). Similar conclusions were reached by Li et al. (2020, 10.1186/s13059-020-02168-z), who found that it is not possible to define coordinates for insertions in VCF, which limits its use for simple variations. In the context of this paper, we believe that this is not the best position to talk about other formats, but to acknowledge the shortcomings of VCF and try to make the format in its current form the most FAIR version it can be. Finally, it should be noted that in future versions of VCF (v4.4 and later) there will be efforts to overcome these shortcomings of the specifications to better represent structural variants in all their complexity (see the following pull requests on github: https://github.com/samtools/hts-specs/pull/465, https://github.com/samtools/hts-specs/pull/553). “Bioinformaticians who have directly performed the genotyping analyses and thus the creation of the VCF files will consider it a comparatively simple task to enter metadata directly into the file.” It would be helpful to specify what tools can be used (and how) to add metadata to VCF headers and how this can be done with minimal risk of getting things wrong (e.g. mislabelling samples). Is manual editing of a header and replacing it with bcftools the best we have, or are there tools out there that can achieve this in a more foolproof/refined fashion? To our knowledge, there is no tool that could do this. One possibility would be that read mapping tools are able to provide metadata on samples and write this data directly into the mapping files.To ensure that the metadata is not lost in the downstream analysis and calculation of all subsequent tools, these metadata fields would need to be known and would not be allowed to be overwritten/edited. In hindsight, this may be too ambitious to implement at this stage and it may make more sense to develop a tool capable of adding this metadata to the final VCF file before submission to public archives. We would like to highlight the role of VCF as a data exchange format in particular, this means that VCFs are in general the result of an analysis pipeline or exported resultset from a database (such as EMBL EVA). Manual maintenance of exchange formats, like JSON or XML-based formats can certainly not be excluded, but should rather be the exception. From our point of view this would mean VCF-generating pipelines should implement necessary components for the user-friendly, correct registration of metadata. We have added a paragraph in the text highlighting the need for appropriate supporting tools or APIs for the validation of VCFs and in particular the VCF metadata. It would be beneficial to mention the ##META header lines for defining phenotype metadata that were introduced in the VCF v4.3 revision and to provide some examples of how they could be used. How do they fit into the existing framework of data in EVA and ENSEMBL? The ##META meta-information of the VCF 4.3 is used to define sample descriptors and not phenotypes in the sense of MIAPPE. They might be used for some of the elements listed in BioSamples checklists, such as the MIAPPE list used by the BioSamples Validator. But our approach was to include only the minimal identification metadata in the VCF (DOIs, ID lists) and rely on BioSamples for a detailed description of the sample. Regarding the ##META field: There is currently a discussion in the VCF community to remove this field completely from the specification (https://github.com/samtools/hts-specs/issues/558#issuecomment-829421610), and basically the trend is more moving towards outsourcing metadata to FAIR archives (like BioSamples). P.7, section “Sample field format”: Please include some detail on what the “registry” entails – is there a standardised way of creating/naming/referring to registries? Thanks, we clarified this point in the paper. P.9, bottom: Please provide a reference and/or URL for ELIXIR in the text here. We added a recent publication about ELIXIR to the manuscript. Figure 2 is an idealised scenario that assumes an institution has both a LIMS and a data steward. Neither is a given – this very much depends on the organisational structure and the levels of funding available to an institution. It would be helpful to have – in addition – an alternative workflow that is more realistic/flexible and describes what can be done when these resources aren’t available. Genotyping of large panels of genotypes or pan-genome projects depend on a well-structured implementation of the necessary data handling processes according to the research data life cycle to allow quality and efficiency of resources as well as to ensure the long-term assured re-usability of the data. The use of process-oriented database-based solutions starting with material and sample description, the assignment of PUIDs for sequences and material, the machine-readable data processing in sequence laboratories and the ingestion into file storage systems, their registration in in-house databases and their final publication in central repositories, such as EMBL-EBI EVA, is an important task for medium to large institutions. The definition of clear specifications for data exchange formats and APIs provides the necessary framework to allow sufficient freedom for technologies. These can range from open source to commercial solutions that are sufficiently available for the process described. A best practice paper has been referenced accordingly in the manuscript: https://doi.org/10.1093/bib/bbab010. We see our contribution to this discussion as a standardised workflow that can occur in many different variations. For example, it is indeed a problem that institutions do not have dedicated data stewards or an institution-wide LIMS, so that these sub-aspects either have to be outsourced or interim solutions have been created. In the context of this manuscript, we cannot and do not want to refer to all the possibilities for implementing good scientific practice, but rather provide a stylised best practice guide to be able to map such a workflow to one's own organisation. Figure 2: Replace pronouns like “he” with gender-neutral equivalents like “they” or use the passive voice. We changed this to gender-neutral equivalents within the manuscript. Figure 2: The header says “…submission of genotypic data to public databases” but then the legend only mentions the EVA specifically. We have changed the text in the figure header accordingly to make it clear that this workflow is intended for use with EMBL-EBI repositories."
}
]
}
] | 1
|
https://f1000research.com/articles/11-231
|
https://f1000research.com/articles/11-544/v1
|
19 May 22
|
{
"type": "Research Article",
"title": "Macroinvertebrate-based index of biotic integrity for assessing the ecological condition of Lake Wanchi, Ethiopia",
"authors": [
"Tolera Kuma",
"Girum Tamire",
"Getachew Beneberu",
"Girum Tamire",
"Getachew Beneberu"
],
"abstract": "Background: Lake Wanchi is one of the Ethiopian lakes that have huge ecological, socio-economic and aesthetic value. This study was conducted to assess the ecological condition of Lake Wanchi using the macroinvertebrate-based index of biotic integrity between September 2016 and should 2017.\nMethods: Four sampling sites (LWS 1, LWS 2, LWS 3, and LWS 4) were purposively selected. A rapid bioassessment protocol criterion was accustomed to categorize the sites. About 1249 macroinvertebrate individuals were collected using the D-frame net with a mesh size of 500µm. Physico-chemical analysis was also done to assess the link between the benthic macroinvertebrate structure and environmental factors within the system.\nResults: The benthic index of biotic integrity ranged from 12.54 to 100 and also the sites were categorized into three quality ranks: LWS 1 and 3 as fair, LWS 2 as good, and LWS 4 as very good.\n\nConclusions: The study confirmed that Lake Wanchi was largely influenced by agricultural and other anthropogenic factors. This study concluded that the benthic index of biotic integrity is an appropriate tool for water quality and ecological assessment in the lakes.",
"keywords": [
"Bioindicators",
"habitat quality",
"Lake Wanchi",
"physiochemical parameters",
"water quality"
],
"content": "Introduction\n\nLakes provide important ecosystem services to lakeside communities including water for domestic use, irrigation, etc. (Naiman and Décamps, 1997; Hood and Naiman, 2000; Raburu et al., 2009). However, most Ethiopian lakes are being threatened by anthropogenic activities such as deforestation, agriculture, urban runoff, and discharge of untreated waters from point sources (Zhang et al., 2015).\n\nPhysico-chemical analysis has been used as a water quality monitoring and ecological assessment tool for many years in many countries including Ethiopia. However, the use of biological quality elements (BQE) or indicators in monitoring and assessment studies is capturing attention as the traditional methods are quite expensive and demand well-trained expertise (Valentine et al, 2011). Biological indicators are increasingly used to assess the effect of anthropogenic activities on aquatic ecosystems. Particularly macroinvertebrates are a good indicator of several anthropogenic pressures in the aquatic ecosystem (Armitage et al., 1983; Armitage et al., 1990) as they reflect not only the quality of the water but also the ecological healthiness of the ecosystem (Rosenberg and Resh, 1993).\n\nSeveral types of research have been done so far on Ethiopian rivers concerning the use of macroinvertebrates in water quality and ecological assessment. For instance, Beneberu (2013) developed a macroinvertebrates-based multimetric index in some selected rivers of Ethiopia as indicators of environmental stress. Lakew (2015) assessed anthropogenic impacts using benthic macroinvertebrates as bio-indicators in Central Highland Streams of Ethiopia. Sitotaw (2006) used various macroinvertebrate metrics and habitat scores in the assessment of environmental degradation in some rivers of Ethiopia. However, little research has been done so far on the use of benthic macroinvertebrates in the assessment and monitoring of Ethiopian lakes (e.g. Gashaw and Mengistu, 2012).\n\nLake Wanchai is one of the Ethiopian lakes that have huge ecological, socio-economic and aesthetic value. Although pollution and environmental degradation in the lake is increasing over time, no monitoring study and management action has been undertaken in the lake. Therefore, this study was conducted to investigate the impact of several stressors on the ecology of the lake using a macroinvertebrate community structure-based index.\n\n\nMethods\n\nThis study was conducted in Lake Wanchi (Figure 1), which is found in the Oromia region, Southwest Shewa (Degefu et al., 2014). The lake is located at 8°47′N and 37°53′E at an altitude of 2887 m a. l. and 150 km Southwest of Addis Ababa, the capital city of Ethiopia. It has a surface area of 5.6 km2. The lake has a closed basin with no surface inlet (Degefu et al., 2014). Walia and Jalewan rivers are the only two outlets of the lake (Shube, 2011). The littoral zone of the lake is characterized by submerged aquatic macrophytes, mainly Potamogeton sp. (Degefu et al., 2014) and Typha latifolia (emergent aquatic plant) (Singanan et al., 2008). The lake receives water primarily from rainfall and subterranean cold and hot springs. Generally, the lake region is characterized by a sub-humid climate with an annual rainfall of 1200 mm (Degefu et al., 2014).\n\nA preliminary survey was conducted in September 2016 to gather general information on the physical characteristics of the study area such as lake features, watershed features, littoral vegetation, and human pressures. Accordingly, sites for habitat quality assessment were selected purposely based on the stressor types (distance from human settlement and anthropogenic effects) and accessibility for a quantitative study. For habitat quality assessment, four habitat plots: hab-plot “A”, hab-plot “B” hab-plot “C” and hab-plot “D”were selected following Lake Habitat Survey (LHS) (Table 4) procedure as outlined in SNIFFER (2004) and McGoff and Irvine (2009). The selected four hab-plots cover approximately 1000 m: about thirteenth of the total shoreline length of 13 km. Each hab plot covers 250 m of shoreline length. The assessment was done visually and scored through observation. The assessment was done by boat to manage the work and time. The four habitat plots are:\n\nHab-Plot”A”: This plot is located the Northwest of Lake Wanchi. It is mainly exposed to agricultural associated impacts. The site lacks vegetation coverage because of intensive deforestation.\n\nHab-Plot”B”: This site is a free grazing area and is dominated by domestic animals. Typha latifolia was the dominant macrophyte in littoral part. Little riparian vegetation existed on this site.\n\nHab-Plot”C”: This hab-plot is found in the valley parts of Lake Wanchi at which untreated wastes (improper waste dumping) from Wanchi Village flow into the lake both via runoff and a small stream that joins the lake. Densely populated submerged aquatic macrophytes (Potamogeton) and riparian vegetations cover this site.\n\nHab-Plot“D”: This hab-plot is located in the Southwest parts of Lake Wanchi. Human interference was minimum compared to the other sites. Potamogeton and Typha latifolia are common aquatic macrophytes and the riparian vegetations are also well developed.\n\nFor physicochemical and macroinvertebrates, the sampling sites were selected based on distance from human settlements, anthropogenic effect, and accessibility for a quantitative study. For macroinvertebrate sampling, four sampling sites were purposely selected following USEPA rapid bioassessment protocol criteria (Barbour et al., 1999). Sites were coded as LWS1, LWS2, LWS3, and LWS4 where, “LWS” represents Lake Wanchi Site, 1, 2, 3, and 4 respectively. The posterior classification approach (based on measured/recorded abiotic and biotic variables) was used for the selection of reference and impaired sites following the procedure outlined in Barbour et al. (1996). This approach is widely utilized as it allows the comparison of metrics response to various levels of impairments.\n\nWater samples were collected with a 1L plastic bottle from each site, labeled with a collection point, stored in an icebox before analysis, and transported to Addis Ababa University, Limnology Laboratory. Water samples were filtered through 0.45 μm glass fiber filters (GF/F) except for total phosphorous (TP). Then the concentration of Nitrate (mg-1) and phosphate (μgL-1) were measured using cadmium reduction and ascorbic acid methods respectively as outlined in APHA (1999). Dissolved oxygen, electrical conductivity, and water temperature were measured on-site using a pre-calibrated HACH multimeter hand-held probe (Model: HQ40D). The pH of the water was also measured on-site using a pre-calibrated portable pH meter (Model: HI96107).\n\nWater transparency was determined using a standard Secchi disc of 20 cm diameter with black and white quarters. The turbidity of water in all sampling sites was determined using a turbidity meter (Model: 2100P, Hach Company, USA).\n\nThe study focused d the shallow part of the lake; hence D-frame net of mesh size 500μm was used to sample macroinvertebrates. Sampling was done at monthly intervals between December 2016 to February 2017. The net was moved vigorously on the target sampling area for about five minutes to dislodge the macroinvertebrate attached to the macrophyte or sediment (Baldwin et al., 2005). Macroinvertebrates were sorted out from other debris preserved in 70% ethanol and transported to the Zoological Sciences Laboratory of Debre Berhan University (DBU), Department of Biology for identification and enumeration. Macroinvertebrates were identified at the family level using a combination of available keys (Gerber and Gabriel, 2002; Bouchard, 2012).\n\nIn the present study metrics representing richness, composition, tolerance/intolerance, functional feeding group, and diversity measures (Shannon Weiner diversity index (SDI) were screened and examined for index development of Lake Wanchai. The metric selection was performed using a stepwise process involving assessment of their variation, redundancy, and sensitivity (Chihart, 2003; Tasew, 2007). Metrics with strong correlation (r>0.80) are considered as redundant metrics and hence only one metric was retained for further assessment in the index development procedure as in Burton and Gerritsen (2003). Box-and-whisker plots, which enabled visualization of variations in the metric ranges were used to estimate the ability of metrics to discriminate between reference and impaired sites. The discriminatory power of each remaining metric was determined according to the degree of overlap of medians and interquartile ranges (Barbour et al., 1996). Metrics that displayed no overlap of interquartile ranges were considered to have good discriminatory power. Metrics with a moderate overlap of interquartile range but at least one median outside the interquartile range over was were considered to have moderate discriminatory power while metrics with an extensive overlap of interquartile range or both medians within the overlap were considered to have no discriminatory power to distinguish between reference and test sites (Barbour et al., 1996). Metrics with good and moderate discriminatory power were considered in the final index development while those with extensive quartile overlap were rejected.\n\nMetric scoring was based on a continuous scoring method (Buchanan et al., 2011). Each metric’s raw value at each sampling site was individually scored on a continuous scale (0-100) reference gradient scoring approach as outlined in Buchanan et al. (2011). Likewise, the reference gradient scoring approach uses the 5th and 95th percentile of each metric’s raw value in the reference community samples in a given region to create a linear scale. For metrics that decrease in value with disturbance, the 5th percentile of the reference was assigned a score of 0 and the 95thpercentile of the reference was assigned a score of 100. Metric values less than or equal to the 5th percentile and greater than or equal to the 95th percentile were scored 0 and 100, respectively. Metric values between the 5th percentile and 95th percentile were scored proportionally from 0 to 100 according to the equation:\n\nWhere X is the metric value (the observed metric’s raw value: could beat impaired or reference site), X95 is the 95th percentile value, and X5 is the 5thpercentile value. The reverse was done for metrics that increase with disturbance. Metric values less than or equal to the 5th percentile of the reference are given a score of 100, values greater than or equal to the 95th percentile of the reference was scored 0, and values between the 5th percentile and 95th percentiles are scored proportionally according to the equation:\n\nFinally, the sum of all core metrics scores at each sample site was averaged by the number of total metrics used for index development to obtain a final index or B-IBI score of Lake Wanchi. Recall! 95th percentile or X95 in the numerator was calculated from the metric value (the observed metric’s raw value) of each site for the metrics that decrease in value with disturbance, but the 95th percentile or X95 in the numerator was calculated from the metric’s raw value of the recorded at reference site for the metrics that increase in value with disturbance. 95th percentile or X95 and 5th percentile or X5 in the denominator part was calculated from the observed metric’s raw value of the reference site; it was calculated using the observed metric’s raw value of LWS 4 in this case. Although there was no ideal health ecosystem, the reference site has better robustness and was given a score of 1000 relatively for comparison purposes. He is an example of how to calculate BIBI for LWS 1.\n\nHabitat features guided by photographs and descriptions were scored according to Lake Habitat Survey (LHS) score per hab-plot for lake Wanchi (SNIFFER, 2004; McGoff and Irvine, 2009) (Table 4). This assessment was done for validation of the response of the macroinvertebrate-based index of biotic integrity.\n\nThe habitat features were quantitatively assessed and explained numerically in percentage as in SNIFFER (2004) and McGoff and Irvine (2009). The diversity index, evenness was assessed using Shannon and Wiener (1949) and Pielou (1966), respectively. Redundancy analysis (RDA) was used to investigate the relationship between macroinvertebrates and environmental variables. The response of metrics to water quality parameters was analyzed using the Mann-Whitney U test. The sensitivity of the multimetric index was determined by assessing whether there was clear discrimination among the classified site group using box-and-whisker plots. Pearson’s correlation analysis was also used to identify relationships between the index scores and environmental variables. Descriptive statistics were used to analyze biological data. The statistical software (SPSS version 20) was used for the statistical analysis.\n\n\nResults\n\nIn most cases, there was variation in the concentration of measured environmental variables between impacted and less impacted sites (Table 1). The value ranged between 4.74×10-2-13.8(±0.1) × 10-2mg L-1 for ammonia (NH3-), 0.136-0.141mg L-1for nitrates (NO3-) and 1.62×10-2-1.65 × 10-2 mg L-1 for ammonia (NH3-). The mean value for soluble reactive phosphorous (PO43-) and total phosphorous (TP) varied from 2.25 × 10-3-2.38 × 10-3 μgL-1 and 1.91 × 10-3-3.55 × 10-3 μgL-1, respectively. The minimum and maximum mean values were 54(±13) cm and 84(±10) cm for Secchi depth reading, respectively. 1.07 NTU and 2.37 NTU for turbidity, 22.5(±0.3)°C and 23.5(±0.5)°C for temperature, 7.20 and 8.70(±0.09) for pH, 6.95(±0.03) and 7.95(±0.02) mgL-1 for dissolved oxygen (DO), 54.40(±0.205) μS/cm and 55.40(±0.3) μS/cm for conductivity. The mean value varied among sites although there was no significant difference (p < 0.05) (Table 1).\n\nA total of 1249 macroinvertebrate individuals representing 15 families were identified in the present study. Three taxa comprised the non-insect group (Hydrobiidae, Physidae, and Planorbidae), and the rest 12 taxa represented insect families. The reference site was rich in taxa (15), while the most impaired site was represented by only 5 taxa. Low Shannon diversity index was recorded at LWS3 (H′=1.08) (Table 2).\n\nAmong the candidate, metrics tested five metrics (number of Ephemeroptera taxa, number of Trichoptera taxa, % Ephemeroptera, % Trichoptera and SDI) were excluded mainly because they had comparatively low values. The metrics that were eliminated for failing to distinguish between reference site and impaired sites were: Odonata individual taxa, % Tolerant taxa, and % Scraper taxa. The % ETO was retained because this metric was frequently used in index development. The % Hemiptera taxa and % to taxa were redundant with each other and hence only percent of Hemiptera taxa were retained. The % Scrapers taxa were redundant with no, families. The number of families was retained as it is frequently used in index development.\n\nWe also included % of Scraper as the metric distinguished very well reference sites from that of moderate. Metrics such as no. families, % Scraper, and % Gatherers displayed no overlap of interquartile ranges and hence considered to have good discriminatory power for identifying reference sites from impaired. ETO individual and % Hemipera showed moderate overlap of interquartile range but had at least one median outside the interquartile range overlap and hence were considered to have moderate discriminatory power. The following metrics (No. Families, ETO individuals, % Hemiptera, % Scraper, s and % Gatherers.) were considered as core metrics and used for final BIBI development. The line between good and fair was taken from the quartile section of the 75th percentile of the reference site (LWS 4) (3/4 × 100 = 75). The 25th percentile of the reference site (1/4 × 100 = 25). The BIBI scores ranging from 25 to 75 were classified as good whereas, scores that are greater or equal to75.55 were categorized as very good. Scores less than the 25th percentile of the reference site (1/4 × 100 = 25) were classified as fair (Table 3).\n\nThe first axis of PCA expressed 97.8% of the faunal variation whereas the second axis explained 92.5% of the variation. The result of RDA indicated a strong relationship between macroinvertebrate metrics and environmental variables. The first axis of RDA is positively correlated with turbidity, phosphorous, and total phosphorous. However, the following taxa (Baetidae, Corixidae, Scirtidae, Pyralidae, and Hydrobiidae) were negatively correlated with turbidity and phosphorous. The Notonectidae and Physidae taxa were positively correlated with turbidity and phosphorous (Figure 2).\n\nAbbreviations: Gom = Gomphidae, Pro = Protoneuridae, Noto = Notonectidae, Baetid = Baetidae, Chiro = Chironomidae, Corix = Corixidae, Cerato = Ceratopogonidae, Calopt = Calopterygidae, Coccin = Coccinellidae, Rhyaco = Rhyacopilidae, Scirt = Scirtidae, Pyra = Pyralidae, Phys = Physidae, Hydro = Hdrobiidae, Planor = Planorbidae, pH = Hydrogen ion, DO = dissolved oxygen, EC = electric conductivity, NH3- = ionized ammonia, NO3- = nitrate ion NO2- = nitrite ion, PO43- = phosphate ion, Tp = total phosphorus, TSS = total suspended solid, TDS = total dissolved solid, Sec = Secchi depth, Temp = Temperature, Turb = Turbidity. Different colors were required to identify macroinvertebrate families and environmental variables.\n\nThe watershed of Lake Wanchi was highly exposed to various levels of degradation. The riparian vegetation removal was more intensive in hab-plot “A” compared to the other hab-plots in the region of Lake Wanchi (Table 4). The result of the comparability habitat assessment and the developed index classified sites into three water quality: fair, good, and very good. Various activities have been observed on the sites such as riparian vegetation clearance, nutrients inlet through flooding, loss of physical habitat structure, and changes in littoral cover, commonly associated with lakeshore. These anthropogenic activities, therefore, affect the distribution and diversity of macroinvertebrates.\n\n\nDiscussion\n\nOne way to assess the water quality of the aquatic ecosystem is by measuring the conventional environmental variables. The measured environmental variables of Lake Wanchi were within the optimum range for the growth and survival of aquatic life in the tropics (Mugo, 2010; Katsallah, 2012; Godswill, 2012). However, Secchi depth showed a dramatic change from 54(±13) cm at LWS1 to 84(±10) cm at LWS 4. The turbidity at site LWS1 was comparable with that of Lake Naivasha (Mugo, 2010). The relatively high turbidity at site LWS 1 might be due to siltation from the catchment as the watershed is highly degraded.\n\nBiological monitoring based on various aquatic biotas may be more effective than measuring water chemistry alone because the organisms integrate the chemical and physical properties of streams over time, which could be overlooked by one-time water chemistry sampling. In the present study 1249, macroinvertebrate individuals representing 15 families were recorded. Three taxa (Gastropod Families; Hydrobiidae, Physidae, and Planorbidae) accounted for the non-insects whereas the rest 12 taxa were represented by insect families. Alpha diversity was higher (13 taxa) at the reference site (LWS4) compared to the impaired site with only 5 taxa (Table 2). This study found different compositions, distribution, and assemblage of macroinvertebrate taxa between reference and impaired sites. This might be due to the influence of physicochemical parameters. A study on the relationship between environmental factors and macroinvertebrates suggested that community composition depends on environmental factors related to habitat, water chemistry, resource partitioning, and predation (Dall et al., 1984; White and Irvine, 2003; Olomukoro and Oviojie, 2015). Usman (2015) also found that particulate matter in fresh or marine waters causes siltation and smothering of benthos and interference with the feeding of bivalve filter feeders.\n\nThe family Planorbidae was the most abundant taxa throughout the study period. This may be due to their tolerance toward pollution or substrates. This observation is in line with the work of Strong et al. (2008) who stated that Planorbidae has a secondary gill (pseudobranch) and efficient respiratory pigment (hemoglobin) enabling the taxa to exploit oxygen-depleted environments.\n\nAs a higher number of family taxa (richness) was recorded at site LWS 4, the Shannon diversity index was expected to be higher. But that was not the case compared to LWS 1 and LWS 2 sites. The presence of relatively well-structured riparian vegetation at the less impacted site could harbor predators, particularly arthropods which are potential predators to aquatic macroinvertebrates. This can affect the abundance as well as the index value as the index takes into account both richness and evenness (Shannon and Weiner, 1949) For instance Burdon and Harding (2008) found a strong negative correlation between riparian arthropod predators and aquatic insects. Similarly, Strayer and Findlay (2010) observed that the terrestrial side of the shore zone often contains large numbers of predators that feed on emerging aquatic insects and aquatic predators affect the distribution, abundance, and behavior of their prey. The correlation between measured environmental variables and metrics was not consistent. This might be because of the variability of the environmental variables among sites. A similar finding was presented by Yorulmaz et al. (2013) in the Esen River in Turkey where metrics differentially respond to biotic and abiotic factors.\n\nThe riparian vegetation removal was more intensive in hab-plot “A” compared to the other hab-plots in Lake Wanchi (Table 4). The percentage comparability habitat assessment and index of biotic integrity categorized sites into three quality ranks: LWS 1 as fair, LWS 2 and 3 as good, and LWS 4 as very good. Various activities have been observed on the sites such as riparian vegetation clearance, nutrients inlet through flooding, loss of physical habitat structure, and changes in littoral cover, commonly associated with lakeshore. These anthropogenic activities could affect the distribution and diversity of macroinvertebrates which in turn influence the total score. This observation agrees with Degefu et al. (2014) who stated that Lake Wanchi was becoming a tourist destination, with a corresponding increase in newly erected resorts and tourist facilities which remove riparian communities and make aquatic biodiversity vulnerable. Hampton et al. (2011) also indicated that the rapid response of nearshore habitats could serve as an early warning signal before deteriorations in water quality happen. The current study also revealed that less density and abundance of macrobenthic fauna were found at site LWS 1. This was in agreement with Kaufmann et al. (2014) who reported reductions in physical habitat structural complexity can deleteriously affect aquatic macroinvertebrates.\n\n\nConclusion\n\nLake Wanchi has started to show signs of degradation and water quality deterioration due to ongoing human activities and a lack of appropriate management. The biological assessment also depicted the presence of anthropogenic impacts in the lake. A total of 1249 benthic macroinvertebrate individuals representing 15 families were recorded in this study. This work demonstrated that the composition and distribution of the macroinvertebrate community varied depending on physicochemical parameters along a gradient of human pressure. It was observed that the responses of macroinvertebrate communities were good indicators for assessing ecosystem integrity. The value of the benthic index of biotic integrity separated the sites into three quality ranks according to the levels of human exposure. The study, therefore, provided information on macroinvertebrates community-based assessment and set a basis for a lake water quality monitoring framework that can inform managers and other decision-makers at the local and national levels on taking integrated ameliorative and preventive measures so that the lake is used sustainably. The authors recommend identification of the taxa to the lower level and further study is needed to understand the seasonal effects on the distribution and abundance of macroinvertebrates.\n\n\nAuthors' contributions\n\nAll of these authors were working in collaboration during data collection, analysis, and manuscript writing; even now during submission of this manuscript, the cooperation is going on.\n\n\nData availability\n\nFigshare. Macroinvertebrate-based index of biotic integrity for assessing the ecological condition of Lake Wanchi, Ethiopia. DOI: https://doi.org/10.6084/m9.figshare.19503709.v2 (Kuma et al., 2022)\n\nThis project contains the following underlying data:\n\n- Lake Wanchi is one of the Ethiopian lakes that have huge ecological, socio-economic and aesthetic value. Although pollution and environmental degradation within the lake is increasing over time, monitoring and management actions have not been undertaken within the lake. This study was conducted to assess the ecological condition of Lake Wanchi using the macroinvertebrate-based index of biotic integrity between September 2016 and should 2017. Four sampling sites (LWS 1, LWS 2, LWS 3, and LWS 4) were purposively selected. A rapid bioassessment protocol criterion was accustomed to categorize the sites. About 1249 macroinvertebrate individuals were collected using the D-frame net with a mesh size of 500μm. Physico-chemical analysis was also done to assess the link between the benthic macroinvertebrate structure and environmental factors within the system. The benthic index of biotic integrity ranged from 37.78 to 75.55 and also the sites were categorized into three quality ranks: LWS 1 as and 3 fair, LWS 2 as good, and LWS 4 as very good. The study confirmed that Lake Wanchi was largely influenced by agricultural and other anthropogenic factors. This study concluded that the benthic index of biotic integrity is an appropriate tool for water quality and ecological assessment in the lakes.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nAbove all our gratitude go to the Almighty God, who is helping us in every aspect of our life. We Debre Birhan University for allowing us and facilitating the condition to conduct this research. Mr. Kasahun Tesema deserved a special thank for his technical assistance during laboratory analysis and Mr. Samson Workaye for his valuable assistance in preparing a map of the study area. We would also like to extend our appreciation to Wanchi Ecotourism Office for their permission to conduct this research work in Lake Wanchi.\n\n\nReferences\n\nArmitage PD, Moss D, Wright JF, et al.: The performance of a new biological water quality score system based on macroinvertebrates over a wide range of unpolluted running-water sites. Water Res. 1983; 17: 333–347. Publisher Full Text\n\nArmitage PD, Pardo, Furse MT, et al.: Assessment and prediction of biological quality. A demonstration of a British macroinvertebrate-based method in two Spanish Rivers. Limnetic. 1990; 6: 147–156. Publisher Full Text\n\nAbolude DS, Chia AM, Yahaya AS, et al.: Phytoplankton Diversity and abundance as a function of Water Quality for Fish Production: a case study of two Manmade Reservoirs in Zaria Nigeria. Trop. Freshw. Biol. 2012; 21(2): 41–48.\n\nAkalu S: Assessing the biological integrity of the greatAkaki river using macroinvertebrates. M.Sc. thesis, Addis Ababa University.2006.\n\nAmerican Public Health Association (APHA): Standard Methods for the Examination of Water and Waste Water. 20th ed.New York, NY: American Public Health Association; 1999.\n\nBaldwin DS, Nielsen DL, Bowen PM, et al.: Recommended Methods for Monitoring Floodplains and Wetlands. MDBC Publication No. 72/04. Canberra, Australia: Murray Darl ing Basin Commission; 2005.\n\nBarbour MT, Gerritsen J, Griffith GE, et al.: A framework for biological criteria for Florida streams using benthic macroinvertebrates. J. N. Am. Benthol. Soc. 1996; 15: 185–211. Publisher Full Text\n\nBarbour MT, Gerritsen J, Snyder BD, et al.: Rapid Bioassessment Protocols for Use in Streams and Wadeable Rivers: Periphyton, Benthic Macroinvertebrates, and Fish. Second ed.Washington, DC: United State Environmental Protection Agency, Office of Water; 1999; 185–211.\n\nBeneberu G: The family Chironomidae (Insecta: Diptera) as indicators of environmental stress and macro-invertebrate-based multimetric index development in some selected rivers in Ethiopia.2013.\n\nBerhe T: The degradation of the Abo- Kebena River in Addis Ababa, Ethiopia. M.Sc. thesis, Addis Ababa University.1988.\n\nBlocksom KA: Performance comparison of metric scoring methods for a multimetric Index for Mid-Atlantic Highlands Streams. Environ. Manag. 2003; 31(5): 670–682. PubMed Abstract | Publisher Full Text\n\nBode RW, Novak MA, Abele LE: Quality Assurance Work Plan for Biological Stream Monitoring in New York State. Albany, NY: NYS Department of Environmental Conservation; 1996; 89.\n\nBouchard RW: Guide To Aquatic Invertebrate Families of Mongolia: Identification Manual for Students, Citizen Monitors, and Aquatic Resource Professionals.2012. Reference Source\n\nBuchanan C, Foreman K, Johnson J, et al.: Development of a Basin-wide Benthic Index of Biotic Integrity for Non-tidal Streams and Wadeable Rivers in the Chesapeake Bay Watershed: Final Report to the Chesapeake Bay Program Non-Tidal Water Quality Workgroup.2011.\n\nBurton J, Gerritsen J: A Stream Condition Index for Virginia Non-Coastal Streams. Benthic Index for Virginia. Richmond, VA: Virginia Department of Environmental Quality; 2003.\n\nBurdon FJ, Harding JS: The linkage between riparian predators and aquatic insects across a stream-resource spectrum. School of Biological Sciences, University of Canterbury, Christchurch, New Zealand. Freshw. Biol. 2008; 53: 330–346.\n\nChihart J: Development of a Macroinvertebrate Index of Biological Integrity (MIBI) for Rivers and Streams of the St. Croix River Basin in Minnesota. Minnesota: MinnesotaPollution Control Agency Biological Monitoring Program; 2003; 41.\n\nDall PC, Lindegaard C, Jonsson E, et al.: Invertebrate communities and their environment in the exposed littoral zone of Lake Esrom. Arch.Hydrobiol. 1984; 69: 477–524.\n\nDegefu F, Herzig A, Jirsa F, et al.: First limnological records of threatened tropical high-mountain crater lakes in Ethiopia. Tropical Conservation Sciences. 2014; 7(3): 365–381. Publisher Full Text Reference Source [22 September2014]\n\nFurey CP, Nordin NR, Mazmuder A: Littoral benthic macroinvertebrates under contrasting drawdown in a reservoir and a natural lake. Journal of North American Benthology Society. 2006; 25(1): 19–31. Publisher Full Text\n\nGashaw H, Mengistu S: Ecological Assessment of Lake Hora, Ethiopia, Using Benthic and Weed-bed Fauna. Momona Ethiopian. Journal of Science (MEJS). 2012; 4(2): 3–15. Publisher Full Text\n\nGerber A, Gabriel MJM: Aquatic Invertebrates of South African Rivers Field Guide, First edition February 2002. Institute for Water Quality Studies Department of Water Affairs and Forestry; 2002; 15–78.\n\nGerritsen J, Carlson RE, Dycus DL, et al.: Lake and Reservoir Bioassessment and Biocriteria. Technical Guidance Document.US environmental Protection Agency. EPA 841-B-98-007. 10 Chapters, Appendices A-G.1998. Reference Source\n\nGezie A, Anteneh W, Dejen E, et al.: Effects of human-induced environmental changes on benthic macroinvertebrate assemblages of wetlands in Lake Tana Watershed, Northwest Ethiopia.2017.\n\nGodswill AC: Crustacean Ecology in Opi Lake, Nigeria. M.Sc. The project, University of Nigeria, Nsukka.2012.\n\nHampton SE, Fradkin SC, Peter R, et al.: Disproportionate importance of nearshore habitat for the food web of a deep oligotrophic lake. Marine and fresh Freshwater Resource. 2011; 62: 350–358. Publisher Full Text\n\nHood WG, Naiman RJ: Vulnerability of riparian zones to invasion by exotic vascular plants. Plant Ecol. 2000; 148(1): 105–114. Kluwer Academic Publishers. Publisher Full Text\n\nJhingran VG, Ahmad SM, Singh AK: Application of Shannon-Wiener index as a measure of pollution of river Ganga at Patna, Bihar. Indian J. Behav. Sci 1989; 58,717–720.\n\nKaaya LT: Biological Assessment of Tropical Riverine Systems Using Aquatic Macroinvertebrates in Tanzania, East Africa. Ph.D. Dissertation, University of Cape Town.2014.\n\nKatsallah GMI: Distribution and Taxonomy of Molluscs (Mollusca) in Some Parts of Northern Nigeria. Ahmadu Bello University; 2012.\n\nKaufmann PR, Peck DV, Paulsen SG, et al.: Lakeshore and littoral physical habitat structure in a national lakes assessment. Lake Reserv. Manag. 2014; 30(2): 192–215. [02 May 2014]. Publisher Full Text Reference Source\n\nKuma T, Tamire G, Beneberu G: Macroinvertebrate-based index of biotic integrity for assessing the ecological condition of Lake Wanchi, Ethiopia. data citation.docx [August 2019].2019.\n\nKuma T, Tamire G, Beneberu G: Macroinvertebrate-based index of biotic integrity for assessing the ecological condition of Lake Wanchi, Ethiopia. figshare.2022. Online resource. Publisher Full Text\n\nLakew A: Assessing anthropogenic impacts using benthic macroinvertebrates as Bio-indicators in Central Highland Streams of Ethiopia. Ethiopian Journal of Environmental Study and Management. 2015; 8(1): 45–56. [Accessed 21 June 2016]. Publisher Full Text Reference Source\n\nLeps J, Smilauer P: Multivariate Analysis of Ecological Data. Ceske Budejovice, Czech: University of South Bohemia; 1999.\n\nMandaville SM: Benthic Macroinvertebrates in Freshwaters-Taxa Tolerance Values, Metrics, and Protocols. Research Scientist III, Division of Water report. New York State Department of Environmental Conservation; 2002.\n\nMcGoff E, Kenneth Irvine K: A test of the association between Lake Habitat Quality Assessment and macroinvertebrates community structure. Aquatic Conservation: Marine and Freshwater Ecosystems. Aquat. Conserv. Mar. Freshwat. Ecosyst. 2009; 19: 520–533. Publisher Full Text\n\nMugo MJ: Seasonal Changes in Physicochemical Status and algal Biomass of Lake Naivasha. M.Sc. thesis, Kenyatta University.2010.\n\nNaiman JR, Décamps H: The Ecology of Interfaces: Riparian Zones Annual Review of Ecology and Systematics.1997; 28: 621–658. [November 1997]. Publisher Full Text\n\nNilsson C, Berggren K: Alterations of riparian ecosystems caused by river regulation. Bioscience. 2000; 50(9): 783–792. Publisher Full Text\n\nOgbeibu AE, Oribhabor BJ: Ecological impact of stream regulation using benthic Macroinvertebrate as bioindicators. J. Aquat. Sci. 2001; 16(2): 132–138.\n\nOlomukoro JO, Oviojie EO: Diversity and Distribution of Benthic macroinvertebrate fauna of Obazuwa Lake in Benin City, Nigeria. Journal of Biology, Agriculture and Health care. 2015; 5(1): 2224–3208.\n\nPielou EC: The measurement of diversity in different types of biological collections. J. Theor. Biol. 1966; 10: 370–383. PubMed Abstract | Publisher Full Text\n\nPond GJ, Call SM, Brumley JF, et al.: The Kentucky Macro invertebrate Bioassessment Index: Derivation of Regional Narrative Ratings for Assessing Wadeable and Headwater Streams. Frankfort: Kentucky Department for Environmental Protection; 2003; 46.\n\nRaburu PO, Okeyo-Owuor JB, Masese FO: Macroinvertebrate-based Index of integrity (M-IBI) for monitoring the Nyando River, Lake Victoria Basin, Kenya. Sciences and Research Essay. 2009; 4(12): 468–1477. Reference Source\n\nRosenberg DM, Resh VH: Introduction to freshwater biomonitoring and benthic macroinvertebrate. Freshwater biomonitoring and benthic macroinvertebrates. Rosenberg DM, Resh VH, editors. New York, London: Chapman and Hall; 1993; pp 1–9.\n\nScotland and Northern Ireland Forum for Environmental Research (SNIFFER): Development of a Technique for Lake Habitat Survey (LHS): Phase 1, Final Report Project WFD40.2004.\n\nShannon CE, Weiner W: The Mathematical Theory of Communication. Urbana, IL: The University of Illinois Press; 1949.\n\nShube H: Carbon dioxide-water-rock interaction and hydrogeochemical evolution of thermal and cold groundwaters in Wonchi Crater Lake and Ambo-Woliso area. M.Sc. thesis, Addis Ababa University.2011.\n\nSinganan M, Wondimu L, Tesso M: Water quality of Wenchi Crater Lake in Ethiopia. Mj. Int. J. Sci. Tech. 2008; 2(2): 361–373. [Accessed 13 June 2008]. Reference Source\n\nSitotaw B: Assessment of benthic-macroinvertebrates structures to environmental degradation in some Ethiopian Rivers. M.Sc. Thesis, Addis Ababa University, Ethiopia.2006.\n\nSmol PJ: Pollution of Lakes and Rivers: A Paleoenvironmental Perspective. Second ed.Blackwell Publishing; 2009.\n\nStrayer DL, Findlay SEG: Ecology of freshwater shore zones. Aquat. Sci. 2010; 72: 127–163. [9 February 2010]. Publisher Full Text Reference Source\n\nStrong EE, Gargominy O, Ponder WF, et al.: Global diversity of Gastropods in freshwater. Freshwater animal diversity assessment. Hydrobiologia. 2008; 595: 149–166. Publisher Full Text\n\nStribling JB, Jessup BK, Gerritsen J: Development of Biological and Habitat Criteria for Wyoming Streams and Their Use in the TMDL Process. Prepared by Tetra Tech, Inc., Owings Mills, MD, for U.S. EPA, Region 8, Denver, CO.1999.\n\nTakhelmayum K, Gupta S: Distribution of aquatic insects in phumdis (floating island) of Loktak Lake, Manipur, and northeastern India. Threatened Taxa. 2011; 3: 1856–1861. Publisher Full Text\n\nTasew A: Assessment of biological integrity using Physico-chemical parameters and macroinvertebrate community index along Sebeta River, Ethiopia. MSc. Thesis, Addis Ababa University.2007.\n\nUnited Nations Environment Program Global Environment Monitoring System (UNEP GEMS): Water Quality for Ecosystem and Human Health. Second ed.GEMS/Water; 2008; 23–38.\n\nUsman A: Determination of Physico-Chemical Parameters and Plankton Composition of Wawan -Rafi Lake in Kazaure, Nigeria.B.Sc. Thesis, (ED), Ahmadu Bello University, Zaria, Nigeria.2015.\n\nValentina SS, Momir P, Branko M, et al.: Water Quality Assessment Based on the Macroinvertebrate Fauna-the Pcinja River Case Study. Water Resour. Manag. 2011; 1: 63–69.\n\nWhite J, Irvine K: The use of littoral microhabitats and their macroinvertebrates assemblages in the ecological assessment of lakes. Aquat. Conserv. 2003; 13: 331–351. Publisher Full Text\n\nYorulmaz B, Sukatar A, Murat Barlas M: Comparative analysis of biotic indices for evaluation of water quality of Esen river in South-West Anatolia, Turkey. International Syposium on Ecology and Environmental Problems (ISEEP2013), December 18-21, 2013, Antalya, Turkey.2013.\n\nZhang WS, Swaney DP, Li XY, et al.: Anthropogenic point-source and non-point-source nitrogen inputs into Huai River basin and their impacts on riverine ammonia-nitrogen flux. Biogeosciences. 2015; 12: 4275–4289. Publisher Full Text"
}
|
[
{
"id": "201394",
"date": "12 Sep 2023",
"name": "Marcus W Beck",
"expertise": [
"Reviewer Expertise water quality assessment",
"statistical analysis",
"indicator development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article describes the development and validation of a macroinvertebrate-based IBI for Lake Wanchi in Ethiopia. The authors use a standard approach to sampling, index development, and validation that follows decades of research on the topic. The approach is also geographically limited and is concerned with comparing biotic integrity between locations within the lake, as compared to a more regional inter-lake comparison. Considering there is likely very little research in this area that can be of practical use to regional managers, this study will have value for developing an ecological baseline and understanding factors that are impacting the lake. Therefore, this study has merit for publishing, although I encourage the authors to describe this work more carefully in a national or international context (see general comments below). This will increase the relevance for a broader readership outside of Ethiopia.\nGeneral comments:\n\nMost of my comments regard clarification on specific topics or methods introduced in the manuscript. First, why did the authors choose to evaluate macroinvertebrates relative to other biological indicators? There is nothing wrong with using macroinvertebrates, but some justification and discussion relative to other biota could be included. What about the potential use of aquatic macrophytes or fish? What are the tradeoffs associated with these different indicators and why did the authors specifically choose macroinvertebrates?\n\nThe authors could also provide some information about the regulatory or management context for surface waters in Ethiopia. Are there laws that define relevant water quality standards for surface waters? How will the information from the BIBI be used to help manage the environmental integrity of Lake Wanchi? These details are important for international readers that know nothing about Ethiopia water quality management and likely will want to know how it compares to other regions with more well-known approaches.\nFinally, I’m wondering if the authors could make their data available in a public repository for use by others. The content of the manuscript is available on figshare, yet actual biological and environmental data may be useful for others that wish to replicate the analyses herein or to use these data for comparison to other regions.\n\nSpecific comments:\n\nAbstract, background, final sentence: Change to “…between September 2016 and 2017.”\nIntroduction:\n2nd paragraph: Change sentence to “Biological indicators are commonly used…”. These approaches have been used for decades.\nFinal paragraph: Fix spelling of Lake Wanchi.\nMethods:\nSite description: Could the authors provide some more information about the watershed of the lake? What type of land use/land cover is present? How big is the watershed relative to the lake area? What is the geological history of the lake?\nSampling sites selection, first paragraph: The authors could describe the goals of the habitat quality assessment in more detail. I gather the data are meant for comparison/validation with the macroinvertebrate results, but this should be explicitly stated. Also, Table 4 is cited here but it is not the first sequential table in the manuscript. Consider omitting the citation or rearranging the table order.\nHab-Plot “C” description: The authors note here that a small stream joins the lake near this habitat plot, yet the previous site description states that the lake has no surface inlets. Which is correct?\nFigure 1: The site and habitat acronyms in the legend should be explained in the figure caption, e.g., LWS: Lake Wanchi site, etc.\nEnvironmental variables: What hour of the day were the samples and measurements taken? For example, dissolved oxygen can vary substantially depending on the time of day. Similarly, at what depth were these samples and measurements taken? At the surface?\n\nMacroinvertebrates sampling: Fix the typo in the first sentence “The study focused on the shallow…”\nMetrics selection: First sentence, can the authors explicitly state how many metrics were evaluated? For example, there are several types of metrics that could be used to describe species composition. Also, please fix the typo in the second to last sentence of the first paragraph “…at least one median outside the interquartile range were considered…”\nMetric scoring and index development: It’s unclear what is meant by the recorded and reference values. Is this a typo or could the authors explain more clearly?\n\nSecond to last paragraph, typos: “…the observed metric’s raw value could exceed impaired or reference site values…”\nFinal paragraph typo: “Recall!” What does this mean? Second to last sentence, typo “1000”. Also, the final sentence indicates there should be an example of how to calculate the BIBI but none is provided.\nData analysis, final sentence: The authors state that descriptive statistics were used to analyze the biological data. Could the authors explain this more clearly with the specific statistics that were used?\n\nResults:\nEnvironmental variables: What were the laboratory detection limits for the water quality measurements? Many of these values are incredibly low (e.g., for TP).\nSelection of core metrics and index development: Please correct some typos in the first paragraph, e.g., is “% to taxa” % tolerant taxa, is “no, family” number of families?\nSecond paragraph: The authors state that the division between fair, good, and very good was based on percentile, i.e., 25th and 75th percentile, but it seems like the division is simply based on the BIBI scores of 25 and 75. Are these actually percentiles based on the distribution of the scores?\nMultivariate: The variation explained for the PCA axes seems to be the reported cumulative variance, not the individual explained variance of each axis.\n\nTable 1: The table reports the means and standard deviations for the water quality parameters. Can the authors also report the sample sizes?\nFigure 2: Some of the environmental variables are not colored red, i.e., Secchi and turbidity.\n\nDiscussion:\nSecond paragraph, fix typo: “In the present study, 1249 macroinvertebrate…”\nConclusion: It would be good to include a more detailed description of the planned future work beyond the final sentence of this section. Is there a plan for additional monitoring to assess changes over time? What about the evaluation of additional biological indicators? What are some appropriate management actions for degraded locations? A discussion of the limitations of this work may also be helpful. For example, how indicative is the BIBI of the overall biotic integrity of Lake Wanchi?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "301539",
"date": "14 Aug 2024",
"name": "Kassahun Tesema",
"expertise": [
"Reviewer Expertise"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe study gives essential and interesting data on lake monitoring based on macroinvertebrate index development as well as information on the lakes' physicochemical parameters. The methodologies utilized are appropriate; nonetheless, the writers did not always follow scientifically established procedures, such as MMI development. In addition, the authors did not use figures to visualize their data. Aside from the minor problem mentioned above, some major concerns will be detailed below. I recommend that the manuscript be indexed once all comments have been addressed.\nSpecific comments Title\n\nThe name of the Lake should be written as Lake Wonchi\n\nAbstract section Authors need to check the following points from the abstract section:-\nBetween September 2016 and 2017 remove the word should In the method of the abstract avoid reporting the result about the collected macroinvertebrate\n\nof 1229 and take to the result part. Remove abbreviation in the abstract of method and result part (LWs1, LWS2, LWS3, and LWS4) Mention the core metrics selected and how they were selected in the result part of the abstract. Some of key words started in capital letter and some in small, start in capital in all.\nIntroduction section Authors need to look the following points from the introduction section\nThe introduction focused on macroinvertebrate community and physico-chemical variables. Need to rewrite including the existing global and national evidences on MMI which is the objective of the study. Check wrongly sited paper like Beneberu 2013 which is not for macroinvertebrate based multimetric index. Methodology section Macroinvertebrate sampling was done from Dec 2016 to Feburary 2017 different from the abstract section which is sept 2016 to 2017 (Page 4 paragraph 5) Change the word “He” in to It (page 5 paragraph 5) Based on what criteria do you select RDA than PCA? (Pag 16 par 2) On the result part it is reported as a PCA result in the first paragraph but again it also reported as RDA which one is correct. Please this is series condition in which the statistical analysis is reported (pg. 16 paragraph 7).\nResults\nSelection of core metrics and index development line 4 the % ETO was retained because this metrics frequently used in index development and similarly line 7 of the same paragraph describes frequently used in index development need to be corrected based on criteria’s not for frequently used. (Page 6 paragraph 5). Show how sites categorized very well, moderate and etc. (Page 6 paragraph 6 line one).\nIn the result section of developments of multimeric index of L.Wonchi Authors need to look the following comments seriously. List and define potential metrics\n\nCalculate their values in reference and impacted sites Make Mann-whitney U test as listed in the methods page 6 par 2 line 4 Select significant metrics/ candidate based on criteria and need to show. Put box and whisker plots at the result section for each as listed in the methodology part pg. 6 par 2. Put sensitivity values Show the selection of core metrics based on (sensitivity score of 2 and 3, and 5) from metric catagories. Need to do redundancy/ correlation analysis between core metrics and remove the redundancy Show how they Select MMI (that have lower values) Show the transformation of core metrics in to MMI Determine the ecological quality classes between very poor and very good condition following the above.\n\nDiscussion\n\nMore focused on Macroinvertebrate community (Assemblage), physicochemical variables and habitat assessment than MMI.\nConclusion\n\nThe conclusion focuses on macroinvertebrate community, so authors need to include the MMI. Based on MMI result authors need to show a clear demarcation between reference and impacted sites. References Authors need to remove Beneberu G 2013 from the text and reference sites because not proper reference to MMI Authors need to add publisher on the reference section e.g. Bouchard Rw at reference section\n\nGeneral Comment If the authors focus on the given comment of MMI it is better to continue as it is, or else I would like to recommend to change the title to:- Application of macroinvertebrate-based metrics and indices of biotic integrity for assessing the ecological condition of Lake Wonchi, Ethiopia.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-544
|
https://f1000research.com/articles/11-543/v1
|
19 May 22
|
{
"type": "Systematic Review",
"title": "High-dose vs low-dose steroid in pregnancy patients with systemic lupus erythematosus and lupus nephritis: A systematic review and meta-analysis",
"authors": [
"Mochammad Thaha",
"Mochamad Yusuf Alsagaff",
"Satriyo Dwi Suryantoro",
"Mutiara Rizky Hayati",
"Hendri Susilo",
"Alfian Nur Rosyid",
"Tri Pudy Asmarawati",
"Emil Prabowo",
"Ibrahim Syamsuri",
"Rais Hakim",
"Muhammad Ilham Aldika Akbar",
"Cahyo Wibisono Nugroho",
"Yusuke Suzuki",
"Mochamad Yusuf Alsagaff",
"Satriyo Dwi Suryantoro",
"Mutiara Rizky Hayati",
"Hendri Susilo",
"Alfian Nur Rosyid",
"Tri Pudy Asmarawati",
"Emil Prabowo",
"Ibrahim Syamsuri",
"Rais Hakim",
"Muhammad Ilham Aldika Akbar",
"Cahyo Wibisono Nugroho",
"Yusuke Suzuki"
],
"abstract": "Background: Management of systemic lupus erythematosus (SLE) and lupus nephritis (LN) in pregnancy has been improving in recent decades. However, SLE can still lead to adverse pregnancy outcomes if not appropriately treated. Optimal dose of steroids, as one of the most commonly used for the treatment of SLE and LN in pregnancy is still a subject of debate. In this review, we determine the pregnancy outcomes in SLE and LN patients treated with low vs high doses of steroids. Methods: ProQuest, Pubmed, Science Direct, Scopus, and Web of Science were carefully searched for relevant studies published in English. A total of 2,596 studies were reviewed. We extracted the data from previous studies showing the use of steroids treatment in high-dose and low-dose related to pregnancy outcomes. We provide larger data about maternal (preterm rupture of membrane, fetal loss, pre-eclampsia, and flare up) and fetal outcomes (prematurity, small gestational age, low birth weight) receiving high vs low steroid in patients with SLE and LN in this systematic review and meta-analysis. Results: A total of 13 studies were included. Of these, one study discussed a group with LN and 12 other studies discussed SLE with related maternal and fetal outcomes. Maternal outcome in the group with low-dose steroid showed a lower risk of fetal loss (odds ratio (OR): 1.93; 95% confidence interval (CI) 1.01-3.70), but there were no differences in other maternal outcomes. The low-dose steroid group showed a better fetal outcome, with a lower risk of prematurity (OR: 3.06; 95% CI 1.98-4.71), small gestational age (OR: 2.63; 95% CI 1.15-6.00), and low birth weight (OR: 2.43; 95% CI 1.23-4.79). Conclusions: In pregnant patients with SLE or LN, high-dose steroids are associated with the high risk of fetal loss during pregnancy, preterm birth, small gestational age, and low birth weight.",
"keywords": [
"systemic lupus erythematosus",
"lupus nephritis",
"steroid",
"high dose",
"low dose",
"health"
],
"content": "Introduction\n\nSystemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that can manifest as mucocutaneous, hematologic, neurologic, and renal.1 This condition affects mostly women of childbearing age. In 1996, the prevalence of women diagnosed with SLE in the United Kingdom in 18 to 65 year olds was 54 per 100,000 cases,2,3 while prevalence in 2012 increased significantly into 97.04 per 100,000 cases with the mean age of 49 years old.4 It makes SLE one of the most common autoimmune diseases in pregnancy.\n\nPregnancy and SLE worsen each other. Adverse effects of SLE in pregnancy include pre-eclampsia or eclampsia, preterm birth, preterm premature rupture of the membrane, intrauterine growth restriction (IUGR), and fetal loss.5 Hypertensive complications, such as pre-eclampsia (PE)/eclampsia (eclampsia), pregnancy-induced hypertension (PIH), and hemolysis, and elevated liver enzymes and low platelets (HELLP) syndrome, are major concern for SLE pregnant patients, especially those with anti-phospolipid autoantibodies (aPL) positivity/antiphospholipid syndrome (APS) and lupus nephritis (LN).6 On the other hand pregnancy may increase SLE activity or induce flare that may lead to unfavorable symptoms.7 In the past decade, physicians contraindicated pregnancy in SLE.8 Nevertheless, with the improvement of therapy and management, pregnant women with SLE could have better outcomes and prognosis.9 A recent comprehensive review of several countries within the past 40 years showed that the rate of fetal loss has decreased from 40% to 17%, whereas the most recent studies found a pregnancy loss rate of 10% to 25%.6\n\nSteroids are the most common therapy for autoimmune and inflammatory disease including SLE to manage flare or maintain therapy.10–12 It has a dual contradicting effect in the treatment of SLE with pregnancy, either making it better and worse. Data showed that increasing dose are also followed by increasing risk of adverse effects.13 During pregnancy, steroid exposure can affect placental growth and gene expression resulting in poor nutrition and gas exchange for the fetus,14,15 hence it should be limited to a minimum level. High doses during pregnancy have been linked to a higher risk of diabetes, hypertension, pre-eclampsia, and premature membrane rupture.16 Short courses of high dosages and/or intravenous pulse methylprednisolone can be administered in the case of disease flares.17 With the lack of information about steroids dose for therapy of SLE in pregnancy, we examine the outcome of pregnancy after low or high dose steroids in this systematic review and meta-analysis.\n\nThe objective of this systematic review and meta-analysis was to examine the effect on high-dose vs low dose of steroid in maternal and fetal outcomes in patients with SLE and LN.\n\n\nMethods\n\nWe conducted an electronic literature search from online databases, ProQuest, Pubmed, Scopus, Science Direct, and Web of Science. In addition, reference lists from previous reviews that had articles related to our criteria for inclusion were searched and literature was included where appropriate. The search was conducted in October 2021 and the last search on each database was on 26 November 2021. Literature searching was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.18 We used a protocol included in the Cochrane Collaboration’s search strategy for randomized control trials with the following terms used to search each database: (systemic lupus erythematosus) OR (SLE) OR (lupus nephritis) OR (LN) AND (pregnancy outcome*) OR (pregnancy complication*) OR (maternal outcome*) OR (maternal complication*) OR (fetal outcome*) OR (fetal complication*) OR (adverse pregnancy outcome*) OR (obstetrical outcome*). No filters and limit used in our search strategy. The search terms used for each database can be found as Extended data.47\n\nWe included studies based on the following criteria:\n\n(1) The studies were randomized control trials, cohort, case-control, or cross-sectional;\n\n(2) Studies reported maternal and fetal complications in pregnant women with SLE or LN;\n\n(3) Studies reported high-dose steroid and low-dose steroid groups;\n\n(4) English language publication.\n\nStudies were excluded when meeting the following criteria:\n\n(1) They were case report, case series, literature review, systematic review, and meta-analysis;\n\n(2) Studies did not report the outcome of pregnancy-related to the group of steroids;\n\n(3) Duplicated studies.\n\nThe searches were performed by author RH. Two authors (EP and IS) independently screened all titles and abstracts, and retrieved the full text of any articles that met the aforementioned criteria. Both authors reviewed full text articles’ eligibility, and disagreement between two authors was resolved by discussion. This process of selection, including the removal of duplicate studies, and reviewing abstracts and full texts was carried out using platform COVIDENCE, a web-based platform designed for the process of systematic reviews.\n\nThe following maternal outcomes were reported: pre-eclampsia/eclampsia, premature rupture of membranes (PROM), flares, oligohydramnios, pregnancy-induced hypertension (PIH), and fetal loss. The fetal outcomes studied were: live birth, preterm birth (under 37 weeks gestational age), small gestational age (SGA), and low birth weight (LBW).\n\nWe defined the outcomes as follows:\n\nMaternal outcomes definition:\n\n(1) Preeclampsia: Preeclampsia is gestational hypertension with one of the following new-onset disorders at or after 20 weeks of pregnancy such as proteinuria, other organ dysfunction including kidney, liver, neurological and hematological involvement, and uteroplacental dysfunction;19\n\n(2) Eclampsia: Seizure that occurs in pregnant women with preeclampsia;20\n\n(3) Preterm Rupture Of the Membranes (PROM): Ruptures of the amniotic sac membranes in pregnant women at gestational age at or 37 weeks before the onset of labor;21\n\n(4) Oligohidramnion: Decreased amniotic fluid volume less than expected gestational age. it can be identified by procedures using ultrasonography with the result of amniotic fluid index lower than 5 centimeters;22\n\n(5) Gestational Hypertension (GH): Chronic de novo hypertension which occurs at or after 20 weeks’ pregnancy with no manifestations of preeclampsia;19\n\n(6) Pregnancy loss: 1) spontaneous abortion: loss of pregnancy less than 20 weeks of gestational age 2) Intrauterine Fetal Death (IUFD): loss of pregnancy more than 20 weeks of gestational age or fetal weight over than 350 gram 3) stillbirth: loss of pregnancy before or during pregnancy. We defined three of them as pregnancy loss;23\n\n(7) SLE flare: 1) signs of new active disease observed through clinical and laboratory factors or change in therapy; 2) elevation of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score;24 3) elevation of Lupus Activity Index in Pregnancy;25 5) elevation of physician global assessment;26 4) elevation of Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k) score.27\n\nFetal outcomes definition:\n\n(1) Live birth: baby born alive during labor28;\n\n(2) Preterm birth: the birth of a baby at gestational age before 37 weeks29;\n\n(3) Small gestational age (SGA) or Intrauterine growth retardation (IUGR): newborn baby or fetal weight less than 10th percentile for gestational age30;\n\n(4) Low birth weight (LBW): newborn baby weight less than 2500 grams.28\n\nData extraction was carried out by pairs of reviewers (EP, IS), and any disagreements were determined by consensus in the team. The studies were then screened for relevance, and those meeting the eligibility criteria were included in the review. In this process, we utilized COVIDENCE, though RevMan 5.4 could be used as an open-source alternative. If the data represented in the article were unclear, we contacted the corresponding authors of each study to clarify and ask for additional data if needed.\n\nWe extracted data from each study using a predesigned table. Data collected were methodological data, mean maternal age during pregnancy, group of high-dose, low-dose steroid, and the related pregnancy outcomes. We used each study’s definition of high-dose or low-dose steroid and the doses were equalized to prednisone equivalent. If the study did not mention the definition of high-dose and low-dose of steroid, we used recommendations from the 2020 American College of Rheumatology (ACR) Guideline31; i.e. if a group received >10 mg/day of prednisone equivalent, it would be considered as high-dose.\n\nThe quality of the observational studies was reviewed independently by EP and IS using the Newcastle-Ottawa Scale (NOS).7 The bias was reviewed by the following parameters: selection, comparability, and exposure or outcome. The total score will be 9 for cohort and 8 for cross-sectional studies. Total score ≥ 7 for cohort and ≥ 6 for cross-sectional studies were used to conclude high-quality studies.7 Disagreements were resolved by consensus. The funnel plots were used to help assess bias of missing results in each study.\n\nWe used RevMan (5.4) software for statistical analysis. Data were represented by Odds Ratio (OR) with 95% confidence intervals calculated for maternal and fetal outcomes. Heterogeneity among studies was assessed by the Q-test and I2 statistic. Subgroup analysis with a p-value equal to or less than.05 was considered statistically significant. Low heterogeneity was defined by an I2 value in the range of 25% and 50 between 50% and 75% for moderate heterogeneity, and greater than 75% as high heterogeneity. We did Egger’s test and a funnel plot for publication bias (p<0.05 was considered statistically significant).\n\nThis study was approved by Airlangga Hospital’s ethical board, certificate number 189/KEH/2019. All analyses for the present study were based on previous published research, thus no patient consent was required. This article is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.47\n\n\nResults\n\nA flow chart of the study selection process is shown in Figure 1. We identified a total of 2,596 studies using search terms from our aforementioned databases. A total of 1,441 duplicated studies were removed. Following screening title and abstract we excluded irrelevant 797 studies, 305 full-text studies were reviewed for eligibility, and finally, a total of 13 studies were included in our quantitative synthesis for systematic review and meta-analysis.\n\nOf 13 studies, nine studies were cohort retrospective, while four studies were cohort prospective. The main characteristics are shown in Table 1. The studies were conducted in various regions such as Canada, China, Italy, Ghana, London, Thailand, Japan, and USA. The patient’s enrollment was from 1996 to 2020. The majority of women included in the study were Asian (53%) (Table 1). The average maternal age was 29 ± 3,09 years old. From the data, most women with SLE received a low-dose steroids (72,2%) than high-dose steroids (27,8%) treatments, with the average cut-off used to classify high-dose steroids was 11,78 mg. A total of participants in the experimental (high dose steroids) group were 448 patients (48 patients were LN) and the control (low dose steroids) group were 1,289 patients (82 patients were LN) (Table 3).\n\nOR, odds ratio; ROC, receiver operating characteristic; RR, risk ratio; HR, hazard ratio.\n\n* Prednisone equivalent dose.\n\nThis research divided the outcomes into two groups: maternal outcomes and fetal outcomes. The maternal outcomes reported were as follows: fetal loss, PROM, pre-eclampsia, oligohydramnios, PIH, and flares. Five of 13 studies discussed fetal loss as a maternal outcome. In the fetal outcomes group, the studies analyzed pre-term, LBW, and SGA. The majority of studies (8/13) discussed pre-term labor as an outcome (Table 2). The SLE diagnostic criteria used for these studies have many variations. The majority of studies were using the ACR 1997 Criteria as reference (Table 2). The criteria used for disease activity also varied in each study. In most studies, the disease severity was defined by organ involvement and laboratory abnormalities, whereas five studies used the systemic lupus disease activity index (SLEDAI) (Table 2). There were also various criteria for defining flares in patients. Most of the studies used flares criteria based on signs of new disease activity either by clinical or laboratory and change in therapy, and 3 other studies used the SLEDAI score (Table 2).\n\nRisk of bias assessment\n\nFor cohort and cross-sectional studies, The Newcastle-Ottawa Score (NOS) was used to evaluate the risk of bias in this study. Table 2 shows the NOS scores from each study. For the cohort studies, the total NOS score was 9. The majority of studies (11/13) have an average score of 8, and two other studies have a score of 7. All of the studies are high quality and have low-risk of bias. We used Egger’s test to evaluate the possibility of publication bias. No indication of publication bias (p<0.05) for all outcomes were detected.\n\nPreterm rupture of membrane (PROM)\n\nFour studies (n=202) with outcomes of PROM were included in the meta-analysis. The risk of PROM in high-dose steroids were not significantly difference compared with low-dose steroids group (OR 1.14, 95% CI 0.44 to 2.98, p=0.79, I2=38%) (Table 3).\n\nFetal loss\n\nFive studies (n=217) with the fetal loss evaluated were included in the meta-analysis. High-dose steroids were associated with a higher risk of fetal loss as compared to low-dose steroids (OR 1.93, 95% CI 1.01 to 3.70, p=0.05, I2=0%) (Table 3).\n\nPre-eclampsia\n\nOnly three studies (n=168) were included in the meta-analysis in relation to preeclampsia outcomes. The risk of preeclampsia in high-dose steroids were not significantly difference compared with low-dose steroids group (OR 1.30, 95% CI 0.51 to 3.30, p=0.58, I2=35%) (Table 3).\n\nFlare\n\nThree studies (n=235) were included in the meta-analysis. The risk of disease flare in high-dose steroids were not significantly difference compared with low-dose steroids group (OR 1.77, 95% CI 0.33 to 9.41, p=0.50, I2=73%) (Table 3).\n\nPreterm birth\n\nEight studies (n=526) were included in the meta-analysis for preterm birth outcome. One study discussed LN. Higher risk or preterm delivery were more associated with high-dose steroids than low-dose steroids (OR 3.06, 95% CI 1.98 to 2.22, p<0.00001, I2=0%) (Table 3).\n\nSmall gestational age (SGA)\n\nFour studies (n=178) were included in the meta-analysis. High-dose steroids were associated with a higher risk of SGA as compared with low-dose steroids (OR 2.63, 95% CI 1.15 to 6.00, p=0.02, I2=0%) (Table 3).\n\nLow birth weight (LBW)\n\nFive studies (n=216) were included in the meta-analysis. The risk of LBW in high-dose steroids were not significantly difference compared with low-dose steroids group (OR 2.43, 95% CI 1.23 to 4.79, p=0.01, I2=34%) (Table 3).\n\nFunnel plots were also done which can be found as Extended data.47 Comparison and detail about outcomes are provided in Figures 2, 3, 4, 5 and Table 3.47\n\nFetal loss during pregnancy\n\nPrematurity\n\nSmall gestational age\n\nLow birth weight\n\n\nDiscussion\n\nIn this systematic review, we examine 13 papers that evaluate at how steroid dose affects pregnancy outcomes in SLE and LN patients. Overall, we discovered that high steroid doses were linked to a higher risk for adverse maternal outcomes, particularly pregnancy loss. Furthermore, increased risks of poor fetal outcomes, such as premature birth, low birth weight, and small gestational age, were linked to high-dose steroid use during pregnancy. Low-dose steroids were given to more SLE patients in this study than high-dose steroids, which were classified as >10 mg/day of prednisone equivalent. The number of pregnancy losses was considerably higher in the high-dose steroid group than in the low-dose steroid group. Furthermore, the premature delivery rate was 58 percent among all live births.\n\nWe used a comprehensive search strategy and careful appraisal following a standard protocol for systematic review to assess the validity of study results. The selected studies mostly have similar characteristics of enrolled patients with respect to age, race, criteria used for diagnosis and disease activity. All of the studies were high quality with low-risk of bias and no indications of publication bias from Egger test. Premature delivery, intrauterine development retardation, and fetal death in pregnant women with SLE were highly associated with steroid dose reflecting managed disease, as well as disease flare-ups during pregnancy, according to our findings. To the best of our knowledge, this is the first meta-analysis that discussed the relationship between steroids and fetal or maternal outcomes in SLE and LN patients.\n\nIn a previous systematic review, Wu et al. reported prevalence of adverse pregnancy outcomes in SLE with LN and identified their significant association.7 However, the study did not look at the differences in the occurrence of the aforementioned outcomes between individuals who were given a high steroid dose and those who were given a low steroid dose. Another meta-analysis showed that higher rates of maternal and fetal complications including preeclampsia, hypertension, fetal loss, premature birth, SGA and congenital defects were strongly associated with SLE.44 Nevertheless, the included studies were limited and antenatal management using steroids was not mentioned. High blood pressure, active nephritis, and the antiphospholipid syndrome (APS) in SLE flares up seemed to be the major factors behind the adverse pregnancy outcomes.\n\nThe role of steroids to control the flare and maintenance therapy in patients with remission are widely used. In both acute and chronic settings, the use of steroids during pregnancy is the preferred choice for a myriad of maternal and fetal purposes.45 In many fetal tissues, such as the liver, lungs, stomach, skeletal muscle, and adipose tissue, steroids are vital for the growth and development to prepare for the life outside the womb. Steroids control prostaglandin production, which has been linked to key roles during implantation by improving stromal vascular permeability and employed in the treatment of mothers who are at risk of preterm delivery.45,46 Their abilities to inhibit the immune system and reduce inflammation are frequently used to control the severity of a patient's condition and flares in pregnant women with autoimmune disorders, such as SLE.46\n\nIn a cohort study on preterm deliveries in women with SLE, Clark et al. demonstrated that lower dose of steroid maintained through pregnancy was associated with extending SLE pregnancies to full term, thus lowering maternal and fetal morbidity.32 On the other hand, Zhang et al. stated that increased fetal loss was not associated with the prednisone dose in pregnant women with SLE, whereas combined APS and SLEDAI were the key risk factors of those complication. All abovementioned results represent limited discussion about optimal doses of steroids to improve the outcome of SLE women. Along with varying population, study design, diagnostic criteria, statistical method, and outcomes reported. This systematic review combined a larger population to provide the risk of steroids in pregnancy outcomes to support the need for dose adjustment of steroid in patients with active SLE and consideration for avoidance of pregnancy until all manifestations are quiscent.\n\nThis study came with some limitations. Our team did not find eligible randomized control trials that study about pregnancy outcome related to the dose of steroid due to limited studies and ethically improper to perform. Most of our included studies were retrospective-observational studies that are more prone to bias and cofounding. We only include the English studies, as consequence the non-English studies that met our criteria could not be reviewed. We did not conduct subgroup analysis of the dosage, route of administration, and kind of steroid. Each center has customary steroid administration in patients with SLE and LN; therefore, to apply the result of this study, clinicians should firstly ensure the indication and determine the most optimal and safe dosage to achieve a good maternal and fetal outcome. Some studies only had small samples with insufficient total samples to be generalized to the entire population. Further observation with larger population on the side effects of steroid in combination with another agent, e.g., immunosuppressants, is required to evaluate maternal and fetal outcome.\n\n\nConclusions\n\nSteroids are used to overcome SLE and LN in pregnancy. High-dose steroids may increase the risk of preterm birth and miscarriage during pregnancy. Besides, it may also cause deterioration, seen in other variables of the maternal and fetal outcome.\n\n\nData availability\n\nFigshare: Data of High-dose vs Low-dose Steroid in Pregnancy Patients with Systemic Lupus Erythematosus and Lupus Nephritis: A Systematic Review and Meta-analysis, https://doi.org/10.6084/m9.figshare.18514970.v5.47\n\nThis project contains the following underlying data:\n\n‐ High vs Low Dose Steroid in Pregnancy Patients with SLE.rm5 (the data of each study used to create the forest and funnel plots. The open source software RevMan is required to open this file).\n\nFigshare: Data of High-dose vs Low-dose Steroid in Pregnancy Patients with Systemic Lupus Erythematosus and Lupus Nephritis: A Systematic Review and Meta analysis, https://doi.org/10.6084/m9.figshare.18514970.v5.47\n\nThis project contains the following extended data:\n\n‐ PubMed 25 Nov.png (search terms in Pubmed database).\n\n‐ Proq-96-25nov.png (search terms in ProQuest database).\n\n‐ SciDir-25nov-138.png (search terms in Science Direct database).\n\n‐ Scopus-nov-670.png (search terms in Scopus database).\n\n‐ Wos-467-25nov.png (search terms in Web of Science database).\n\n‐ PRISMA flow.png (PRISMA flow diagram)\n\n‐ Funnel plot_PROM.svg\n\n‐ Funnel plot_Fetal Loss.svg\n\n‐ Funnel plot_Flare up.svg\n\n‐ Funnel plot_LBW.svg\n\n‐ Funnel plot_Prematurity.svg\n\n‐ Funnel plot_Pre eclampsia.svg\n\n‐ Funnel plot_SGA.svg\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReporting guidelines\n\nFigshare: PRISMA checklist for ‘High-dose vs low-dose steroid in pregnancy patients with systemic lupus erythematosus and lupus nephritis: A systematic review and meta-analysis’, https://doi.org/10.6084/m9.figshare.18514970.v5.47",
"appendix": "References\n\nDalal DS, Patel KA, Patel MA: Systemic L Erythematosus and Pregnancy: A Brief Review. J. Obstet. Gynecol. India 2019; 69: 104–109. Publisher Full Text\n\nLim SS, Drenkard C: Epidemiology of lupus: An update. Vol. 27, Current Opinion in Rheumatology. Lippincott Williams and Wilkins; 2015; 427–432.\n\nPons-Estel GJ, Alarcón GS, Scofield L, et al.: Understanding the Epidemiology and Progression of Systemic Lupus Erythematosus. Semin. Arthritis Rheum. 2010; 39: 257–268. PubMed Abstract | Publisher Full Text\n\nRees F, Doherty M, Grainge M, et al.: The incidence and prevalence of systemic lupus erythematosus in the UK, 1999–2012. Ann. Rheum. Dis. 2016 Jan; 75(1): 136–141.\n\nPetri M: Pregnancy and Systemic Lupus Erythematosus. Best Pract. Res. Clin. Obstet. Gynaecol. 2020 Apr; 64: 24–30. Publisher Full Text\n\nLazzaroni MG, Dall’Ara F, Fredi M, et al.: A comprehensive review of the clinical approach to pregnancy and systemic lupus erythematosus. J. Autoimmun. 2016 Nov; 74: 106–117. PubMed Abstract | Publisher Full Text\n\nWu J, Ma J, Zhang WH, et al.: Management and outcomes of pregnancy with or without lupus nephritis: a systematic review and meta-analysis. Ther. Clin. Risk Manag. 2018 May 11 [cited 2022 Jan 16]; Volume 14: 885–901. PubMed Abstract | Publisher Full Text\n\nClark CA, Spitzer KA, Laskin CA: Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J. Rheumatol. 2005 Sep; 32(9): 1709–1712. PubMed Abstract\n\nKnight CL, Nelson-Piercy C: Management of systemic lupus erythematosus during pregnancy: challenges and solutions. Open Access Rheumatol. 2017 Mar 10 [cited 2022 Jan 16]; 9: 37–53. PubMed Abstract | Publisher Full Text\n\nAteka-Barrutia O, Khamashta MA: The challenge of pregnancy for patients with SLE. Lupus. 2013 Oct [cited 2022 Jan 16; 22(12): 1295–1308. Reference Source\n\nFerguson CB, Mahsud-Dornan S, Patterson RN: Inflammatory bowel disease in pregnancy. BMJ. 2008 Jul 19 [cited 2022 Jan 16]; 337(7662): 170–173. Reference Source\n\nØstensen M, Förger F: Management of RA medications in pregnant patients. Nat. Rev. Rheumatol. 2009 [cited 2022 Jan 16]; 5(7): 382–390. PubMed Abstract | Publisher Full Text\n\nPalmsten K, Bandoli G, Watkins J, et al.: Oral Corticosteroids and Risk of Preterm Birth in the California Medicaid Program. J Allergy Clin Immunol Pract. 2020 Aug 11 [cited 2022 Jan 16]; 9(1): 375–384.e5. PubMed Abstract | Publisher Full Text Reference Source\n\nWieczorek A, Perani C v, Nixon M, et al.: Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta. Am. J. Physiol. Endocrinol. Metab. 2019 Jul 1; 317(1): E109–E120. PubMed Abstract | Publisher Full Text\n\nHutter S, Hepp P, Hofmann S, et al.: Glucocorticoid receptors α and β are modulated sex specifically in human placentas of intrauterine growth restriction (IUGR). Arch. Gynecol. Obstet. 2019 Aug 14; 300(2): 323–335. PubMed Abstract | Publisher Full Text\n\nØstensen M, Khamashta M, Lockshin M, et al.: Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res. Ther. 2006; 8(3): 209. PubMed Abstract | Publisher Full Text\n\nLateef A, Petri M: Managing lupus patients during pregnancy. Best Pract. Res. Clin. Rheumatol. 2013 Jun; 27(3): 435–447. PubMed Abstract | Publisher Full Text\n\nPage MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29 [cited 2022 Jan 16]; 372. Reference Source\n\nBrown MA, Magee LA, Kenny LC, et al.: Hypertensive Disorders of Pregnancy. Hypertension. 2018 Jul; 72(1): 24–43. Publisher Full Text\n\nACOG Practice Bulletin No. 202 Summary: Gestational Hypertension and Preeclampsia. Obstet. Gynecol. 2019 Jan 1 [cited 2022 Jan 16]; 133(1): 211–214. Reference Source\n\nACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes. Obstet. Gynecol. 2018 Jan 1 [cited 2022 Jan 16]; 131(1): e1–14. PubMed Abstract | Publisher Full Text\n\nACOG committee opinion no. 560: Medically indicated late-preterm and early-term deliveries. Obstet. Gynecol. 2013 [cited 2022 Jan 16]; 121(4): 908–910. PubMed Abstract\n\nMetz TD, Berry RS, Fretts RC, et al.: Management of Stillbirth. The American College of Obstetricians and Gynecologists. 2009 [cited 2022 Jan 16]. Reference Source\n\nBombardier C, Gladman DD, Urowitz MB, et al.: Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992 [cited 2022 Jan 16]; 35(6): 630–640. PubMed Abstract | Publisher Full Text\n\nBuyon JP, Kalunian KC, Ramsey-Goldman R, et al.: Assessing disease activity in SLE patients during pregnancy. Lupus. 1999 [cited 2022 Jan 16]; 8(8): 677–684. PubMed Abstract | Publisher Full Text\n\nHarrington JT: The uses of disease activity scoring and the physician global assessment of disease activity for managing rheumatoid arthritis in rheumatology practice. J. Rheumatol. 2009 May [cited 2022 Jan 16]; 36(5): 925–929. PubMed Abstract | Publisher Full Text\n\nGladman DD, Ibañez D, Urowitz MB: Systemic lupus erythematosus disease activity index 2000. J. Rheumatol. 2002 [cited 2022 Jan 16]; 29(2). PubMed Abstract Reference Source\n\nICD-10: international statistical classification of diseases and related health problems: tenth revision.[cited 2022 Jan 16]. Reference Source\n\nSimhan HN: Practice Bulletin No. 159: Management of Preterm Labor. Obstet. Gynecol. 2016 [cited 2022 Jan 16]; 127(1): e29–e38. Reference Source\n\nACOG Practice Bulletin No. 204: Fetal Growth Restriction. Obstet. Gynecol. 2019 Feb 1 [cited 2022 Jan 16]; 133(2): e97–e109. Publisher Full Text Reference Source\n\nSammaritano LR, Bermas BL, Chakravarty EE, et al.: 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2020 Apr 1 [cited 2022 Jan 16]; 72(4): 529–56. PubMed Abstract | Publisher Full Text\n\nClark CA, Spitzer KA, Nadler JN, et al.: Preterm deliveries in women with systemic lupus erythematosus. J. Rheumatol. 2003 Oct; 30(10): 2127–2132. PubMed Abstract\n\nDey ID, Coleman J, Kwarko H, et al.: Outcome of pregnancy in patients with systemic lupus erythematosis at Korle-bu Teaching Hospital. Ghana Med. J. 2016 Jun 1; 50(2): 72–77. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoria A, Cutolo M, Ghirardello A, et al.: Steroid Hormones and Disease Activity During Pregnancy in Systemic Lupus Erythematosus.2002.\n\nEnglert HJ, Derue GM, Loizou S, et al.: Pregnancy and Lupus: Prognostic Indicators and Response to Treatment. Q. J. Med. 1988; 66. PubMed Abstract Reference Source\n\nFoocharoen C, Nanagara R, Salang L, et al.: Pregnancy and Disease Outcome in Patients with Systemic Lupus Erythematosus (SLE): A Study at Srinagarind Hospital. J. Med. Assoc. Thail. 2009; 92: 167–174. PubMed Abstract Reference Source\n\nKobayashi N, Yamada H, Kishida T, et al.: Hypocomplementemia correlates with intrauterine growth retardation in systemic lupus erythematosus. Am. J. Reprod. Immunol. 1999; 42(3): 153–159. PubMed Abstract | Publisher Full Text\n\nLouthrenoo W, Trongkamolthum T, Kasitanon N, et al.: Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: A STROBE-compliant study. Medicine. 2021 Feb 5; 100(5): e24553. PubMed Abstract | Publisher Full Text\n\nMurata T, Kyozuka H, Fukuda T, et al.: Maternal disease activity and serological activity as predictors of adverse pregnancy outcomes in women with systemic lupus erythematosus: a retrospective chart review. Arch. Gynecol. Obstet. 2021. PubMed Abstract | Publisher Full Text\n\nOishi Y, Ikeuchi H, Hamatani H, et al.: Pregnancy outcomes in patients with systemic lupus erythematosus with or without a history of lupus nephritis. Clin. Exp. Nephrol. 2021 Aug 1; 25(8): 835–843. Publisher Full Text\n\nTakahashi K, Mimura K, Kanagawa T, et al.: Disease flare-ups and obstetric outcomes in pregnant women with systemic lupus erythematosus Hypertension Research in Pregnancy. Hypertens. Res. Pregnancy. 2013; 1: 103–107. Publisher Full Text\n\nUeda A, Chigusa Y, Mogami H, et al.: Predictive factors for flares of established stable systemic lupus erythematosus without anti-phospholipid antibodies during pregnancy. J. Matern. Fetal Neonatal Med. 2020: 1–6. PubMed Abstract | Publisher Full Text\n\nZhang LL, Shu H, Zhang S, et al.: Pregnancy outcomes and risk factors in pregnant women with systemic lupus erythematosus. Clin. Exp. Obstet. Gynecol. 2020 Apr 15; 47(2): 189–193. Publisher Full Text\n\nBundhun PK, Soogund MZS, Huang F: Impact of systemic lupus erythematosus on maternal and fetal outcomes following pregnancy: A meta-analysis of studies published between years 2001-2016. J. Autoimmun. 2017 May 1 [cited 2022 Jan 16]; 79: 17–27. PubMed Abstract | Publisher Full Text\n\nLunghi L, Pavan B, Biondi C, et al.: Use of glucocorticoids in pregnancy. Curr. Pharm. Des. 2010 Dec 19 [cited 2022 Jan 16]; 16(32): 3616–3637. Publisher Full Text Reference Source\n\nBandoli G, Palmsten K, Forbess Smith CJ, et al.: A Review of Systemic Corticosteroid Use in Pregnancy and the Risk of Select Pregnancy and Birth Outcomes. Rheum. Dis. Clin. N. Am. 2017 Aug 1 [cited 2022 Jan 16]; 43(3): 489–502. PubMed Abstract | Publisher Full Text\n\nSuryantoro SD: Data of High-dose vs Low-dose Steroid in Pregnancy Patients with Systemic Lupus Erythematosus and Lupus Nephritis: A Systematic Review and Meta-analysis. figshare. [Dataset].2022. Publisher Full Text"
}
|
[
{
"id": "148772",
"date": "30 Aug 2022",
"name": "Eduardo F. Borba",
"expertise": [
"Reviewer Expertise Clinical Reserch in Rhematology - Associate Professor in my Institution - University of Sao Paulo - Brazil"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe objective of this paper is to perform a systematic review and meta-analysis in order to evaluate the effect on high-dose vs low dose of steroid in maternal and fetal outcomes in patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN). This is a very important issue in this disease.\nSome minor questions arise:\nAuthors should revise all the text for grammatical errors.\n\nTitle: OK.\n\nAbstract: OK.\n\nKeywords: Please use “therapy” instead of “health”.\n\nIntroduction: Please insert some comments about a recent review that provide recommendations for therapy during pregnancy in SLE (reference #31) and provide a short description of it in order to describe the main suggestions of this paper. In fact, authors used these recommendations for defining high and low steroid dose (Methods section).\n\nPatients and methods: Interesting design and selection. Outcomes were well-defined. Methods were appropriate for analysis.\n\nResults: No further comments.\n\nDiscussion: In the same way, authors should include comments in this section about the review that provides recommendations for therapy during pregnancy in SLE (reference #31). Authors should describe these recommendations and compare to those identified in their study. This suggestion will highlight their findings and make clear their conclusions.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-543
|
https://f1000research.com/articles/11-542/v1
|
19 May 22
|
{
"type": "Research Article",
"title": "Non-technical dimensions of communal wastewater treatment plant sustainability in peri-urban Yogyakarta, Indonesia",
"authors": [
"Widodo Brontowiyono",
"Thomas Boving",
"Adelia Anju Asmara",
"Suphia Rahmawati",
"Andik Yulianto",
"Noviani Ima Wantoputri",
"Annisa Nur Lathifah",
"Yuli Andriansyah",
"Thomas Boving",
"Adelia Anju Asmara",
"Suphia Rahmawati",
"Andik Yulianto",
"Noviani Ima Wantoputri",
"Annisa Nur Lathifah",
"Yuli Andriansyah"
],
"abstract": "Background: This study focuses on identifying non-technical aspects that influence the sustainability of communal wastewater treatment plants (WWTPs) in a peri-urban area of Indonesia. Methods: A questionnaire survey was conducted by random sampling using a method of descriptive analysis that combines qualitative and quantitative approaches. Economic support for communal WWTPs was measured by the community’s Willingness to Pay (WTP) and Ability to Pay (ATP). Results: The results indicate that social dimension, such as a community’s level of participation are critically important in sustaining communal WWTPs. In addition, institutional dimension influences the degree of satisfaction a community has toward the WWTP management. This support is reinforced by social capital in the form of a philosophy of mutual cooperation, like gotong royong (cooperation by members of a community to achieve a common goal) and swadaya (self-reliance). Conclusions: The findings of this study can be used in Indonesia to make policy recommendations for managing and ensuring sustainability of communal WWTPs on a non-technical dimension. Additionally, gotong royong deserves to be promoted internationally as a fundamental value for fostering participation and contribution.",
"keywords": [
"Communal WWTP",
"gotong royong",
"non-technical dimensions"
],
"content": "Introduction\n\nWastewater treatment plants (WWTP) are vital parts of the environmental infrastructure and becoming increasingly important in the densely populated urban and suburban areas around the world.1,2 WWTP can be operated as centralized and communal entities. For example, in Yogyakarta, Indonesia, the city’s WWTP is centralized, while in the peri-urban area surrounding Yogyakarta, WWTPs are communal. In total, the Special Region of Yogyakarta Province cur-rently operates 376 communal WWTPs, although not all are operational. Centralized WWTP are often inefficient, which is why communal WWTPs are critical in reducing environmental pollution problems.3\n\nProper environmental sanitation is a strategic issue in Yogyakarta’s peri-urban area and the sustainable management of the regions WWTPs is critically important. The sustainability of WWTPs depended on a number of indicators, including technical, participatory, or social, institutional, and economic factors.4 These sustainability indicators suggest that current environmental sanitation efforts in the Yogyakarta region are insufficient and more efforts are required.5–7\n\nSustainability encompasses structural, engineered aspects, such treatment facilities, equipment, and supplies. These aspects are largely supported by both government and non-government agencies. Meanwhile, sustainability also depends on non-technical aspects, such as community dynamics, that, if developed and managed optimally, can sustain the management of communal WWTPs. Previous research indicated that not all communal WWTPs in Yogyakarta are well managed8 and their some performance evaluation standards are not well achieved.9,10 Some issues raising from previous research indicated the needs to also evaluate some non-technical aspects in managing communal WWTPs. Wastewater management requires the use of appropriate decision-making models. However, there are still gaps, particularly in terms of socioeconomic factors and sustainability analysis.11–14 These gaps often limit the usefulness of decision-making models.\n\nThis research focuses on these non-technical sustainability aspects, including community participation, institutionalization, and economy, as well as community’s perception and the understanding of communal WWTP management. This study focuses on Indonesia and an area in Yogyakarta’s peri-urban zone that is situated in Sleman Regency. It includes the districts of Depok, Mlati, and Ngaglik. This area (574.8 km2) is characterized by a very high settlement density (1,902 people per km2, 2010 Census). Data on environmental management performance indicates that ten rivers in Yogyakarta has E. coli bacteria value that exceeds the quality standard.15 Since pathogenic E.coli bacteria can cause bloody diarrhea,16 it is understable that the incidence rate of diarrhea in Sleman Regency was 17.85% in 2019 with approximately 19,126 cases.17 The high number of cases was attributed to the high settlement density, which reduces the distance between septic tanks and wells. Hence, in these densely populated areas, the urgency of communal WWTPs is a non-negotiable development priority.\n\nThe purpose of this study is to identify non-technical sustainability aspects that may affect the management of communal WWTP in this study area. The study’s findings are expected to serve government entities and WWTP managers, and inform community policies and programs aimed at ensuring the long-term viability of communal WWTP operations.\n\n\nMethods\n\nThe design of this study, based on Grimes and Schulz,18 was descriptive study. This type of study fall under the observational study. Since the purpose was to analyze non-technical aspects of the communal WWTPs, this study described responses of participants to some questions in the questionnaire. This implies that this study can also be categorized as cross-sectional study.19 Since its characteristics was descriptive, this study did not assign any exposures to participants. Although the data was collected from locations in three sub-districts that can be used to grouping data, comparative analysis was not applied. This study focused on measuring the responses from participants and considered its analysis on data from three sub-districts as a holistic data.20,21\n\nThis study involved users of WWTPs in peri-urban in Yogyakarta. It implies that human factors and legal issues should be handled carefully. For this reason, this study was prepared and conducted using the steps as follows. The research proposal that this study was based on, including its attachments, was submitted to the Directorate of Research and Community Development, Islamic University of Indonesia. The Directorate of Research and Community Development, the Directorate of Human Resources, and the Board of Ethics and Law, Islamic University of Indonesia conducted an initial check for the proposal and its attachments in terms of feasibility, ethical concerns, government regulation, legal issues, and others. Once everything is completed and approved based on university standards, the proposal was sent for review. After that, the proposal was presented to reviewers and university management. The Directorate of Research and Community Development, Islamic University of Indonesia finally accepted the proposal and provided an approval sheet signed by the Director and Chief of Research Center.\n\nAfter this step, surveyors for this study asked for approval from the Heads of villages, Lurahs in Bahasa Indonesia, to conduct the research in their area. They were informed about the purpose of the research, the type of data to collect, and respondents’ characteristics who would be provided with the questionnaire to fill out. It took additional time due to the many villages in which the study was planned to be conducted. Once all of Lurahs agreed and approved the study and questionnaire, data collection was started.\n\nA small talk with potential respondents was initiated before collecting data. It is considered polite to start communication with this type of talk among Javanese, the majority of people living near communal wastewater treatment plants in the study, as part of Eastern hospitality. The surveyors explained the purpose of the study and showed permission by Lurah to potential respondents before asking them to become respondents. After that, a page of the consent form was presented to respondents. If the respondents agreed, they signed the consent form and a questionnaire was presented to each respondents. They filled it until all items were completed. All questionnaires were checked and only fully filled-out ones were used for analysis.\n\nThe study was conducted by collecting data from users of WWTPs in three sub-districts in peri-urban Yogyakarta, Indonesia, that are part of Sleman Regency: Ngaglik, Depok, and Mlati (Figure 1). These three sub-disctrict consisted of some villages and were characterized as rural area. However, due to recent development and increasing population, these area can now be characterized as peri-urban in Yogyakarta. Each of three sub-districts has different numbers of WWTPs that this study used to collect data. Depok has the most number with sixteen WWTPs, followed by Ngaglik with fifteen WTTPs. Mlati has the least number with six WWTPs. Data was collected between September and November 2021.\n\nSource: Badan Informasi Geospasial (BIG).22 Note: Badan Informasi Geospasial (BIG) hold copyright of the maps used and allowed users to download, distribute, adapt, and derive Informasi Geospasial Dasar (IGD) or Basic Geospatial Information on their website with a condition users should include citation and source to Badan Informasi Geospasial (BIG).23 Based on these term and condition, the authors modified the map for research purpose.\n\nThe population of this study is the entire community using the communal WWTPs in three sub-disctricts: Mlati, Ngaglik, and Depok. Quota sampling technique was used to select a representative sample from a population that shares certain characteristics with the desired population size.24,25 The primary reason this study used quota sampling technique is to sample a subgroup that is of particular interest to the study.26\n\nBeing user of a communal WWTP was main characteristics for a respondent to be chosen in this study. Additional eligibility criteria was being in the specific area of the communal WWTP of this study. To ensure that potential participants were captured in the data colletion, this study also ask manager of the communal WWTP in selecting potential participants. Manager of the communal WWTP is considered has proper understanding of the users in the area. Thus, having one of them in determining sample could help the study find more reliable participants for research source.\n\nSince there were 37 WWTPs in three sub-disctricts, this study focused on finding minimum of two representative respondents for each location. Thus, the basis for analysis was centered in sub-disctrict and not in individual WWTPs. This strategy was chosen as consequences of quota sampling technique used in the study as well as other reasons such as budget and time limitations.27\n\nThis study collected data from participants on three non-technical aspects of the communal WWTPs sustainability. These aspects are social, institutional, and economic ones. Social aspects of the communal WWTPs consist of (a) the reason behind participant decision to join a communal WWTP as a user; (b) the presence of a socialization before the construction of the communal WWTP; (c) participation of the user in the construction of the communal WWTP; (d) participation of the user in the maintenance of the communal WWTP; and (e) willingness of user in the maintenance of the communal WWTP.\n\nInstitutional aspects in this study include (a) user awareness of managerial team of the communal WWTP; (b) compiling process in selection of the managerial team of the communal WWTP; (c) user willingness to beome a member the managerial team of the communal WWTP; (d) user knowledge of conflict in the management of the communal WWTP; (e) user perception of the performance of the communal WWTP managerial team; and (f) user satisfaction with the communal WWTP services.\n\nEconomic aspects of this study were (a) average family income; (b) average family expenditure; (c) the presence of communal WWTP fee; (d) the amount of the communal WWTP monthly fee; (e) willingness to pay a regular monthly fee; (f) appropriateness of the the communal WWTP monthly fee; (g) ability to pay the communal WWTP monthly; (h) suggestion on the communal WWTP fee; and (i) collection of fee for the communal WWTP reparation.\n\nData sources for variables mentioned in sub-section above was results of questionairre distributed to participants. Quantitative variables were analyzed using a frequency distribution and presented in a frequency distribution table. The grouping is done based on the location of the respondent’s sub-district, because the study uses a sub-district analysis unit.\n\nQuota sampling suffers from a number of drawbacks as a result of its non-probability nature, including nonrepresentative samples and external risks to the validity of a study. Additionally, quota sampling has the potential to produce inaccurate estimates or findings about the proportion of specified traits in the population of interest. When it comes to demographic data, it is frequently difficult to obtain the most up-to-date information available. It is also likely that quota sampling will leave out hidden populations that are disadvantaged and disenfranchised. These populations are frequently left out of non-probability sampling, including quota sampling, because they are difficult to track down and may refuse to participate in an interview session.25,28,29\n\nThis study used quota sampling technique which make it potent for some biases as mentioned above. For this particular reason, some efforts have been tried to address potential sources of bias by seeking proper explanations regarding potential participants in collaboration with communal WWTP managers. If the participants chosen based on manager’s explanation did not agree to be surveyed, then other potential participants were approached until minimum two participants for each communal WWTP. Once participants filled out the questionnaire, initial checklist was conducted to ensure that all questions were answered. If the questionairre was fully filled out, then it was considered eligible for further analysis. If, in any case, a questionairre was not fully filled out, the additional participants would be approached and asked to fill out the questionnaire. The survey was considered sufficient once minimum of two fully filled out questionairres were collected within a communal WWTP.\n\nQuota sampling begins with the determination of the proportion of a population’s specified characteristics that exists. Following the determination or identification of the proportions, the study might proceed to the collection of interviews from respondents.25 This study follows the same steps in determining its study size. It first decided that the unit of analysis used was based on sub-district. Each sub-district has different numbers of the communal WWTPs and for each of them, a minimum of two participants were selected to fill questionairre. With 37 communal WWTPs in research location, it took minimum 74 participants as study size for this research.\n\nParticipants’ answer in the questionairre became main quantitative data that were combined in the same sub-district coverage. Quantitative variables were analyzed using a frequency distribution and presented in a frequency distribution table. The grouping is done based on the location of the respondent’s sub-district, because the study uses a sub-district analysis unit. In the case of missing data, imputation technique was applied. It consisted of the process of filling in or replacing the missing values in a dataset with plausible values based on the information obtained in the dataset.\n\nThe descriptive analysis method was used in this study, with qualitative and quantitative approaches serving as the basis for analysis and interpretation in the context of communal WWTP management. The approach is empirical, utilizing analytical methods capable of explaining cause and effect based on factual conditions.30,31 This study analyzed many aspects in the context of communal WWTP management, such as social, institutional, and economic.\n\nFor social and institutional aspects, this study usee perception data related to community participation. The analysis method is descriptive qualitative with the assistance of a frequency table based on respondents’ responses. Economic data are used to determine a person’s willingness and ability to contribute. The analysis method was descriptive qualitative with quantification based on respondents’ responses. Quantification of data was performed through analysis of Willingness to Pay (WTP) and Ability to Pay (ATP).32–35\n\nIn this research, the term “WTP” refers to a community’s willingness to implement communal WWTPs. The WTP for communal WWTPs is determined through a questionnaire survey that follows a question format based on stated preferences methods. The stated preference method employs the Referendum Contingent Valuation (CV) technique, which is more effective with “willing” or “no”. ATP was analysed via open-ended quest ions in surveys. Open-ended questions, also known as unstructured questions, are surveys for which no response options are provided thus leaving respondents to formulate their own responses.36,37 This method was chosen because it imposes no value constraint on determination of ATP level. The ATP value is calculated using average responses of respondents. A capability value equal to or greater than estimated cost ensures communal WWTP’s sustainability.\n\n\nResults\n\nFinal data collected for this study came from 120 participants who were current communal WWTP users. Table 1 summarizes the number of respondents and their distribution by sub-district. Data in Table 1 indicates that for all sub-disctrict a minimum of two participants was completed. Mlati is the sub-district with most average participants, followed by Depok and Ngaglik. The difference in average participation among these three sub-disctricts was based on many factors. Among these factors were willingness of participants to be part of the study.\n\nCharacteristics of participants based on age are presented in Table 2. Majority of participants are older than 40 years which implies that most of respondents have been living near the communal WWTP for some time. It could help this study to ensure that participants have proper relationships with with the environment.\n\nCharacteristics of participants based on sex are presented in Table 3. The data indicates that most participants are male. It should be understood that among common thing within Javanese culture is that male side used to have significant role especially as head of household. When a surveyor came for data collection, it would be common that a father or other head of household take first cahnce to fill out the questionairre. Thus, this difference should be addressed as potential bias for this study.\n\nSocial aspects in sustainability of communal WWTPs\n\nThe majority of WWTPs were constructed top-down with government assistance. The willingness to become a communal WWTP customer was found contingent upon the community’s motivation or encouragement. Overall, the conditions at the re-search site were favorable (Table 4), i.e. the majority of customers (47.5 percent) and self-initiatives (45 percent) were motivated to participate freely, while only a small percentage felt obligated (7.5 percent). This distribution influenced the participation and contribution needs for ensuring the sustainability of communal WWTP’s.\n\nPublic outreach and consultation with the communities were required during planning and pre-construction stages (Table 5). The underlying assumption was that a WWTP development will meet community needs. The survey results indicate that most respondents, 95%, were aware of and/or received information regarding the development of communal WWTP. Altogether, the conditions were found favorable for communal participation in the WWTP management.\n\nMost of the development of communal WWTP infrastructure is through government assistance from The Ministry of Public Works and Housing of Indonesia. Another form of assistance is through community participation through the swadaya (self-reliance) system. The forms of community swadaya are varied and combined, among others, labor through community service or mutual cooperation, consumption, funds, and others. The majority of the community, e.g., 93.3%, participated in the development of swadaya communal WWTPs (Table 6). The rest did not because they believed there was no activity and respondents were unaware of developments. Table 6 shows details of types of swadaya participation provided by the community during the communal WWTP development process. The largest types of participation are con-sumption and funds (28.3%) and mutual cooperation (26.7%).\n\nParticipation in swadaya was also required during operations and maintenance. The majority of the community, 92.5%, contributed to the operation and maintenance of communal WWTPs through swadaya (Table 7). The remainder did not participate because they believed there were no swadaya activities or because of unawareness. Table 5 details the various forms of community swadaya participation in the operation and maintenance of the communal WWTP. The most widespread form of participation is gotong royong (mutual assistance) (50.8 percent). A community sharing gotong royong principles shares responsibility and prevents conflict in between the commu-nity members. Gotong royong can manifest itself in social activities or traditional communal work (cooperative labor), such as cleaning the environment in the neigh-borhood.38,39\n\nThe sustainability of communal WWTPs will require high participation in the future. This requires a commitment in the form of a future willingness to participate independently. The majority of community members who use communal WWTPs stated that they were unconditionally willing to use it (52.5 percent), followed by respondents that made their willingness contingent on the situation and circumstances (40.8 percent), and only 6.7 percent who stated that they were unwilling to use the WWTPs (Table 8). These responses provide reason to be optimistic about the the sustainability of communal WWTPs.\n\nInstitutional aspects in the sustainability of communal WWTPs\n\nInstitutions are required to maintain and optimize communal wastewater treatment plant operations in order to ensure their sustainability. Each communal WWTP in the research area has a management agency. The majority of customers were aware of the institution’s existence (97.5 percent; Table 9). The majority of current positions (77.5 percent) were held by community members. Only a small percentage believed these positions were held by administrators (20 percent).\n\nThe establishment of institutions coincided with the completion and operation of the communal WWTP. Each location had its own mechanism for establishing institutions, despite the fact that government standard operating procedures have been provided. The majority of people (55 percent) understood that the management agency was formed through discussion, followed by designation of government officials (23.3 percent) and voting (12.5 percent), while 9.2 percent were unaware of this procedure (Table 10).\n\nCommitment to being a manager is an important guarantee for the sustainability of communal WWTPs. The majority of people (76.6 percent) were comitted to serve as a communal wastewater treatment plant administrator with 57.5 percent willing to participate if members elected them and 19.1 percent willing if government officials appointed them (Table 11). Only 23.3 percent indicated a lack of interest in becoming an administrator.\n\nCommunal wastewater treatment plant management is undoubtedly colored by its own dynamics. One of them may manifest itself as conflict. The public perception was found to be quite favorable, with majority believing there is no conflict (56.7 percent), while 11.7% believed that minor conflict existed which can been resolved (Tabel 12). Some (31.7 percent) were unaware of any conflict.\n\nThe performance of institutions in serving and managing communal WWTPs was found to be critical because it influenced the trust of the people involved and de-termined sustainability. Non-governmental organizations required members’ or users’ perceptions of their performance. Table 13 illustrates how performance was per-ceived on a scale of moderate, good, and very good, including not good.\n\nThe performance perceptions outlined above determined how satisfied communal WWTP users were. Perceived satisfaction was in a range of sufficient, satisfied, and very satisfied, and no one was dissatisfied (Table 14).\n\nEconomic aspects in the sustainability of communal WWTPs\n\nWWTP management costs money to operate according to technical standards. In the study area, the user community is responsible for financing communal WWTP operations. The portion of government assistance is small and only covers operation and maintenance cost. Therefore, a community’s economic conditions, willingness to pay, and ability to pay all have an impact on sustainability of WWTP financing. This research site is a peri-urban area with a primarily non-agricultural economy. The majority of people have an average expenditure that exceeds the district’s minimum wage, which is approximately Rp. 2,000,000.00 (Table 15). As a result of this compreably high income niveau, the economic conditions were favorable for communal WWTP financing.\n\nThe nominal routine fees paid vary according to each manager’s policies (Table 13). The majority of nominal values are less than Rp. 10,000.00. This nominal is, of course, quite small, and affordable in comparison to aforementioned average expenditures. Whether this small nominal value is sufficient for standard communal WWTP operations determines the system’s economic sustainability.\n\nAll communal WWTPs charge a monthly fee on a consistent basis. Most peo-ple (89.2%) paid on time, followed by 2.5 percent who paid but not on time, and 8.3 percent who did not pay or are unable to pay (Table 16).\n\nEconomic contribution is not only a requirement; it is also a motivation to ensure sustainability. Monthly fees and incidental fees in event of damage or major mainte-nance needs are types of fees that users must be prepared to pay. All respondents in-dicated a willingness to pay monthly fees (Table 15). Among the variations in will-ingness, there were those who were willing according to their economic status (10.8 percent), those who were willing to pay the same amount (87.5 percent), and those who were sincerely willing (1.7 percent).\n\nUnexpected expenses that cannot be met through monthly contributions required in-cidental contributions on an as-needed basis. In contrast to their willingness to pay monthly fees, some users stated that they were unwilling to pay incidental fees, regard-less of how small they were (5.0 percent). The remainder were mostly agreeable, with 48.3 percent proposing a flat or equal pay, 31.7 percent sincerely, and 15.0% based on economic status (Table 17).\n\nFollowing the willingness to pay, a commitment to the ability to pay (ATP) is required to ensure economic sustainability. 68.0 percent indicated they would be able to pay if the contribution remained same as it is currently, and 31.7 percent indicated they would still be able to pay if the contribution increased. No one declared incapability to avoid paying dues.\n\nOther analysis was conducted on sentiment based on expectation and feedback from participants. Participants was asked about their expectation and feedback from fellow users of the communal WWTPs, from managers of the communal WWTPs, and from government. Figure 2 depicts participants’ responses to question regarding their expectations from and feedback for fellow users. The word IPAL which was translated WWTP appears as dominant word. It reflects the importance of WWTP for users and their expectations that the plant was kept as communal assets. Some participants express their expectation that other fellow users keep the WWTP clean.\n\nSource: Primary data, authors’ analysis.\n\nOther significant words that appear are saluran (canal) and sampah (non-water waste). Many participants have concern regarding inappropriate practice by other fellow users who throw some waste on canal of the WWTP. It indicates that some users have not been fully understood the importance of canal cleaness for sustainability of the communal WWTP.\n\nFigure 3 describes the results of word count based on participants’ response on expectation and feedback to communal WWTPs mangers. The word IPAL also appears to be dominant which reflect its importance in this context. The word saluran and sampah also appear as indication of users concern about the importance of managers’ task in handling the cleaness of WWTPs. Among words that highly related with managerial task were saling (reciprocal) and kompak (unified). Participants view managerial task should be handled in a well-organized team. The unity of managerial team in handling issues related to the communal WWTP is considered important. This finding is in line with the relatively calm or free of conflict as indicated before.\n\nSource: Primary data, authors’ analysis.\n\nParticipants’ response on expectation and feedback to the government is presented in Figure 4. The word IPAL, saluran, sampah are still among the prioritized aspects of WWTPs as viewed by users. The word dana which is translated fund appears among the dominant word. The word count for 25 times and all indicate participants expectation that the government support the communal WWTPs through specific funding. With this frequency of word dana being mentioned, it is understandable that users of communal WWTPs really have developed swadaya as cultural force in handling their environmental issues.\n\nSource: Primary data, authors’ analysis.\n\n\nDiscussion\n\nEcological, economic, and social dimensions of sustainable urban infrastructure, such as WWTPs, are just as critical as their technological dimensions.40 The socioeconomic dimension is frequently overlooked in development, both during planning and operationalization. Sustainability is frequently translated as cost effectiveness, despite the fact that underlying dynamics require complex interpretations, such as environmental, social, and economic dimensions.41–43\n\nThe conditions investigated herein underline social vulnerabilities of communal WWTPs at every stage. The most serious consequence is that the sustainability of community level programs are not guaranteed, frequently resulting in their termination. The distribution of power and influence in a society is at the core of numerous environmental and development challenges, implying that resolving development problems requires a participatory approach based on local appraisal.44–49 Therefore, the principle of sustainability must be considered in order to meet mutually agreed-upon development criteria, namely meeting current needs without compromising future needs.50–52\n\nNon-technical support for communal WWTP operations is typically comprised of social and institutional participation, as well as economic contributions. This non-technical assessment of sustainability requires a multi-criteria approach in order to identify the most suitable system.53 Furthermore, the higher waste pollution prevention and control index, the less work is required to protect the environment and population from pollution and its adverse effects.54 The results of this study contributed to the identification of relevant non-technical aspects which can ensure the long-term viability of communal WWTPs. Specifically, the results describe the conditions that support the social, institutional, and economic dimensions of communal WWTP sustainability. The social dimension revealed a high and diverse level of community involvement in the management of communal WWTPs in the study area. The large participation in the form of gotong royong demonstrates the strong sense of community inherent in the Indonesian culture. Gotong royong is accomplished in a straightforward but diverse manner through the use of manpower, funds, or goods, either independently or voluntarily.\n\nIn the lives of Indonesian people, the tradition of gotong royong is a relic of the past that has been transformed generationally (traditional heritage).55 Gotong royong is an institution tasked with the responsibility of mobilizing community solidarity and fostering social cohesion in the Indonesian nation’s life.56,57 Futhermore, it is an expression of solidarity, mutual assistance, and unity that has become a habit in people’s lives.58,59 Gotong royong, as the value of local wisdom, must be constantly developed and, in case of communal WWTPs, adjusted to modern realities. Besides economic efficiency; its social ties and interactions can strengthen the sustainabiliyt of communal WWTPs in Indonesia.\n\nThe social support aspect as quantified herein is motivated by public awareness that being a WWTP user is not mandatory or obligatory. This is consistent with and relevant to the finding of previous research that show attitudes and intentions have a positive and significant effect on environmental activities.60 Previous research show that many aspect determine community acceptance of wastewater reuse.61–63 Some of these aspects are knowledge and information sources, demographic characteristics, and the importance of communication in increasing social sustainability.64\n\nThe existence of institutional assets is also a critical non-technical aspect of communal WWTP sustainability. The research findings indicate that the institutions’ dynamics are participatory, democratic, and elicit satisfaction from community members. Infrastructure asset management provides services through the use of a fundamental framework of operating systems, management, and governance. Satisfaction with the service demonstrates an institution’s effectiveness and optimal management of communal WWTPs in collaboration with the community. These institutional conditions reaffirm previous research that suggest that sanitation or water infrastructures face governance and sociocultural suitability challenges.65–67 Previous research recommended that projects and their operation should be a collaborative effort involving the government, institutions, and community. Some recommendations have also been implemented at the research site, specifically strengthening key stakeholder groups through a participatory approach to ensure success.\n\nSustainable water management has been identified as a critical strategic issue in the transformation process to a circular economy. Water and wastewater management are critical components of this process.68–71 Thus far, the linear economy has exacerbated resource depletion and pollution, resulting in environmental conflicts. Circular economy mechanisms are required for non-conflict sustainable alternatives.72,73 Wastewater treatment plants urgently need to transition from a linear economy operation/design concept to a circular economy, with resource recovery and more sustainable waste management as a result.74,75\n\nSwadaya and its economic dimensions are also part of the transition to a circular economy. Swadaya is based on the willingness and ability to contribute and this study indicates a high level of willingness to contribute through regular or incidental contributions to WWTPs. This demonstrates a sense of ownership, confidence in the WWTP managers, and a sense of benefit. Hence, swadaya establishes a solid foundation for the long-term development and management of communal WWTPs. Different findings were obtained in Latin America where social and economic variables were valued lower compared to technical ones.76 The findings of the current study suggest that the swadaya approach cannot necessarily transplanted to other regions of the world. In conclusion, the current study findings underline that whatever technology is used, it must be technically, environmentally, socially, and economically feasible.77 This research strengthens and adds to evidence that operating communal WWTPs are not only feasible but also sustainable.\n\nMain limitations of this study were number of participants and lack of feedback in the form of focused group discussions. Due to budget and time constraints, this study took 120 participants from three sub-disctrict with quota sampling technique. As its nature, this technique might limit the potential population during research. Furthermore, as a study tried to capture the non-technical aspects, this study could not add focused group discussions to improve its findings. Taking pandemic situation, altough it was controlled during the researh time, these limitations are understandable. Focused group discussions with participants would require additional permissions related to health issues. On the other hand, inviting participants to a virtual meeting would not be advised since the participants were living in peri-urban locations and less appropriate in accordance with the culture they live with.\n\nThis study shows the importance of non-technical aspects of communal WWTPs in peri-urban in Yogyakarta. These non-technical aspects can be based on social, institutional, and economic sides that encounter users of the communal WWTPs on daily basis. This study also shows that the users have developed understanding of the importance of self-management in communal WWTPs so that they were not dependents on the government supports. On the other hand, the management team also did not play capitalistic role as sole sellers of the services. These two aspects of management indicate the capacity of communal WWTPs to sustain. However, since the benefit of such communal WWTPs exceed its users, additional contributions from the government need to be disscused for further action.\n\nGeneralisability of findings in this study should be limited to relevant context of the communal WWTPs. When the WWTPs are located in a peri-urban and local people are mostly Javanese, the findings of this study can potentially also be found. Swadaya and gotong royong as two main importance drivers for the enacments of many communal WWTPs in this study would be easily found in rural area or peri-urban where Javanese people in Java island live. These drivers are generally transmitted and became part of the way of their life. Thus, applying the findings of this study in different contexts could be irrelevant.\n\n\nConclusions\n\nThis study’s findings underlines the importance of non-technical sustainability as-pects toward the operation of communal WWTPs. Social dimensions positively influ-enced community participation, willingness to pay and ability to pay. The institutional dimensions influence a community’s satisfaction with WWTP performance. A major challenge is to attract qualified managers, as interest in administrative positions remains low in the studied communities. In this part of Indonesia, the gotong royong philosophy supports and influences non-technical aspects of communal WWTP’s sustainability. Starting with voluntary acceptance of communal WWTPs, understanding their benefits, trust in manager, ownership are critical for the sustainability of communal WWTPs. Gotong royong or other local wisdoms should be accounted for to support communal WWTPs in other regions or countries, especially in other developing nations.\n\n\nData availability\n\nFigshare. Dataset for Non-technical dimensions of communal wastewater treatment plant sustainability in peri-urban Yogyakarta, Indonesia. DOI: https://doi.org/10.6084/m9.figshare.19612938.78\n\nThis project contains the following underlying data:\n\n- This dataset contains the results of questionnaires to 120 community members around the communal WWTPs in peri-urban Yogyakarta, particularly the Districts of Depok, Ngaglik, and Mlati.\n\n- The data was collected using a questionnaire that had been approved by the Directorate of Human Resources, Islamic University of Indonesia. Respondents were collected by using uncontrolled quota sampling method.\n\n- The number of respondents from Depok sub-district was 54 people, 32 people from Mlati sub-district, and 34 people from Ngaglik sub-district.\n\n- Respondents answered questions regarding the social, institutional, and economic aspects of the communal WWTPs in their area of residence.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAuthor roles\n\nBrontowiyono W: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Methodology, Resources, Supervision, Validation, Writing – Original Draft Preparation; Boving T: Supervision, Writing – Review & Editing; Asmara AA: Data Curation, Formal Analysis, Project Administration; Rahmawati S: Data Curation, Formal Analysis, Project Administration; Yulianto A: Data Curation, Formal Analysis, Project Administration; Wantoputri NI: Formal Analysis, Writing – Review & Editing; Lathifah AN: Formal Analysis, Writing – Review & Editing; Andriansyah Y: Formal Analysis, Writing – Review & Editing.",
"appendix": "Acknowledgments\n\nThe authors thank Direktorat Sumber Daya Manusia, Universitas Islam Indonesia for funding research that this article was based on and Direktorat Pengembangan Akademik, Universitas Islam Indonesia for financial support for publishing this article. The authors also thank Local Governments of Depok, Mlati, and Ngaglik Sub-Districts, Villages in Depok, Mlati, and Ngaglik Sub-Districts, Managers of communal WWTPs in Depok, Mlati, and Ngaglik Sub-Districts for their supports during the research process.\n\n\nReferences\n\nMassoud MA, Tarhini A, Nasr JA: Decentralized approaches to wastewater treatment and management: Applicability in developing countries. Journal of Environmental Management. 2009 [cited 2022 Mar 17]; 90(1): 652–659. Publisher Full Text Reference Source\n\nKohler L, Silverstein J, Rajagopalan B: Predicting life cycle failures of on-site wastewater treatment systems using generalized additive models. Environmental Engineering Science. 2016; 33(2): 112–124. Publisher Full Text\n\nSantos E, Lisboa I, Eugénio T: Economic Sustainability in Wastewater Treatment Companies: A Regional Analysis for the Iberian Peninsula. Applied Sciences. 2021 [cited 2022 Mar 17]; 11(21): 9876. Reference Source\n\nBalkema AJ, Preisig HA, Otterpohl R, et al.: Indicators for the sustainability assessment of wastewater treatment systems. Urban Water. 2002 [cited 2022 Mar 17]; 4(2): 153–161. Reference Source\n\nCronin AA, Odagiri M, Arsyad B, et al.: Piloting water quality testing coupled with a national socioeconomic survey in Yogyakarta province, Indonesia, towards tracking of Sustainable Development Goal 6. International Journal of Hygiene and Environmental Health. 2017; 220(7): 1141–1151.\n\nFathmawati F, Fachiroh J, Sutomo AH, et al.: Origin and distribution of nitrate in water well of settlement areas in Yogyakarta, Indonesia. Environmental Monitoring and Assessment. 2018 Nov [cited 2022 Mar 23]; 190(11): 628. Reference Source\n\nFajarwati A, Setyaningrum A, Rachmawati R, Prakoso BSE: Keys of sustainable community-based waste management (lesson learnt from Yogyakarta City). Haryono E, Lavigne F, Omar RC, et al., editors. 1st Geosciences and Environmental Sciences Symposium (icst 2020). Cedex A: E D P Sciences; 2020; 200. : p. 02018. Publisher Full Text\n\nBrontowiyono W, Yulianto A, Utami S, Lupiyanto R: Evaluation of Decentralized Communal Wastewater Treatment in Yogyakarta. 1st International Conference on Rehabilitation and Maintenance in Civil Engineering (ICRMCE). Solo, Indonesia: 2009; p. 1–10.\n\nRahmawati I, Retno DS, Soedirham O, et al.: Confirmatory factor analyze on education characters of teenagers based on the character system theory in sexual prevention of premarital in Jember district. Indian Journal of Public Health Research and Development. 2019; 10(12): 1724–1728. Publisher Full Text\n\nYulianto A, Pramudita AF, Wantoputri NI, et al.: Evaluation of Post-Construction Communal Wastewater Treatment Plants (WWTPs) in Sleman District, Special Region of Yogyakarta. IOP Conf Ser: Earth Environ Sci. 2021 Nov [cited 2022 Mar 23]; 933(1): 012019. Publisher Full Text\n\nPadilla-Rivera A, Morgan-Sagastume JM, Noyola A, et al.: Addressing social aspects associated with wastewater treatment facilities. Environmental Impact Assessment Review. 2016 [cited 2022 Mar 22]; 57: 101–113. Publisher Full Text Reference Source\n\nLancaster K, Rhodes T, Kylie V, et al.: A ‘promising tool’? A critical review of the social and ethico-political effects of wastewater analysis in the context of illicit drug epidemiology and drug policy. Current Opinion in Environmental Science & Health. 2019 [cited 2022 Mar 22]; 9: 85–90. Publisher Full Text Reference Source\n\nSinsuw AAE, Wuisang CE, Chu CY: Assessment of environmental and social impacts on rural community by two-stage biogas production pilot plant from slaughterhouse wastewater. Journal of Water Process Engineering. 2021 [cited 2022 Mar 22]; 40: 101796. Publisher Full Text Reference Source\n\nRobbins CA, Du X, Bradley TH, et al.: Beyond treatment technology: Understanding motivations and barriers for wastewater treatment and reuse in unconventional energy production. Resources, Conservation and Recycling. 2022 [cited 2022 Mar 22]; 177: 106011. Publisher Full Text Reference Source\n\nDinas Lingkungan Hidup dan Kehutanan Daerah Istimewa Yogyakarta: Dokumen informasi kinerja pengelolaan lingkungan hidup daerah Daerah Istimewa Yogyakarta tahun 2020 [Information document on environmental management performance in the Special Region of Yogyakarta in 2020]. Yogyakarta, Indonesia: Dinas Lingkungan Hidup dan Kehutanan Daerah Istimewa Yogyakarta; 2021. Reference Source\n\nLim JY, Yoon J, Hovde C: A Brief Overview of Escherichia coli O157:H7 and Its Plasmid O157. Journal of Microbiology and Biotechnology. 2010; 20(1): 5–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDinas Kesehatan Kabupaten Sleman: Profil Kesehatan Kabupaten Sleman Tahun 2020 [Sleman District Health Profile 2020]. Sleman, Indonesia: Dinas Kesehatan Kabupaten Sleman; 2020. Reference Source\n\nGrimes DA, Schulz KF: An overview of clinical research: the lay of the land. The Lancet. 2002 Jan 5 [cited 2022 Apr 16]; 359(9300): 57–61. PubMed Abstract | Publisher Full Text Reference Source\n\nSetia MS: Methodology Series Module 3: Cross-sectional Studies. Indian Journal of Dermatology. 2016 [cited 2022 Apr 19]; 61(3): 261–264. PubMed Abstract | Publisher Full Text Reference Source\n\nHealth Liaison Librarians: LibGuides: Quantitative Study Designs: Introduction.2021 [cited 2022 Apr 16]. Reference Source\n\nHealth Liaison Librarians: LibGuides: Quantitative Study Designs: Cross-Sectional Studies.2021 [cited 2022 Apr 19]. Reference Source\n\nBadan Informasi Geospasial (BIG): Peta Rupabumi Digital Indonesia [Indonesia’s Digital Topographic Map]. Indonesia Geospasial Portal.2019 [cited 2022 Apr 23]. Reference Source\n\nBadan Informasi Geospasial (BIG): Syarat dan Ketentuan [Terms and Conditions]. Indonesia Geospasial Portal.2019 [cited 2022 Apr 23]. Reference Source\n\nPreston V: Questionnaire Survey. Kitchin R, Thrift N, editors. International Encyclopedia of Human Geography. Oxford: Elsevier; 2009 [cited 2022 Mar 23]; p. 46–52. Publisher Full Text Reference Source\n\nRukmana D: Quota Sampling. Michalos AC, editor. Encyclopedia of Quality of Life and Well-Being Research. Dordrecht: Springer Netherlands; 2014 [cited 2022 Mar 23]; p. 5382–5384. Publisher Full Text\n\nExplorable.com Quota Sampling Applied in Research - Non-Probability Sampling. Explorable; 2009 [cited 2022 Apr 18]. Reference Source\n\nCooksey R, McDonald G: How Do I Manage the Sampling Process?. Cooksey R, McDonald G, editors. Surviving and Thriving in Postgraduate Research. Singapore: Springer; 2019 [cited 2022 Apr 19]; p. 827–894. Publisher Full Text\n\nMoser CA: Quota Sampling. Journal of the Royal Statistical Society Series A (General). 1952 [cited 2022 Apr 16]; 115(3): 411–423. Publisher Full Text Reference Source\n\nMoser CA, Stuart A: An Experimental Study of Quota Sampling. Journal of the Royal Statistical Society Series A (General). 1953 [cited 2022 Apr 16]; 116(4): 349–405. Publisher Full Text Reference Source\n\nWilson LA: Quantitative Research. Liamputtong P, editor. Handbook of Research Methods in Health Social Sciences. Singapore: Springer; 2019 [cited 2022 Mar 23]; p. 27–49. Publisher Full Text\n\nChen X: Quantitative Descriptive Epidemiology. Chen X, editor. Quantitative Epidemiology. Cham: Springer International Publishing; 2021 [cited 2022 Mar 23]; p. 61–89. (Emerging Topics in Statistics and Biostatistics). Publisher Full Text\n\nHan F, Yang Z, Wang H, et al.: Estimating willingness to pay for environment conservation: a contingent valuation study of Kanas Nature Reserve, Xinjiang, China. Environmental Monitoring and Assessment. 2011 Sep 1 [cited 2022 Mar 23]; 180(1): 451–459. PubMed Abstract | Publisher Full Text\n\nShen L, Chen LY, Su AT: User’s willingness to pay for natural environment conservation and protection with commitment. Landscape and Ecological Engineering. 2021 Jul 1 [cited 2022 Mar 23]; 17(3): 339–349. Publisher Full Text\n\nSalam MA, Noguchi T, Alim MA: Factors Affecting Participating Farmers’ Willingness-to-pay for the Tree Farming Fund: A Study in a Participatory Forest in Bangladesh. Environmental Monitoring and Assessment. 2006 Jul 1 [cited 2022 Mar 23]; 118(1): 165–178. PubMed Abstract | Publisher Full Text\n\nAl-Khateeb AJ, Al-Sari MI, Al-Khatib IA, et al.: Factors affecting the sustainability of solid waste management system—the case of Palestine. Environmental Monitoring and Assessment. 2017 Jan 31 [cited 2022 Mar 23]; 189(2): 93. PubMed Abstract | Publisher Full Text\n\nMitsui S, Kubo T, Shoji Y: Understanding residents’ perceptions of nature and local economic activities using an open-ended question before protected area designation in Amami Islands, Japan. Journal for Nature Conservation. 2020 Aug 1 [cited 2022 Mar 23]; 56: 125857. Publisher Full Text Reference Source\n\nAltintzoglou T, Honkanen P, Whitaker RD: Influence of the involvement in food waste reduction on attitudes towards sustainable products containing seafood by-products. Journal of Cleaner Production. 2021 Feb 20 [cited 2022 Mar 23]; 285: 125487. Publisher Full Text Reference Source\n\nWati EP, Hidayah A: Kearifan Lokal Menjaga Lingkungan Hidup Melalui Program Gotong Royong di Kota Palembang [Local Wisdom Protects the Environment Through the Gotong Royong Program in Palembang City]. Bina Hukum Lingkungan. 2017 [cited 2022 Apr 19]; 2(1): 57–69. Publisher Full Text Reference Source\n\nRahman F, Lestariono W: Keteraturan Sosial dalam Bentuk Gotong Royong Mengelola Kebersihan Lingkungan di Kelurahan Menteng Kecamatan Jekan Raya Kota Palangka Raya [Social Order in the Form of Mutual Cooperation in Managing Environmental Cleanliness in Menteng Village, Jekan Raya District, Palangka Raya City]. Jurnal Sociopolitico. 2020 [cited 2022 Apr 19]; 2(2): 70–82. Publisher Full Text Reference Source\n\nSchinkel U, Becker N, Trapp M, et al.: Assessing the Contribution of Innovative Technologies to Sustainable Development for Planning and Decision-Making Processes: A Set of Indicators to Describe the Performance of Sustainable Urban Infrastructures (ISI). Sustainability. 2022 [cited 2022 Mar 17]; 14(4): 1966. Reference Source\n\nBalogh JM, Mizik T: Trade-Climate Nexus: A Systematic Review of the Literature. Economies. 2021 Sep [cited 2021 Oct 29]; 9(3): 99. Publisher Full Text Reference Source\n\nKim J: Social dimension of sustainability: From community to social capital. Journal of Global Scholars of Marketing Science. 2018 Apr 3 [cited 2022 Mar 23]; 28(2): 175–181. Publisher Full Text\n\nChoi S, Ng A: Environmental and Economic Dimensions of Sustainability and Price Effects on Consumer Responses. Journal of Business Ethics. 2011 Dec 1 [cited 2022 Mar 23]; 104(2): 269–282. Publisher Full Text\n\nAzapagic A: Developing a framework for sustainable development indicators for the mining and minerals industry. Journal of Cleaner Production. 2004 Aug 1 [cited 2022 Mar 23]; 12(6): 639–662. Publisher Full Text Reference Source\n\nKemp D: Mining and community development: problems and possibilities of local-level practice. Community Development Journal. 2010 Apr 1 [cited 2022 Mar 23]; 45(2): 198–218. Publisher Full Text\n\nWatson RT, Boudreau MC, Chen AJ: Information Systems and Environmentally Sustainable Development: Energy Informatics and New Directions for the IS Community. MIS Quarterly. 2010 [cited 2022 Mar 23]; 34(1): 23–38. Publisher Full Text Reference Source\n\nScott CA, Kurian M, Wescoat JL: The Water-Energy-Food Nexus: Enhancing Adaptive Capacity to Complex Global Challenges. Kurian M, Ardakanian R, editors. Governing the Nexus: Water, Soil and Waste Resources Considering Global Change. Cham: Springer International Publishing; 2015 [cited 2022 Mar 23]; p. 15–38. Publisher Full Text\n\nPolasky S, Kling CL, Levin SA, et al.: Role of economics in analyzing the environment and sustainable development. Proceedings of the National Academy of Sciences. 2019 Mar 19 [cited 2022 Mar 23]; 116(12): 5233–5238. PubMed Abstract | Publisher Full Text\n\nWang C, Cardon PW, Liu J, et al.: Social and economic factors responsible for environmental performance: A global analysis. PLoS One. 2020 Aug 27 [cited 2022 Mar 23]; 15(8): e0237597. PubMed Abstract | Publisher Full Text\n\nMeacham B, Bowen R, Traw J, et al.: Performance-based building regulation: current situation and future needs. Building Research & Information. 2005 Mar 1 [cited 2022 Mar 23]; 33(2): 91–106. Publisher Full Text\n\nDavis AP, Hunt WF, Traver RG, et al.: Bioretention Technology: Overview of Current Practice and Future Needs. Journal of Environmental Engineering. 2009 Mar 1 [cited 2022 Mar 23]; 135(3): 109–117. Publisher Full Text\n\nSpeakman JR, Blount JD, Bronikowski AM, et al.: Oxidative stress and life histories: unresolved issues and current needs. Ecology and Evolution. 2015 [cited 2022 Mar 23]; 5(24): 5745–5757. PubMed Abstract | Publisher Full Text\n\nStarkl M, Brunner N, Das S, et al.: Sustainability Assessment for Wastewater Treatment Systems in Developing Countries. Water. 2022 Jan [cited 2022 Mar 17]; 14(2): 241. Publisher Full Text Reference Source\n\nOdiete WE: Novel metric for managing the protection of humanity and the environment against pollution and its adverse effects. Heliyon. 2020 Nov 1 [cited 2022 Mar 17]; 6(11): e05555. PubMed Abstract | Publisher Full Text Reference Source\n\nWinardi UN: Gotong Royongand the Transformation of Kampung Ledok Code, Yogyakarta. City Society. 2020 Aug [cited 2022 Mar 23]; 32(2): 375–386. Publisher Full Text Reference Source\n\nSubagyo: Pengembangan nilai dan tradisi gotong royong dalam bingkai konservasi nilai budaya [Development of values and traditions of gotong royong within the framework of conservation of cultural values]. Indonesian Journal of Conservation. 2012 [cited 2022 Mar 17]; 1(1): 61–68. Reference Source\n\nSuwignyo A: Gotong royong as social citizenship in Indonesia, 1940s to 1990s. Journal of Southeast Asian Studies. 2019 Sep [cited 2022 Mar 23]; 50(3): 387–408. Publisher Full Text Reference Source\n\nEndro G: Tinjauan filosofis praktik gotong royong [A philosophical review of the practice of gotong royong]. Respons: Jurnal Etika Sosial. 2016 [cited 2022 Mar 17]; 21(01): 89–111. Reference Source\n\nNainggolan FMR, Subroto TYW, Marsoyo A: The Value of Gotong-royong in the Mountainous Settlement of Kepuharjo Village at Pagerjurang Permanent Shelter in Yogyakarta, Indonesia. International Journal of Built Environment and Sustainability. 2021 [cited 2022 Mar 23]; 8(3): 93–106. Publisher Full Text Reference Source\n\nLiu Q, Xu Q, Shen X, et al.: The Mechanism of Household Waste Sorting Behaviour—A Study of Jiaxing, China. International Journal of Environmental Research and Public Health. 2022 Jan [cited 2022 Mar 17]; 19(4): 2447. Reference Source\n\nPo M, Nancarrow BE, Leviston Z, et al.: Predicting community behaviour in relation to wastewater reuse: What drives decisions to accept or reject?. Commonwealth Scientific and Industrial Research Organisation (CSIRO); 2007 May [cited 2022 Mar 23]. Reference Source\n\nAsano T, Maeda M, Takaki M: Wastewater reclamation and reuse in Japan: Overview and implementation examples. Water Science and Technology. 1996 Jan 1 [cited 2022 Mar 23]; 34(11): 219–226. Publisher Full Text Reference Source\n\nBuyukkamaci N, Alkan HS: Public acceptance potential for reuse applications in Turkey. Resources. Conservation and Recycling. 2013 Nov 1 [cited 2022 Mar 23]; 80: 32–35. Publisher Full Text Reference Source\n\nChfadi T, Gheblawi M, Thaha R: Public Acceptance of Wastewater Reuse: New Evidence from Factor and Regression Analyses. Water. 2021 Jan [cited 2022 Mar 23]; 13(10): 1391. Reference Source\n\nRoutray P, Schmidt WP, Boisson S, et al.: Socio-cultural and behavioural factors constraining latrine adoption in rural coastal Odisha: an exploratory qualitative study. BMC Public Health. 2015 Sep 10 [cited 2022 Mar 23]; 15(1): 880. PubMed Abstract | Publisher Full Text\n\nPrescott MF, Dobbie MF, Ramirez-Lovering D: Green Infrastructure for Sanitation in Settlements in the Global South: A Narrative Review of Socio-Technical Systems. Sustainability. 2021 Jan [cited 2022 Mar 23]; 13(4): 2071. Reference Source\n\nHaggerty JH, Dunn J, Gansauer G, et al.: Social memory and infrastructure governance: a century in the life of a rural drinking water system. Environmental Research: Infrastructure and Sustainability. 2021 Nov [cited 2022 Mar 23]; 1(3): 035004. Publisher Full Text\n\nSmol M, Koneczna R: Economic Indicators in Water and Wastewater Sector Contributing to a Circular Economy (CE). Resources. 2021 [cited 2022 Mar 17]; 10(12): 129. Reference Source\n\nSmol M, Adam C, Preisner M: Circular economy model framework in the European water and wastewater sector. Journal of Material Cycles and Waste Management. 2020 May 1 [cited 2022 Mar 23]; 22(3): 682–697. Publisher Full Text\n\nGuerra-Rodríguez S, Oulego P, Rodríguez E, et al.: Towards the Implementation of Circular Economy in the Wastewater Sector: Challenges and Opportunities. Water. 2020 May [cited 2022 Mar 23]; 12(5): 1431. Reference Source\n\nSgroi M, Vagliasindi FGA, Roccaro P: Feasibility, sustainability and circular economy concepts in water reuse. Current Opinion in Environmental Science & Health. 2018 Apr 1 [cited 2022 Mar 23]; 2: 20–25. Publisher Full Text Reference Source\n\nHalbac-Cotoara-Zamfir R, Colantoni A, Mosconi EM, et al.: From Historical Narratives to Circular Economy: De-Complexifying the “Desertification” Debate. International Journal of Environmental Research and Public Health. 2020 Jan [cited 2022 Mar 23]; 17(15): 5398. Reference Source\n\nMihai FC, Minea I: Sustainable Alternative Routes versus Linear Economy and Resources Degradation in Eastern Romania. Sustainability. 2021 [cited 2022 Mar 17]; 13(19): 10574. Reference Source\n\nMannina G, Badalucco L, Barbara L, et al.: Enhancing a Transition to a Circular Economy in the Water Sector: The EU Project WIDER UPTAKE. Water. 2021 Jan [cited 2022 Mar 23]; 13(7): 946. Reference Source\n\nMannina G, Badalucco L, Barbara L, et al.: Roadmapping the Transition to Water Resource Recovery Facilities: The Two Demonstration Case Studies of Corleone and Marineo (Italy). Water. 2022 Jan [cited 2022 Mar 23]; 14(2): 156. Reference Source\n\nBenavides L, Avellán T, Caucci S, et al.: Assessing Sustainability of Wastewater Management Systems in a Multi-Scalar, Transdisciplinary Manner in Latin America. Water. 2019 Feb [cited 2022 Mar 23]; 11(2): 249. Reference Source\n\nBetanzo-Torres EA, Piñar-Álvarez M d l Á, Sierra-Carmona CG, et al.: Proposal of Ecotechnologies for Tilapia (Oreochromis niloticus) Production in Mexico: Economic, Environmental, and Social Implications. Sustainability. 2021 [cited 2022 Mar 17]; 13(12): 6853. Reference Source\n\nBrontowiyono W: Dataset for Non-technical dimensions of communal wastewater treatment plant sustainability in peri-urban Yogyakarta, Indonesia. figshare. 2022 [cited 2022 Apr 20]. Reference Source"
}
|
[
{
"id": "192887",
"date": "14 Aug 2023",
"name": "Vishal Narain",
"expertise": [
"Reviewer Expertise Water governance",
"peri-urban"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPaper summary and strengths\nThe paper describes eloquently the non-technical dimensions of a communal wastewater treatment plant sustainability in a peri-urban location in Jakarta, Indonesia. It has a very well developed and designed methodology that is clearly presented. It is also noteworthy for its emphasis on the concept of \"gotong royong\" and \"swadaya\", refering to aspects of social capital and a spirit of self-reliance, respectively, aspects that receive scant attention in discourses on sustainability of wastewater treatment systems.\n\nThe paper is useful but some points need attention before the paper becomes worthy of indexing.\nMajor comments.\n\nThe paper makes a claim that the community-based wastewater treatment systems perform better than state based water treatment plants. What is the reason for this ? Does the current study support this claim.\nThe research site is located in a peri-urban context. What are the implications of this for the research findings ? Is the peri-urban context simply incidental to the research or does it have specific implications for the findings. There are passing references to this in the text, but they need to be spelt out more clearly,\nMinor comments. The paper refers to institutional factors. We need a working definition of institutions here. Are institutions the same as organizations, or do we imply something different ?\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "10379",
"date": "27 Oct 2023",
"name": "Widodo Brontowiyono",
"role": "Author Response",
"response": "The following passages are our response to Reviewer 1’ comments on our manuscript. Reviewer 1: The paper makes a claim that the community-based wastewater treatment systems perform better than state based water treatment plants. What is the reason for this ? Does the current study support this claim. Response: In our understanding and opinion, a community-based system is an integration of top-down and bottom-up approaches with the latter is more dominant. A top-down approach in a a community-based system is mostly formalized in funding support. While, in a state-based system, top-down approach is more dominant. Here are some works supporting our claim based on empirical evidence in Indonesia. Handoko et al. (1) indicate that the Coastal Resilience Zone Development (Pengembangan Kawasan Pesisir Tangguh abbreviated PKPT in Bahasa Indonesia) driven by an empowerment spirit combining top-down and bottom-up approaches, still bears a strong top-down influence. While the initially participatory nature of PKPT held promise for the sustainability of development programs beyond mere projects, the existing bottom-up space was limited by policymaker control. Additionally, the presence of Coastal Community Groups (Kelompok Masyarakat Pesisir abbreviated KMP in Bahasa Indonesia) implies a top-down formation, contributing to the diversity of pre-existing community groups. Paradoxically, the abundance of these community groups opens room for the dominance of long-established elites within various village functional institutions. The conclusion of this study underscores the importance of expanding the scope for bottom-up approaches in future development programs and strengthening the pre-existing coastal community groups as a means of ensuring the sustainability aspect of these development programs. Furthermore, Desriadi (2) also argues that a centrally planned (top-down) development approach is not in line with the desires of the community, as there are weaknesses in its implementation in the field. Development based on grassroots aspirations (bottom-up) is considered by many experts to be more effective and efficient when implemented at present. Reviewer 1: The research site is located in a peri-urban context. What are the implications of this for the research findings ? Is the peri-urban context simply incidental to the research or does it have specific implications for the findings. There are passing references to this in the text, but they need to be spelt out more clearly. Response: Peri-urban areas exhibit a dominant urban physical character, but socially, they still retain rural characteristics, such as social bonds, local culture, and communal cooperation. This condition strongly supports the sustainability of community-based wastewater treatment systems. Reviewer 1: The paper refers to institutional factors. We need a working definition of institutions here. Are institutions the same as organizations, or do we imply something different ? Response: Offe (3) outlines three fundamental differences between institutions and organizations. Firstly, the task of an organization is dyadic, involving a two-way interaction between one person and one or two others. In contrast, institutions are triadic, established and enforced by a 'third party' not directly involved in the institutionalized interaction. Secondly, tasks in organizations are more modest compared to the anticipated outcomes but are grounded in a shared vision. Thirdly, organizational tasks are far more limited in terms of scope, validity, and their impact on the individuals involved. References Handoko W, Marwah S, Widyastuti TR. Menjaga sustainabilitas pengembangan masyarakat pesisir kebumen: Antara corak top-down, partisipatif dan inisiasi kelembagaan lokal [Maintaining the sustainability of the development of coastal communities in Kebumen: Between top-down, participatory styles and local institutional initiation]. Sosiohumaniora [Internet]. 2017;19(3):244–52. Available from: http://jurnal.unpad.ac.id/sosiohumaniora/article/view/10291 Desriadi D. Partisipasi masyarakat dalam musyawarah perencanaan pembangunan desa di Desa Pisang Berebus Kecamatan Gunung Toar Kabupaten Kuantan Singingi [Community participation in village development planning forum in Pisang Berebus Village, Gunung Toar District, Kuantan Singingi Regency]. Jurnal Trias Politika [Internet]. 2018 Apr 20;2(1):63–85. Available from: https://www.journal.unrika.ac.id/index.php/jurnaltriaspolitika/article/view/1240 Offe C. Designing institutions in East European. In: Goodin RE, editor. The theory of institutional design. Cambridge [England] ; New York, NY, USA: Cambridge University Press; 1996. p. 199–226."
}
]
},
{
"id": "212493",
"date": "07 Nov 2023",
"name": "Maria Prihandrijanti",
"expertise": [
"Reviewer Expertise Municipal/domestic wastewater treatment",
"sustainable city",
"sustainable architecture"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPaper summary and strengths:\n\nThis paper describes the non-technical aspects of communal wastewater treatment plant's sustainability in peri-urban Yogyakarta, Indonesia. Aspects such as community involvement, institutionalization, economic factors, community's perception and understanding of communal WWTP management were identified. Social and institutional dimensions have critical influence/ importance for the communal WWTP's sustainability, particularly the philosophy of 'gotong royong' and 'swadaya'.\n\nWhile the paper offers valuable insights, there are some aspects that require attention before it meets the criteria for indexing.\n\nMajor comments:\nIt would be beneficial to provide additional clarity and elaboration in the gap analysis.\n\nIt is suggested to kindly revise and establish a more concise and clear research framework. The ethical and legal considerations could be condensed to focus primarily on the research design. Justify the efforts made to address potential biases and limitations in the chosen sampling techniques and sample size. If possible, the quantitative analysis and statistical methods could be improved.\n\nEnhancements are necessary for the presentation of results through more streamlined and effective data visualization.\n\nIt is suggested to expand the analysis and discussion of the results by delving deeper than merely describing or narrating the data.\n\nI kindly suggest that there might be an opportunity to enhance the paper with a more substantive discussion, especially regarding the analysis and comparison with prior research findings.\nMinor comments:\n\nThe foundational rationale could benefit from a more structured presentation, and it would be advantageous to use a more recent data and acknowledge the data sources.\n\nKindly revise and/or provide more extensive detail for the paper's objectives or goals. Is it just to identify the non-technical aspects?\n\nFigure 1 should be put in the Setting part.\n\nIt might be beneficial to refine the conclusion for a more precise formulation that effectively addresses the study's intended purpose.\n\nThere are only around 63% references taken from the last 5 years. Kindly incorporate additional references from more recent scientific literatures.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-542
|
https://f1000research.com/articles/11-541/v1
|
19 May 22
|
{
"type": "Research Article",
"title": "Design of a High Efficiency Switched-Capacitor (SC) DC-DC Converter",
"authors": [
"Ahmad Khawarizmi",
"Lini Lee",
"Ahmad Khawarizmi"
],
"abstract": "Portable electronic devices and miniaturized devices would require different operating voltages and load current which can be powered through DC-DC converter. In this paper, the proposed converter is based on a multiple topology of DC-DC converter circuit for more than one voltage gain regions using switched capacitor (SC) method. The post layout implementation showed that the high efficiency networks are achieved with low voltage drop and low internal resistance. The efficiency of 95% and 85% are shown, on the networks in the 1/2 and 2/3 voltage gain regions respectively, proving that this method is advantageous compared to other literature papers.",
"keywords": [
"High-efficiency",
"DC-DC converter",
"switched-capacitor method"
],
"content": "Introduction\n\nPortable electronic devices such as mobile phones have become smaller and more compact. This evolution has led to smaller battery size that require less voltage than its previous version.1 There is also a growth of applications in wearable technology to enhance the quality of life through healthcare, education, security and many more.2–5 As wearable designs grow, power and battery management become crucial, therefore there is a need to extend the battery life of a wearable design by employing energy efficient, while boosting circuit blocks. Different loads in the miniaturized wearable devices would require different operating voltages and load current which can be powered by battery through DC-DC converters. Converters are needed to regulate the voltage to the device requirement. There are two main types of converters which are electronic conversion and magnetic conversion.6 Electronic conversion uses switching technology, while magnetic conversion utilizes magnetic field property in an inductor or a transformer. Most of the step-down DC-DC converters used in the system are buck converters. As the devices become smaller, a buck converter seems to be bulky, and its electromagnetic field becomes noisy due to the present of inductor in the circuit.7 Magnetic field noise is bad for communication devices such as cell phones and laptops.8 It also requires more components to build the circuit such as capacitor, diode, transistor as switch and sometimes it requires a filter to operate. Some of the problems include the size of buck converter, which is bulky due to multiple electronic components, compared to switched-capacitor converter. As for the inductor-based converter, it is dominantly noisy with magnetic field effects.\n\nThe focus of this project is to design a step-down converter circuit based on the switched-capacitor method which is smaller and cheaper. The design also focused on how to achieve higher efficiency to make it competitive compared to conventional inductor-based converter. This project also aims to minimize the number of electronic components used to reduce the cost. The project aims to use only capacitor and transistor as a switch in the circuit.\n\n\nMethods\n\nThis section describes the methods used to complete the project including the design flow of the network, the circuit design, and the Electronic Design Automation (EDA) tools used. The design flow of this project is shown in Figure 1. The circuit is designed using complementary metal-oxide semiconductor (CMOS) 0.5um process using open-source EDA tools, namely LTSpice® software tool for schematic simulation and Electric very large-scale integration (VLSI) design tool for layout implementation.\n\nThe circuit or network as shown in Figure 2 has been designed using Kirchhoff Voltage Law (KVL) method,9 which was divided into two phases: common phase and discharge phase. Common phase is the phase where the capacitor is charged and connected in parallel, while in discharge phase the capacitor is connected in parallel for the 1/2 gain region and in series for the 2/3 gain region.\n\nTable 1 shows the switch cycle when the switches (S1 – S10) are turned on or off depending on the phase and gain regions.\n\n\nResults and discussion\n\nThis section discusses the results obtained in this project and compares these results to those of previous study findings.10–12 Simulation results of the post layout implementation show that the high efficiency networks are achieved with low voltage drop and low internal resistance. The efficiency of the network is calculated and compared with other literature papers as shown in Table 2. In this work, efficiency is calculated based on the following equation.13\n\nThe method is shown to be advantageous over previously developed analysis methods because of its simplicity.\n\nFrom Table 2, the efficiency of this work or network is the highest compared to the other networks. The designed network used much less CMOS transistors compared to other networks. Hence, the designed network produced lower voltage drop across the transistor.\n\n\nConclusion\n\nA multiple gain topology of DC-DC converter circuit for networks in the 1/2 and 2/3 voltage gain region using switched capacitor method has been designed with efficiency of 95% and 85%, respectively. This method has shown to be advantageous over previously developed analysis methods because of its simplicity. The network/circuit can be further improved by implementing clock cycle controller to control the phase of the clock in order to reduce any uncertainty at the output.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nEthical approval\n\nThe authors declared that no human or animal experiments were involved in supporting this work.\n\n\nAuthor’s contribution\n\nAhmad Khawarizmi performed data curation, formal analysis, investigation, methodology, software, validation, visualization, writing – original draft preparation. L. Lee performed conceptualization, data curation, methodology, project administration, resources, software, supervision, writing – original draft preparation, writing – review & editing.",
"appendix": "Acknowledgements\n\nThe authors would like to thank the Multimedia University, facility, and staff for their contributions to this project.\n\n\nReferences\n\nMa M: Design of High Efficiency Step-Down Switched Capacitor DC/DC Converter. Oregon:2003.\n\nVallurupalli S, Paydak H, Agarwal S, et al.: Wearable technology to improve education and patient outcomes in a cardiology fellowship program-a feasibility study. Heal. Technol. 2013; 3: 267–270. Publisher Full Text .\n\nFan H, Heidari H, Maloberti F, et al.: High resolution and linearity enhanced SAR ADC for wearable sensing systems. IEEE Int. Symp. Circuits Systems (ISCAS). 2017; pp. 1–4\n\nPantelopoulos A, Bourbakis NG: A survey on wearable sensor-based systems for health monitoring and prognosis. IEEE Trans. Systems Man Cybernetics Part C (App. Rev.) 2010; vol. 40: pp. 1–12.\n\nLiang X, Heidari H, Dahiya R: Wearable Capacitive-Based Wrist-Worn Gesture Sensing System. IEEE New Generation Circuits Systems (NGCAS). 2017; pp. 181–184.\n\nTrzynadlowski AM: Power Electronics Handbook. Butterworth Heinemann;4th ed.2018.\n\nShenoy P, Fagnani A: Common Mistakes in DC/DC Converters and How to Fix Them. Texas Instruments Incorp;2018.\n\nKivrak EG, Yurt KK, Kaplan AA, et al.: Effects of electromagnetic fields exposure on the antioxidant defense system. J. Microsc Ultrastruct. Aug 2017; 5(4): 167–176. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPremoli A: Revisited topology of Kirchoff’s circuits. IEEE Trans. Educ. Aug 1989; 32(3): 298–304. Publisher Full Text\n\nChen W-C, Ming D-L, Su Y-P, et al.: A Wide Load Range and High Efficiency Switched-Capacitor DC-DC Converter with Pseudo-Clock Controlled Load-dependent Frequency. IEEE Trans. On Circuits and Systems I: Regular Papers. 2014; 61(3): 911–921. Publisher Full Text\n\nChen Y-T, Liu K-J: The Switched-Capacitor Step-Down DC-DC Converter with Improved Voltage Stability and Load Range. IEEE Conf. on Industrial Electronics and Applications. 2010.\n\nKushnerov A: High-efficiency Self-adjusting Switched Capacitor DC-DC Converter with Binary Resolution. Israel:2009.\n\nKotowski J, McIntyre WJ, Parry JP: United States Patent 6,055,168.Apr. 25, 2000."
}
|
[
{
"id": "193767",
"date": "12 Oct 2023",
"name": "Divya Navamani J",
"expertise": [
"Reviewer Expertise Power converters"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nEfficiency analysis is not clearly presented. The main objective of this work is high efficiency. So they need to extend the work.\n\nCircuit diagram is not clear.\n\nNo validation with simulation and experimental results.\n\nThe derived topology is not compared with any reported topologies in the literature.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "204811",
"date": "12 Oct 2023",
"name": "Yugal Kishor",
"expertise": [
"Reviewer Expertise Power electronics Converter"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nLack of technical content, i.e. there no equivalent circuit diagram in different operating modes.\n\nThere is no clarity on input and output voltage range.\n\nThere is no simulation and hardware results that support the claim.\n\nThere is no proper explanation of each section.\n\nNot recommending for indexing.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "186484",
"date": "12 Oct 2023",
"name": "Jéssika Melo de Andrade",
"expertise": [
"Reviewer Expertise dc-dc converter"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe introduction needs to further explore the gain techniques in the literature and more recent references should be used.\nThe topology proposed in the paper needs to be further explored statically, description of the converter operation, design equations...\nIn addition, it is necessary to present experimental results (waveforms) to prove the theoretical study, as well as analysis of experimental efficiency and theoretical losses of the converter.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-541
|
https://f1000research.com/articles/11-539/v1
|
19 May 22
|
{
"type": "Research Article",
"title": "Simulation model for the dynamics of dengue with asymptomatic transmission and the effect of temperature",
"authors": [
"Julián Alejandro Olarte García",
"Steven Raigosa Osorio",
"Oscar Andrés Manrique Arias",
"Carlos Alberto Abello Muñoz",
"Cesar Augusto Acosta Minoli",
"Steven Raigosa Osorio",
"Oscar Andrés Manrique Arias",
"Carlos Alberto Abello Muñoz",
"Cesar Augusto Acosta Minoli"
],
"abstract": "Background: One of the fastest spreading vector-borne diseases in tropical and subtropical regions is dengue, which generates cost overruns for public health entities. Several factors can influence the dynamics of dengue virus transmission: environmental and climatic (abundance of vectors), interactions between hosts (infections by asymptomatic individuals), and population immunological factors. Given these conditions, it is necessary to carry out theoretical studies based on meteorological factors and asymptomatic transmission that are associated with both the existence of the vector and its incidence, in order to provide a scientific basis for health entities in decision-making. Methods: A mathematical model based on nonlinear ordinary differential equations is proposed to interpret the dynamics of dengue transmission in humans coupled to the dynamics of the Aedes aegypti species, considering the population of symptomatic and asymptomatic infected humans and the effect of temperature variability. The basic reproduction number was found and some simulation results based on the Runge-Kutta numerical method were obtained. Results: The simulations showed that the temperature had a directly proportional relationship with the basic reproduction number. The cases of infected people and carrier mosquitoes increased when the temperature peaks increased drastically; in low temperatures the infection persisted with low morbidity due to the survival of asymptomatic people. Conclusions: High temperatures tolerable by mosquitoes increase their life expectancy and their numbers in the environment which, together with a reservoir of asymptomatic infected people, leads to a higher incidence of the dengue virus in certain seasons or maintains its circulation in seasons of low temperatures, despite lower vector survival rates.",
"keywords": [
"Dengue",
"temperature",
"Aedes aegypti",
"asymptomatic",
"basic reproduction number",
"simulation model"
],
"content": "Introduction\n\nDengue is a viral disease transmitted by mosquitoes of the Aedes genus, mainly by the Aedes aegypti species, characterized by biphasic fever, myalgia, skin rash, among other symptoms, and can evolve into a clinical condition called severe dengue that can lead to death1; this disease is a public health problem worldwide, since it is estimated that about 390 million people are infected annually, and no effective vaccine is available to reduce its incidence.2 As a consequence, the approaches to reduce its transmission are directed towards control of vector transport by humans through land, air and sea transportation, which has caused its successful colonization around the world.3 For this reason, and due to the introduction of infectious people into new territories, the dengue virus has spread to more than 100 countries.1\n\nScientifically, it is known that some people infected with dengue are asymptomatic, defined as those infected who do not present clinical symptoms detectable by public health systems; asymptomatic people were considered dead points in the transmission of the dengue virus, since it was believed that their average level of viremia was not high enough to transmit the virus to the mosquito vector, however, recent studies have shown that asymptomatic people, despite their low average level of viremia, are potentially infectious for mosquitoes. It is estimated that of the nearly 390 million cases of dengue infections per year, around 300 million are asymptomatic, that is, no apparent disease interrupts the daily routine of these individuals.4-6\n\nThis article is organized as follows: the mathematical model that interprets the dynamics of dengue transmission including the asymptomatic human population coupled to the life cycle of Aedes aegypti and temperature variability is formulated in the subsequent sections Methods and Mathematical model formulation; the basic reproduction number of the infection is determined and interpreted in the Basic reproduction number section; the Results and discussion section presents facts from numerical simulations based on the Runge-Kutta approximation method. Finally, the turn of this research considering other factors that affect the transmission dynamics of the dengue virus is discussed in the Conclusions section.\n\n\nMethods\n\nA mathematical model based on nonlinear ordinary differential equations was formulated to describe the dynamics of dengue virus transmission through the interaction of human populations and female Aedes aegypti mosquitoes. This is an extension of the susceptible-infected-recovered dynamic for the human population and a susceptible-infected type dynamic for the mosquito population. Some parameters sensitive to temperature depend on it and, in turn, the daily temperature varied over time, in order to delimit the effect of temperature changes on the behavior of populations. The system simulations were carried out in Matlab R2020b software, implementing an algorithm of the fourth order using the Runge-Kutta numerical method7,8 with values for the constant parameters extracted from the literature.\n\nThe formulated mathematical model is an extension of the susceptible-infected-recovered dynamic (SIR) for the human population and a susceptible-infected (SI)-type dynamic for the mosquito population; a single dengue serotype is assumed in the transmission dynamics; the infected persons capable of transmitting the dengue virus are divided into two states, symptomatic and asymptomatic, and only the population of female mosquitoes is considered; once a mosquito has become a carrier of a dengue virus serotype, it never ceases to be so.\n\nTo interpret the dynamics of dengue transmission, it is assumed that the average number of susceptible people S(t) increases constantly at the rate μN and decreases proportionally to the human mortality rate μ; at time t, susceptible persons can become an average number I(t) of infected or an average number A(t) of asymptomatic by having effective contact with the population of carrier mosquitoes at rates λ1 and λ2, which represent the incidence of the population of symptomatic people and the population of asymptomatic people, respectively. The rate of change of susceptible persons with respect to time is given by:\n\nPopulations of symptomatic and asymptomatic infected persons increase at incidence rates λ1 and λ2, respectively, and decrease proportionally to the natural death rate μ, as well as by the rate of persons recovering from a dengue virus serotype and who acquire immunity proportionally to the recovery rate θ; the population of recovered people R(t) decreases proportionally to the natural death rate μ and increases according to the recovery rate θ of the infected populations. The equations that represent the change of the infected asymptomatic, symptomatic people and the recovered population over time are given by:\n\nTo describe the dynamics of the female mosquito population, an intrinsic growth rate ϕ in the population of non-dengue virus-carrying mosquitoes is considered, and the variable U(t) denotes the average number of non-carrier mosquitoes; denoting the average number of dengue virus-carrying mosquitoes by V(t), the rate of change of this variable depends on the proportion of non-carrier mosquitoes that come into effective contact with the population of infected people and become carrier mosquitoes, proportional to the incidence rates λI and λA, which represent the population incidence of carrier and non-carrier mosquitoes, respectively. Both virus carrier and non-carrier mosquito populations decrease proportionally to the natural death rate of mosquitoes ε(T) which depends on temperature. Therefore, the equations that describe the change in the population of female mosquitoes over time are given by:\n\nFrom the equations described above, the system of nonlinear ordinary differential equations (7) - (12) emerges to interpret the dynamics of the dengue virus, including the population of the Aedes aegypti vector and the human population.\n\nThe terms λ1 and λ2 are governed by a standard incidence, where the rate of newly infected people passing from the susceptible state to the symptomatic or asymptomatic infected state is proportional to the total number of effective contacts between susceptible individuals and the proportion of mosquitoes carrying a dengue virus serotype; these terms are described by:\n\nSimilarly, the terms λI and λA are also governed by a standard incidence. Here the rate of new cases of carrier mosquitoes is proportional to the total number of effective contacts between non-carrier mosquitoes and infected symptomatic or asymptomatic persons, respectively, these terms are described for:\n\nThe total population of humans and female mosquitoes, described by N = S + A+ I + R and M = U + V respectively, grow at rates:\n\nThese rates are such that:\n\nFrom the equations (13) it can be deduced that the total population of humans N is constant over time, in addition to the fact that asymptotically, the total population of female mosquitoes tends to ϕ/ϵ.\n\nFor the system of equations (7) - (12), the following initial conditions were considered: S0=S0,A0=A0,I0=I0,R0=R0,U0=U0,V0=V0, as well as the following restrictions for the parameters: 0<α,0<θ,0<ϵ,0<μ,0<ϕ,0<f<1,0<β<1,0<σ<1. The region of epidemiological sense is given by:\n\nThe temperature-dependent parameters are represented by the following functional expressions described and compiled by authors such as Hyojung Lee et al. in Ref. 9, Liu-Helmersson et al. in Ref. 10 and Polwiang in Ref. 11:\n\nDaily biting rate:\n\nProbability of mosquito-to-human transmission:\n\nProbability of human-to-mosquito transmission:\n\nNatural death rate of the mosquito:\n\nThe description and the value of the parameters used for the construction of the model are shown in the Table 1.\n\nIn the epidemiology of infectious diseases, the basic reproduction number (R0) is one of the most relevant quantitative parameters in situations of epidemic outbreaks. As a biological definition, the basic reproduction number R0 is said to be the number of secondary cases produced by an infected individual introduced into a fully susceptible population during its entire infectious period. Mathematically, the R0 is characterized by considering the infectious process as a demographic process in which the increase in offspring is not considered as a birth, but rather as the introduction of new cases of infected through transmission, which entails to look at transmission in terms of consecutive generations of infected individuals.12,13\n\nSince R0 is considered a disease threshold, its value determines whether or not an epidemic exists: if R0 > 1, an infected person will infect more than one susceptible person during their infectious period and the disease will spread, generating an epidemic; otherwise, if R0 < 1 the disease will tend to disappear, as this indicates that an infected person introduced into a totally susceptible population transmits the disease on average to less than one person, so the disease will tend to become extinct over time.13,14\n\nConsidering the methodology of the spectral radius of the matrix of the next generation,19 the equilibrium point without the presence of the disease E0=N000ϕϵ0 and the asymptotic behavior of the total population of mosquitoes M, we proceeded to calculate the basic reproduction number R0, which is determined by the following expression:\n\nIn order to have a clearer conception of what the expression of (18) represents, the terms that compose it must be interpreted. First, the additive effect that represents one of the considerations of the model can be appreciated, since it takes into account two routes or sources of infection caused by the population of asymptomatic and symptomatic infected people: the expression 1−fαβθ+μ in the first additive term represents the incidence of new cases of asymptomatic infections in the human population; on the other hand, the expression fαβθ+μ in the second additive term represents the incidence of new cases of asymptomatic infections in the human population, and the expression ασϵ shared by the two additive terms represents the new cases of mosquitoes carrying the virus.\n\nAfter having an expression for the basic reproduction number based on the parameters considered in the model, R0 was simulated taking the values included in Table 1; for the temperature-dependent parameters, the daily temperature data collated by the meteorological forecasting company AccuWeather Inc.28 were used and the functions (14) - (17) were evaluated for the mean value between the minimum and the maximum daily temperatures of the city of Armenia - Quindío, Colombia, as shown in Figure 1.\n\nFigure 1 shows the graphical representation of the basic reproduction number (R0) throughout a year, compared with the daily temperature data for the year 2019. First, highlighting the biological definition of R0, it can be seen that most of the time considered in the simulation, the value of the basic reproduction number exceeds the epidemic level 1, from which it can be deduced that throughout the year there was a continuous epidemic risk. Another result of importance observed is the effect produced by changes in temperature over time, since comparing the continuous red line that represents R0 and the blue dotted line that represents daily temperature, the increase in temperature produces in R0 a increase in its value, from which it can be deduced that the increase in temperature increases the risk of producing an epidemic of dengue disease in the city of Armenia.\n\n\nResults and discussion\n\nThe simulations of the system (7) - (12) are carried out in Matlab R2020b software, implementing an algorithm of the fourth order Runge Kutta numerical method7,8 with values for the parameters retrieved from the literature and described in Table 1. The following simulations show the variation over time of the populations considered and the variation over time of the daily temperature, in order to demarcate the effect of temperature changes on the behavior of the populations. Figure 2 shows the behavior of the symptomatic and asymptomatic infected population, considering that the fraction of people who acquire the virus and are symptomatic is f = 0.75, which means that a quarter of those infected have no symptoms.\n\nFrom Figure 2 it appears that when considering a lower fraction of asymptomatic infected than of symptomatic infected people, the population of symptomatic people is higher than that of asymptomatic people; however, the population of asymptomatic people permanently marked the evolution of the symptomatic class throughout the simulation, since asymptomatic people are those infected with the dengue virus with the ability to transmit it despite not presenting any type of clinical symptomatology. Other important characteristics that could be observed were the high and low peaks of the blue curve in the lower graph of Figure 2, which represents the daily temperature variability in Armenia (Quindío) in the year 2019, are reflected in the time-series of populations of symptomatic and asymptomatic people. From this, it can be deduced that the increase in temperature increases the cases of symptomatic and asymptomatic infected people, and more specifically, that sudden changes in temperature have a significant impact on the increase or decrease of these two populations.20–23\n\nThe first graph in Figure 3 shows that the population of non-carrier female mosquitoes grew and quickly stabilized; the second graph of Figure 3 shows that the trend of the population of mosquitoes carrying the dengue virus reaches its maximum on day 50 and day 250. From this it can be deduced that a transmission pattern is present during most of the year and the variability of the temperature represented by the blue dotted curve is a significant determinant for the population of carrier mosquitoes, since the tendency of the mosquitoes to increase carriers coincided with temperature peaks. However, it is not as evident as in the behavior of the population of symptomatic and asymptomatic infected in Figure 2. When comparing both graphs, it can be said that the largest population of carrier female mosquitoes and of symptomatic and asymptomatic infected were found in between 50 to 250 days, which seems reasonable, since a greater number of carrier mosquitoes causes a greater number of new infection cases.\n\nWith the aim of determining the effect of the asymptomatic population on the dynamics of dengue transmission, in the following simulations the same parameters considered in previous simulations exposed in Table 1 were used, changing the value of the fraction of people who acquire the virus and were symptomatic to f = 0.25. In other words, it will be considered that the fraction of people who acquire the virus and are asymptomatic is equivalent to three quarters of the total number of people infected with a dengue virus serotype, which has been suggested in the literature.4-6,24 The graphs for the populations of symptomatic and asymptomatic infected people are shown below.\n\nAs expected, in Figure 4 the population size of asymptomatic infected people was greater than that of symptomatic people, which is due to a lower value of the fraction of people who acquire the virus and are symptomatic (f = 0.25) than for previous simulations; in this case, it could be interpreted that when considering the suggestions exposed in the literature mentioned in the previous paragraph, most of the infected population are asymptomatic, which causes a great challenge for creating virus transmission control strategies; this population represents a constant reservoir of the virus that is not identified as an infected population in the clinical history (patients usually appear to health professionals after symptoms have already manifested) and interruption of the early cycle of transmission is difficult.25–27\n\nGiven that f and (1− f) are fractions that complement each other and the population of mosquitoes carrying a dengue virus serotype considers both populations in its dynamics (observe equation (12)), the behavior of the population did not present any change with respect to Figure 3 and its inclusion in the simulations using f = 0.25 becomes unnecessary.\n\n\nConclusions\n\nWe presented a simulation model based on nonlinear ordinary differential equations describing the transmission dynamics of the dengue virus, considering the population of asymptomatic infected people and some entomological parameters that vary depending on the temperature of the city of Armenia (Quindío), Colombia. The basic reproduction number was determined and the simulations were carried out using a temporal a window of one year; the graphs show that the R0 exceeds the epidemic level 1, from which it is deduced that throughout the year there was a risk of continuous epidemic; in addition, the temperature had a directly proportional relationship with the basic reproduction number, and therefore climatic change increases the risk of a dengue epidemic.\n\nThe simulations of the proposed system of equations reveal that the population of asymptomatic people prevails over time, which can be considered as a constant reservoir of the dengue virus; in addition, the cases of infected people and carrier mosquitoes increased when the peaks of temperature increased drastically, a phenomenon which could be explained by the idea that the city of Armenia has a temperate climate, for which rain leads to a decrease in temperature, which results in clean water deposits; this in turn favors the reproduction of the vector as temperatures rise, increasing the average number of mosquitoes in the environment. Combined with a reservoir of asymptomatic infected people, this leads to a higher incidence of dengue virus.\n\nIn the future, the effect of human population movements will be determined considering that, as mentioned in this paper, the asymptomatic population has the capacity to transmit the dengue virus and its condition facilitates the transport of the virus to different areas of the city of Armenia (Quindío) Colombia. Since this population presents no symptoms, preventive measures are not taken to avoid the transmission of the virus.\n\n\nData availability\n\nZenodo: Daily temperature data of the city of Armenia, Colombia year 2019, https://doi.org/10.5281/zenodo.6328228.29\n\nThis project contains the following underlying data:\n\n- Daily temperature data of the city of Armenia, Colombia year 2019.csv\n\nZenodo: Parsing Code, https://doi.org/10.5281/zenodo.6328289.30\n\nThis project contains the following extended data:\n\n- parametros1.m\n\n- rk4modelo.m\n\n- solverrk4modelo.m\n\n- temperaturaarmenia2019.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nArchived analysis code as at time of publication: https://doi.org/10.5281/zenodo.6328289\n\nLicense: Creative Commons Attribution 4.0 International",
"appendix": "Acknowledgements\n\nThe authors would like to thank the reviewers for their careful reading of this manuscript and for their comments and suggestions that improved it. They also thank the Vicerrectoría de Investigaciones of the Universidad del Quindío for taking responsibility for the APC of this publication and the Grupo de Modelación Matemática en Epidemiología of the Universidad del Quindío for being an integral part of the authors’ scientific practice.\n\n\nReferences\n\nHalstead SB, editor. Dengue. World Scientific; 2008; vol. 5.\n\nOrganización Mundial de la Salud (OMS):Dengue.2017. Reference Source\n\nMustafa MS, Rasotgi V, Jain S, et al.: Discovery of fifth serotype of dengue virus (DENV-5): A new public health dilemma in dengue control. Med J. Armed Forces India. 2015; 71(1): 67–70. PubMed Abstract | Publisher Full Text\n\nDuong V, Lambrechts L, Paul RE, et al.: Asymptomatic humans transmit dengue virus to mosquitoes. Proc. Natl. Acad. Sci. 2015; 112(47): 14688–14693. PubMed Abstract | Publisher Full Text\n\nGrange L, Simon-Loriere E, Sakuntabhai A, et al.: Epidemiological risk factors associated with high global frequency of inapparent dengue virus infections. Front. Immunol. 2014; 5: 280. Publisher Full Text\n\nQuirine A, Clapham HE, Lambrechts L, et al.: Contributions from the silent majority dominate dengue virus transmission. PLoS Pathog. 2018; 14(5): e1006965. Publisher Full Text\n\nLynch S: Dynamical systems with applications using MATLAB. Boston: Birkhäuser; 2004.\n\nQuarteroni A, Sacco R, Saleri F: Numerical mathematics. Springer Science & Business Media; 2010; vol. 37.\n\nLee H, Kim JE, Lee S, et al.: Potential effects of climate change on dengue transmission dynamics in Korea. PloS one. 2018; 13(6): e0199205. PubMed Abstract | Publisher Full Text\n\nLiu-Helmersson J, Stenlund H, Wilder-Smith A, et al.: Vectorial capacity of Aedes aegypti: effects of temperature and implications for global dengue epidemic potential. PloS one. 2014; 9(3): e89783. PubMed Abstract | Publisher Full Text\n\nPolwiang S: The seasonal reproduction number of dengue fever: impacts of climate on transmission. PeerJ. 2015; 3: e1069. PubMed Abstract | Publisher Full Text\n\nDiekmann OJ, Heesterbeek AP, Metz JAJ: On the definition and the computation of the basic reproduction ratio R0 in models for infectious diseases in heterogeneous populations. J. Math. Biol. 1990; 28: 365–382. PubMed Abstract\n\nDiekmann O, Heesterbeek JAP, Roberts MG: The construction of next-generation matrices for compartmental epidemic models. J. R. Soc. Interface. 2009; 7(47): 873–885. PubMed Abstract | Publisher Full Text\n\nChávez JP, Götz T, Siegmund S, et al.: An SIR-Dengue transmission model with seasonal effects and impulsive control. Math. Biosci. 2017; 289: 29–39. PubMed Abstract | Publisher Full Text\n\nEnduri MK, Jolad S: Dynamics of dengue disease with human and vector mobility. Spatial and spatiotemporal epidemiology. 2018; 25: 57–66. PubMed Abstract | Publisher Full Text\n\nAndraud M, Hens N, Marais C, et al.: Dynamic epidemiological models for dengue transmission: a systematic review of structural approaches. PloS one. 2012; 7(11): e49085. PubMed Abstract | Publisher Full Text\n\nGarba SM, Gumel AB, Bakar MA: Backward bifurcations in dengue transmission dynamics. Math. Biosci. 2008; 215(1): 11–25. PubMed Abstract | Publisher Full Text\n\nSardar T, Rana S, Chattopadhyay J: A mathematical model of dengue transmission with memory. Commun. Nonlinear Sci. Numer. Simul. 2015; 22(1-3): 511–525. Publisher Full Text\n\nVan den Driessche P, Watmough J: Reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission. Math. Biosci. 2002; 180(1-2): 29–48. PubMed Abstract | Publisher Full Text\n\nWatts DM, Burke DS, Harrison BA, et al.: Effect of temperature on the vector efficiency of Aedes aegypti for dengue 2 virus. Am. J. Trop. Med. Hyg. 1987; 36(1): 143–152. PubMed Abstract | Publisher Full Text\n\nLambrechts L, Paaijmans KP, Fansiri T, et al.: Impact of daily temperature fluctuations on dengue virus transmission by Aedes aegypti. Proc. Natl. Acad. Sci. 2011; 108(18): 7460–7465. PubMed Abstract | Publisher Full Text\n\nCarrington LB, Armijos MV, Lambrechts L, et al.: Fluctuations at a low mean temperature accelerate dengue virus transmission by Aedes aegypti. PLoS Negl. Trop. Dis. 2013; 7(4): e2190. PubMed Abstract | Publisher Full Text\n\nCarrington LB, Seifert SN, Armijos MV, et al.: Reduction of Aedes aegypti vector competence for dengue virus under large temperature fluctuations. Am. J. Trop. Med. Hyg. 2013; 88(4): 689–697. PubMed Abstract | Publisher Full Text\n\nBhatt S, et al.: The global distribution and burden of dengue. Nature. 2013; 496(7446): 504–507. PubMed Abstract | Publisher Full Text\n\nBeckett CG, Kosasih H, Faisal I, et al.: Early detection of dengue infections using cluster sampling around index cases. Am. J. Trop. Med. Hyg. 2005; 72(6): 777–782. PubMed Abstract | Publisher Full Text\n\nYoon IK, Rothman AL, Tannitisupawong D, et al.: Underrecognized mildly symptomatic viremic dengue virus infections in rural Thai schools and villages. J. Infect. Dis. 2012; 206(3): 389–398. PubMed Abstract | Publisher Full Text\n\nGordon A, Kuan G, Mercado JC, et al.: The Nicaraguan pediatric dengue cohort study: incidence of inapparent and symptomatic dengue virus infections, 2004–2010. PLoS Negl. Trop. Dis. 2013; 7(9): e2462. PubMed Abstract | Publisher Full Text\n\nAccuWeather: 2019. Reference Source\n\nOsorio SR: Daily temperature data of the city of Armenia, Colombia year 2019.2022. Publisher Full Text\n\nOsorio SR: Parsing Code.2022. Publisher Full Text"
}
|
[
{
"id": "212410",
"date": "16 Nov 2023",
"name": "Sangeeta Saha",
"expertise": [
"Reviewer Expertise Mathematical Biology",
"Nonlinear Dynamics",
"Ecological Modelling",
"Epidemiological Modelling"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors, in the manuscript, have proposed a compartmental epidemic model of dengue transmission where the mosquito biting rate and the transmission rates from host to vector as well as vector to host are assumed to be temperature dependent. The calculations are basic ones and seem to be ok, but there are few points which I need to mention. Firstly, whenever a model is proposed, it is very important to show the biological well-posedness of the system. So, proving the non-negativity and boundedness of the system variables make the base on which the rest of the analysis is performed. Secondly, I am unable to understand how the transmission from mosquito to human depends on the temperature with two types of conditions (noted in equations 15 and 16). It could have been analysed appropriately. Moreover, it is not demonstrated properly how the time variable is connected with the temperature. So, a proper analysis of the second subfigures of each of Figure 2- Figure 4 could improve the work. Also, as per the model assumption, the parameter denoting 'the increase in female mosquito population' should also depend on temperature, but it is chosen as a constant value only. The reason supporting it needs to be mentioned. Altogether I have found the concept interesting, but the mentioned points, if taken care of, will make the work more strong and presentable only.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "205738",
"date": "16 Nov 2023",
"name": "J H Arias-Castro",
"expertise": [
"Reviewer Expertise Dynamical systems",
"mathematical epidemiology",
"biomathematics",
"optimal control theory"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article aims to analyze the effects of temperature on dengue transmission considering the asymptomatic population. Initially, a model in which some temperature-dependent parameters are considered is presented. But then, the classical analysis of the model is performed without considering the dependence of the parameters on temperature, which simplifies the analysis of the model and puts it in the classical scheme, which practically makes the subject to be treated lose novelty. Additionally, some scenarios are presented in Figures 3 and 4, which turn out to be analogous because they model situations that have no differences, since the equations turn out to be equivalent, in the case of asymptomatic and infected humans.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-539
|
https://f1000research.com/articles/11-536/v1
|
18 May 22
|
{
"type": "Review",
"title": "Pulse fortified whole wheat bread: A review on dough rheology, bread quality, and sensory properties",
"authors": [
"Mominul Hoque",
"Rahul Biswas",
"Mahabub Alam",
"Animesh Sarkar",
"Md Ismail Haque",
"Md. Moinul Hasan",
"Mominul Hoque",
"Rahul Biswas",
"Animesh Sarkar",
"Md Ismail Haque",
"Md. Moinul Hasan"
],
"abstract": "The increase in the consumption of pulses can perform a key role in preventing protein deficiency among people specifically in developing countries. The fortification of whole wheat bread with pulses is an efficient approach to boost the nutritional profile of bread as protein, starches, dietary fiber, vitamins, minerals, antioxidants, and phytochemicals are all abundant in pulses. The optimum ratio of the pulse to whole wheat flour is necessary to determine for producing bread with good quality, sensory attributes, and handling properties. This review investigated the impact of the pulse addition on the whole wheat dough rheology, bread quality, and sensory characteristics, with a particular focus on dough stability, elasticity, strength, and bread volume. The improvement in the nutritional value as well as the negative impact of pulses on whole-wheat bread was also reviewed. The research gaps in pulse supplemented whole grains bread were identified, and further study directions were recommended. Fortification of whole wheat bread with pulses produced affordable bread with a balanced diet for all classes of people. The addition of a higher level of pulses develops a weak gluten structure, which negatively affects dough stability, strength, elasticity, and handling properties. The volume of bread also decreased, and the off-flavor compound produced at a higher level of pulse fortification. The addition of additives and prior processing of pulses not only promote the nutritional value but also produce bread with better dough stability, bread volume, and sensory score.",
"keywords": [
"Whole wheat",
"Pulses",
"Bread",
"Dough",
"Sensory",
"Chickpea",
"Pea",
"Pigeon pea"
],
"content": "Introduction\n\nWhite bread is a common major item that consumers prefer all over the world because of its organoleptic properties. However, recently whole wheat flour has gained the spotlight for bread making as it provides a higher amount of fibers, vitamins, minerals, and phytochemicals compared to wheat flour that has been refined (Bressiani et al., 2017; Olagunju et al., 2020). Moreover, the bran and germ in whole wheat flour provide the majority of the nutrition components such as vitamins, proteins, minerals, antioxidants, and dietary fiber (Previtali et al., 2014). Thus, whole/entire wheat/grains bread is ideal for the aged and those who are health-conscious because it reduces the danger of diabetes, cancer and cardiovascular diseases (Olagunju et al., 2020). However, wheat bread supplies a very low quantity of vital amino acids, especially lysine and threonine (Shrivastava & Chakraborty, 2018; Turfani et al., 2017). It is frequently called an unbalanced diet as it contains a very low amount of lysine (Erukainure et al., 2016). Figure 1 illustrates the unbalanced and balanced diet to compare whole wheat and pulse fortified whole wheat bread. Moreover, the application of refined wheat flour in making bread significantly decrease the fiber content as well as the density of nutrient in comparison with the whole wheat bread (Dewettinck et al., 2008). Fortifying whole wheat flour with pulses can greatly enhance the nutritional content of bread since pulses possess a complete amino acid profile to cereals and are abundant in fibers and phytochemicals (Hossain et al., 2021; Roy et al., 2021; Turfani et al., 2017).\n\nPulses, also known as grain legumes, are mainly produced because of edible seeds (Boukid et al., 2019a). The worldwide importance of pulses to a structured and integrated human-environment relationship is seen in Table 1. Pulses are highly enriched in protein (18.5–30%), dietary fiber (14.6–26.3%) as well as starch (35– 52%) as compared to other plant-origin foods (Mohammed et al., 2012; Previtali et al., 2014). Moreover, pulses flour also supplies minerals, vitamins (Rysová et al., 2010), oligosaccharides, polyphenols, and antioxidants (Boschin & Arnoldi, 2011; Campos-Vega et al., 2010; Han et al., 2010). The regular intake of pulses is also helpful in reducing the danger of atherosclerosis disease (Flight & Clifton, 2006), cancer, hypertension (Feregrino-Pérez et al., 2008), obese and overweightness (Mollard et al., 2012), type 2 diabetes (Jenkins et al., 2014). However, the consumption of pulses is declining in many countries and could be because of changes in eating habits together with the low sensory score for minimally processed pulse foods (Baik & Han, 2012; Kohajdová et al., 2013). The addition of pulses to wheat bread will enhance pulse consumption while also improving bread nutritional quality.\n\nTo improve nutritional value of wheat bread, several attempts were executed to fortify bread with pulses in the form of flour and protein isolate particularly with chickpea (Mohammed et al., 2014; Pasqualone et al., 2019; Shrivastava & Chakraborty, 2018), pea (Dabija et al., 2017; Shivaani, 2020), pigeon pea (Olagunju et al., 2020), lentil (Kohajdová et al., 2013; Previtali et al., 2014; Turfani et al., 2017), cowpea (Olapade & Oluwole, 2013), soy protein isolate (Shivaani, 2020), soya bean flour (Ndife et al., 2011), kidney bean and black gram (Wani et al., 2016). As pulses were added to wheat flour, the nutritional quality of the bread improved, notably the amino acid, fat, vitamins, dietary fiber, and mineral content, when compared to wheat flour bread (Boukid et al., 2019a; Indrani et al., 2011).\n\nThe rheology of dough is significantly affected by the addition of pulses which is known for its high-water absorption, foaming, emulsifying, solubility, and gelling properties (Barac et al., 2015; Foschia et al., 2017). However, the fortification of bread with pulses influences the dough rheology, functional properties and possibly affects the processing and product quality (Baik & Han, 2012; Olagunju et al., 2020). This is attributed to the gluten that performs a significant role in dough gas retention properties and dough characteristics (Olagunju et al., 2020). The incorporation of gluten-free protein causes dilution of gluten which hinders the development of gluten during mixing. Thus, a weak and sticky dough is produced that impairs the handling properties and subsequently the quality of bread (Ribotta et al., 2005). Moreover, the addition of a high level of pulse flour can also negatively affect the sensory properties of bread (Mohammed et al., 2012; Previtali et al., 2014). The high fiber content in the whole wheat bread is responsible for lower loaf volume, unsuitable mouth feel, hard crumb, and bitter flavor (Ficco et al., 2018). Several structuring agents were used to counteract the described negative impact and improve the dough characteristics along with the sensory quality of bread at a higher level of supplementation (Alasino et al., 2011; Previtali et al., 2014). These compounds develop a bond with proteins and complexes with starch to recover the dough structure and sensory acceptability of bread (Alasino et al., 2011; Mastromatteo et al., 2012; Miñarro et al., 2012). The addition of additives can also neutralize the negative impact induced by the incorporation of non-wheat compounds (Indrani et al., 2010). Hydrocolloids are also added with gluten-free bread formulations because of their ability to imitate the function of gluten and improve the stability, appearance, baking quality of bread (Capriles & Arêas, 2014; Xu et al., 2020). The prior processing of pulses before added with wheat flour also reported improving sensory properties, mineral absorption, and protein digestibility by inactivating ant nutrient compounds (Millar et al., 2019; Ouazib et al., 2016; Roland et al., 2017).\n\nThis review mainly focused on the implementation of pulses in the whole wheat bread formula and their influences on dough rheology, baking performance, and bread sensory quality. The enhancement in the nutritive value, as well as the negative impact on whole wheat bread by incorporation of pulses, is also discussed. Moreover, it included the study that focused on improving the nutritional and sensory characteristics of pulse-fortified whole wheat bread by using a structuring agent and prior treatment of pulses for inactivating ant nutrients responsible for off-flavor compounds and low mineral absorption.\n\n\nDough rheology affected by pulse fortification\n\nThe impact of fortification of whole wheat flour with pigeon pea on dough rheological properties was reported by Olagunju et al. (2020). According to mixolab, the fortified flour exhibits increased water holding capacity, dough development time, stability time while lower hydration capacity than the whole wheat flour. The maximum hydration capacity and the lowest stability time were due to the high amount of non-storage protein, fat as well as bran fractions present in the whole wheat flour (Hadnađev et al., 2011). The high-water holding capacity of composite flour is mainly because of increased protein content (Mohammed et al., 2014). While the dough development time reduced continuously with increasing acha flour level, the higher amount of pigeon pea increased softening and decreased the stability time of composite flour. The author explained that pigeon pea protein particularly sulphydryl groups hinders the progress of the gluten association and responsible for the lower stability time at a higher level (Tang & Liu, 2017). However, the replacement of whole wheat with buckwheat flour was reported to decrease the dough stability and development time (Hadnađev et al., 2011). Increased water absorption was also noted for whole wheat bread fortified with pea and soy pulses in the form of protein isolates (Shivaani, 2020). A similar increase in water absorption was reported by Wani et al. (2016) for the preparation of unleavened flat bread from the whole wheat flour supplemented with kidney bean and black gram flours. The water holding capacity of wheat bread increases slightly with the accumulation of chickpea flour for refined wheat flour (Sulieman et al., 2013). Water absorption capacity was increased of pulse fortified blends than whole wheat flour and also protein solubility fraction, recovery, and residue found higher than whole wheat flour shown in Figure 2 (Dhingra & Jood, 2002). This is perhaps because of the absence of bran and a lower amount of fiber present in the refined wheat flour than the whole wheat flour. The fortification of wheat flour with black chickpea also significantly increased the dough development time, water absorption, and loss of consistency, while decreased the stability of dough progressively (Pasqualone et al., 2019). The gluten-free pulse flour is enriched in fiber, able to interact with the gluten network, resulting in dilution of gluten. This is maybe responsible for low dough stability together with increasing development time and consistency loss. Thus, the incorporation of pulses at higher concentrations worsens the bread-making characteristics of flour and perhaps more significant for the whole wheat flour as it is enriched in fiber than refined wheat flour. Moreover, the incorporation of bran significantly decreased the gluten content resulting in weak gluten structure (Elawad et al., 2016). Figure 2 illustrates the dry gluten content of wheat flour and combined various wheat-pulse blends and the author found data lower gluten content of pulse fortified blend than whole wheat flour (Dhingra & Jood, 2002).\n\nData from Dhingra and Jood (2002).\n\nThe impact of the substitution of whole wheat flour with multigrain to prepare north Indian parotta was reported by Indrani et al. (2011). Farinograph results showed higher water absorption and dough development with an increased level of multigrain in the blend, while dough stability decreased from 4.8 to 2.5 min for 40 g/100 g multigrain blend. The rise in development time might be due to the variation of physicochemical properties between pulses and wheat flour. A continuous fall in elasticity, extensibility as well as dough strength was observed with an increased level of multigrain in the blend. Thus, the stretching characteristics of dough are negatively affected by the higher multigrain content. A similar decrease in the extensibility of dough and resistance to deformation was noted for chickpea fortified wheat flour bread with the rising replacement of chickpea flour (Mohammed et al., 2012). According to Gómez et al. (2003) and Elleuch et al. (2011), the addition of dietary fiber had a marked impact on dough characteristics particularly increasing the water holding capacity, tenacity along with mixing tolerance while decreasing extensibility compared with those without the inclusion of fiber. However, the addition of a low level of lentil flour to whole meal durum wheat bread showed statistically non-significant value for tenacity, maximum stress and fracture stress when compared to whole wheat bread (Previtali et al., 2014). Chickpea-fortified wheat flour also exhibits extension properties similar to that of control at a lower level, while for a greater amount of chickpea addition dough turned sticky (Mohammed et al., 2012). The pasting properties of whole wheat flour fortified with pulses were observed particularly for kidney bean and black gram flour (Wani et al., 2016), pigeon pea (Olagunju et al., 2020) and, multigrain (Indrani et al., 2011). According to Olagunju et al. (2020), the composite flour displayed higher peak viscosity, trough viscosity as well as final viscosity at the increasing level of pigeon pea when compared to the whole wheat flour. Higher pasting characteristics of composite flour perhaps due to the low amylose content in the pigeon pea than the whole wheat flour (Narina et al., 2014). These results are opposite to the study executed by Wani et al. (2016) for the preparation of Chapatti from the whole wheat flour fortified with different levels (5–20%) of a kidney bean and black gram flour. In this study peak viscosity, trough viscosity, final viscosity and the setback of composite flour decreased significantly for kidney bean at a higher level of supplementation (15 and 20%) while black gram decreased notably for all level of fortification. Composite flour containing pigeon pea showed lower breakdown value than whole grain wheat flour, while a higher setback value was observed for all fortified whole wheat flour (Olagunju et al., 2020). However, a lower setback and breakdown value was reported for multigrain fortified whole wheat flour (Indrani et al., 2011). Fortified flour bread will be softer because of lower setback viscosity as there is less staling (Wani et al., 2016). The composite flour has a higher pasting time, the time required for starch to obtain the highest viscosity, compared to the whole wheat flour (Olagunju et al., 2020). Pasting temperature is the determination of the lowest temperature needed to cook any food. The addition of a higher level of multigrain in whole wheat flour increased the gelatinization temperature while reduced peak viscosity and hot paste viscosity (Indrani et al., 2011). A lower peak viscosity, final viscosity, and holding strength than the wheat flour were also observed for chickpea fortified flour (Gómez et al., 2008). According to Van Hung et al. (2007), whole wheat and fortified flour showed a lower value of peak viscosity than white wheat flour because of lower level of carbohydrate and high content of dietary fiber. As the whole wheat flour contains a high amount of fiber, it develops dough with lower stability, strength, elasticity, and peak viscosity when fortified with pulses. To produce a dough with higher stability from whole wheat the addition of structuring agent with treated pulses is very essential. However, there are a very few research available on the effect of additives on dough rheology of pulse fortified whole wheat flour. Indrani et al. (2011) used a mixture of additives with multigrain to promote the rheology of the whole wheat dough. The surface properties of whole wheat and various levels of pulse (chickpea) fortified of dough illustrate Figure 3(a). In this study, they noted that incorporation of additives with multigrain significantly improved dough stability, water absorption, elasticity, extensibility, strength and pasting characteristics of whole-wheat flour was reported Table 2 (Zhang et al., 2021). Although very few data available for the whole wheat flour fortified with processed pulses, several analysis were executed to improve the quality of white wheat flour (Baik & Han, 2012; Millar et al., 2019). According to Baik and Han (2012), the addition of cooked and roasted chickpea greatly improve the handling properties by decreasing stickiness and develop better gluten network. Similar improvement in dough quality by prior treatment of pulses may be obtained for whole wheat pulses while greatly promoted the nutritional value.\n\nThe figure was reproduced with permission from the publisher.\n\n\nQuality of pulse fortified whole wheat bread\n\nThe volume of the loaf is a significant parameter in determining bread characteristics as it gives a measurable evaluation of the performance of baking (Tronsmo et al., 2003). A significant reduction in bread volume and dough expansion was noted for soya bean flour fortified whole wheat bread (Ndife et al., 2011). This is caused by the dilution of gluten by the inclusion of fiber which hinders the gas retention capacity of dough rather than the production of gas (Elleuch et al., 2011). The decrease of loaf volume was also observed for whole wheat flour fortified with fermented chickpea flour (Shrivastava & Chakraborty, 2018), pea and soy protein isolate (Shivaani, 2020). The addition of pulse hinders the development of an elastic matrix resulting in gas retention significantly decreased during proofing and thus bread volume became lower (Rizzello et al., 2014; Rostamian et al., 2014). According to Van Hung et al. (2007) decrease in volume is because of the dietary fiber which causes dilution of protein and impairs the gluten matrix development. The impact of fiber on the volume of bread is caused by the interaction between hydroxyl groups of fiber and water by hydrogen bonding (Wang et al., 2002). The interaction between the water, fiber, and gluten together with gluten dilution is responsible for the decreased bread volume (Anil, 2007; Collar et al., 2007). However, a minor increase in specific volume was also reported for chickpea supplemented wheat flour (Sulieman et al., 2013). Elawad et al. (2016) observed the volume of the whole wheat bread fortified with pulse bran. They observed that although the volume of the bread containing wheat bran and soya bean bran decreased significantly, the addition of chickpea, fava bean and pigeon pea bran notably increased the bread volume. This is attributed to the low level of bran and high gluten content of the bread containing bran of chickpea, fava bean and pigeon pea.\n\nThe effect of chickpea and emulsifier on the bread quality of whole wheat and white bread was reported by Yamsaengsung et al. (2010) and Table 3 shown effects of emulsifiers and other factor ingredients on dough properties. In this study, the whole wheat bread has a 10-30% lower specific volume when compared to white bread for each formulation. The high amount of bran in the whole wheat flour is responsible for the lower volume. However, the white bread specific volume decreased more by the inclusion of chickpea flour than in the whole wheat bread. They conclude that for white bread, only emulsifier significantly (p<0.05) increase the bread specific volume while both water and emulsifier can significantly increase the whole wheat bread volume. The texture is a critical property as analysis of texture is a way to determine the bread firmness (Yamsaengsung et al., 2010) and Table 2 shown moisture content and hardness of whole wheat/pulse bread during one-week storage (Zhang et al., 2021). In this investigation, they noted that the addition of chickpea significantly raised the firmness of white and whole wheat bread which can be prevented by the addition of enough water and emulsifier. Emulsifier addition improves the gluten network and produces a bread with the porous crumb. They concluded that the toughness of whole wheat bread fortified with 20% chickpea was unacceptable if no emulsifier is used.\n\nA similar increase in firmness was noted for the whole wheat bread fortified with lentil flour (Previtali et al., 2014) and fermented chickpea flour (Shrivastava & Chakraborty, 2018). This increase in bread firmness perhaps due to the addition of pulses resulting in the crumb wall to be thickened around the air cell and protein particles are responsible for a stronger crumb structure (Previtali et al., 2014; Shrivastava & Chakraborty, 2018). The addition of pea and soy protein with whole wheat decreases the pore size in the bread and produce a dense and compact bread (Shivaani, 2020). The partially solubilized starch formed cross-links with gluten protein responsible for bread hardness and moisture mimic the activity of plasticizer acting on cross-links (Mohammed et al., 2014). According to Previtali et al. (2014), the inclusion of 10% lentil flour showed crumb firmness statistically comparable to that of whole wheat bread while at a higher level it negatively affected the bread quality. The effect of the addition of multigrain with whole wheat flour on the bread quality was observed by Indrani et al. (2011). In this analysis, they noted that the addition of a higher level of multigrain significantly increase the bread thickness and shear force which indicating the texture of north Indian parotta. They concluded that the addition of additives can be greatly promoted the texture of the bread.\n\nThe baking performance of the pulse fortified unleavened wheat flatbread prepared from the whole wheat flour was observed by Wani et al. (2016). Puffing is a desirable baking quality of flatbread and a continuous decrease in puffing was observed for black gram fortified whole wheat flatbread in this investigation. This is attributed to the high-water absorption of black gram flour resulting in suppressing the steam generation. The quantity of water lost from bread at the time of baking is known as the baking loss and the baking loss was significantly higher for the whole wheat bread than the pulse fortified bread (Wani et al., 2016). They observed that the baking time for kidney bean flour supplemented bread was much more than that of control flatbread. This increase in baking time perhaps because of the higher number of polysaccharides present in kidney bean flour which increased viscosity and water holding capacity. A similar rise in baking time was observed for whole wheat bread fortified with soy protein isolates (Shivaani, 2020). Wheat flour was replaced with chickpea flour at a percentage of 10 to >20%, resulting in a dough with nearly identical qualities to wheat flour dough. Chickpea inclusion of <20% dramatically reduced the volume, internal structure, and texture of the breads in baking tests. The explanation for this is that the gluten component, which was diluted by the addition of chickpea protein, was predominantly responsible for these effects. Consumers disliked the bread because it was dark brown in color and had a firm crust. It was also permissible to replace 10% to >20% of the flour in wheat bread with chickpea flour and bread loaf volume, crust color, and crumb structure with various quantities of chickpea fortified bread were illustrated Figure 3(b) (Mohammed et al., 2012).\n\nColor is a critical bread quality factor as it affects the decision and interest of consumers. Bread quality can be measured by golden-brown crust together with creamy white crumb (Ghoshal et al., 2013). According to Van Hung et al. (2007) high phenolic substances present in the bran are accountable for the darker color of whole wheat flour. Similarly, a minor rise in L*, a*, b* value was noted for pea fortified whole grain wheat bread (Tuncel et al., 2010). However, the reduction of lightness and an increase in yellowness (b*) of bread fortified with pigeon pea flour was reported by Ghoshal et al. (2013). A similar decrease in lightness was also reported for whole wheat bread fortified with soy and pea protein isolate (Shivaani, 2020), fermented chickpea flour (Shrivastava & Chakraborty, 2018). According to Shrivastava and Chakraborty (2018), the addition of chickpea resulting in darker bread as chickpea flour has a very low lightness and higher yellowness value. Indrani et al. (2011) observed that with the increasing multigrain level, the north Indian parotta became yellowish as multigrain contains chickpea.\n\nThe color of the crust is a vital bread quality parameter. Yamsaengsung et al. (2010) observed that the incorporation of chickpea significantly reduces the lightness for white bread while a minor increase in lightness for whole wheat bread. They also reported that the yellowness of the white bread was greatly increased by chickpea while for the whole wheat bread effect was statistically insignificant. They concluded that the impact of whole wheat bran was responsible for the color of the whole bread crust. According to Shrivastava and Chakraborty (2018), there was a direct relationship between the fermented chickpea flour level with the whole bread crust color. This is attributed to the increased amount of melanoidins produced by the reaction of amino acid with reducing sugar developed from protein and starch hydrolysis during fermentation.\n\n\nSensory and nutritional quality affected by pulses\n\nThe sensory properties of bread are a critical parameter as the preference of consumer depend on sensory quality. A panel of 10 judges assessed bread produced with wheat flour and different cereal-pulse blends for crust color, flavor, appearance, taste, crust texture, and overall acceptability using a nine-point Hedonic Rating Scale ranging from like highly (9) to dislike extremely (1) for each sensory attribute, and found overall acceptability from combined wheat-pulse blends bread to be satisfactory, as shown in Figure 2, with varied amounts of wheat-pulse blends (Dhingra & Jood, 2002). The effect of pea flour on the consumer acceptance of whole wheat bread, white bread and wheat bran bread was reported by Tuncel et al. (2010). They noticed that the mixing of pea flour significantly reduced the consumer acceptability of white bread in terms of texture, appearance, and flavor while no significant impact on whole wheat and bran bread. This is because of the difference in pea flour color compared to the refined wheat flour. They concluded that the incorporation of 5% pea flour is acceptable for the whole wheat flour as it does not adversely alter the sensory characteristics. Moreover, the negative effect of a higher level of pulses on sensory properties of whole wheat bread was observed by several authors particularly for soya bean flour (Ndife et al., 2011), acha and pigeon pea (Olagunju et al., 2020), lentil flour (Previtali et al., 2014), kidney bean and black gram flour (Wani et al., 2016), pea and soy protein isolate (Shivaani, 2020) and multigrain (Indrani et al., 2011). According to Ndife et al. (2011), the addition of soya bean flour showed an insignificant effect on the crust color and the crumb appearance score with a higher level of substitution. However, a higher level of addition significantly improved the texture and decrease the flavor score for whole wheat bread. In this study, the fortification of whole wheat with 10% of soya bean flour produced bread with overall acceptability close to that of whole wheat bread. However, the addition of 20% soy also showed overall acceptability similar to the whole wheat flour when incorporated in the form of protein isolate (Shivaani, 2020). The effect of pigeon pea on the sensory quality of whole wheat bread was observed by Olagunju et al. (2020). The sensory quality of composite flour was very low compared to the whole wheat flour, particularly for pigeon pea fortified bread. This was attributed to the beany off-flavor of composite flour perceived by the panelist. According to Previtali et al. (2014), the incorporation of 10% lentil flour increases the overall acceptability while the consumer acceptability for 20% lentil fortified sample was similar to the whole wheat bread. They concluded that the overall acceptability of bread fortified with a higher level of lentil can be improved by the addition of structuring agents. Similar results were observed by Shrivastava and Chakraborty (2018) for fermented chickpea fortified whole bread. They found that the score of 5% chickpea fortified bread is like that of control and panelist like the sample with a higher level of xanthan gum.\n\nThe sensory characteristics of chapatti prepared from pulse fortified whole wheat was reported by Wani et al. (2016). The addition of kidney bean flour at 10% and higher amount significantly decrease the flat bread color score while no relation with black gram flour level was observed. The addition of pulses increased the lysine content which induces the Maillard reaction responsible for the decrease in color value (Hallén et al., 2004). They observed that composite flour bread had a lower score for taste, aroma and stickiness compared to the control flat bread, while the chewability score was non-significant for both kidney bean and black gram composite bread. The higher amylose content of pulses is responsible for lower stickiness. The addition of 10% or higher kidney bean and black gram flour significantly decrease the overall acceptability of the flat bread. The effect of multigrain on sensory characteristics of north Indian parotta was reported by Indrani et al. (2011). They observed that score for appearance, pliability, layer separation and eating quality for parotta with 10% multigrain was like that of whole wheat parotta. The highest overall quality was noted for 10% multigrain parotta which significantly decrease at a higher level of multigrain supplementation. However, the addition of 30% multigrain with a combination of additives showed similar overall quality to that of 10% multigrain fortified parotta. They concluded that the higher level of substitution decreased overall quality significantly which can be greatly improved by using structuring agents.\n\nThe addition of pulses significantly boosted the nutritional value of whole wheat bread particularly increasing protein, fiber and minerals. Previtali et al. (2014) observed that the addition of 25% lentil flour notably increased the protein, fat as well as dietary fiber content of the bread compared with the whole wheat control bread. This is due to the greater content of protein, starch as well as dietary fiber of lentil regarding wheat flour (Boukid et al., 2019a; de Almeida Costa et al., 2006; Kohajdová et al., 2013). The addition of pea and soy protein isolate increased the protein content of the whole wheat bread and protein content was higher at a higher level of substitution (Shivaani, 2020). The effect of the addition of pulse bran on the composition of whole wheat bread was reported by Elawad et al. (2016). The bran of fava bean, pigeon pea, chickpea and soybean significantly improved the protein along with fiber content of whole wheat bread while decreased the available carbohydrate content. According to Anderson et al. (1987), high-fiber bread can be consumed as low-calorie food to control diabetes. Similar results were also observed for soybean flour fortified whole wheat bread by Ndife et al. (2011). In this study, they reported that the protein, fat, ash, and fiber content of bread raised with the higher level of soybean while the carbohydrate content and energy value decreased. The increasing ash content is directly connected with higher mineral compounds in the bread (Olagunju et al., 2020). The inclusion of multigrain containing chickpea and soybean increased protein, fat, mineral and dietary fiber content of the north Indian parotta (Indrani et al., 2011).\n\nAccording to Olagunju et al. (2020), pigeon pea notably enhanced the protein, fat and mineral present in whole wheat bread. However, a decrease in crude fiber and carbohydrate was noted at a greater amount of substitution for whole wheat bread. The whole wheat bread is mainly deficient in lysine and sulfur-containing amino acids particularly methionine, cysteine, and tryptophan. They found that pigeon pea improved the methionine and cysteine content of the bread significantly and it is increased at a higher level of supplementation with pigeon pea. Moreover, the fortified bread had a well-balanced amino acid profile which is supported by the higher predicted protein efficiency ratio for a higher level of supplementation with pigeon pea flour. This is because of the high lysine and Sulphur amino acid content of fortified bread resulting in balanced amino acid composition. The fortification of wheat bread with gram horse flour improved the polyphenol together with antioxidant activity while obtaining a high sensory score (Moktan & Ojha, 2016).\n\nThe nutrition value of the bread can be improved by prior processing of pulses and wheat. Germination is a cost-effective process for increasing the nutritive value along with the functional properties of legume seeds (Duenas et al., 2016). Pulses are soaked in water during germination which resumes the process of cellular metabolism together with growth resulting in stimulation of enzymes. These enzymes disintegrate macronutrients which release valuable nutrients together with changes in the functional characteristics of protein and starch for improving digestibility (Duenas et al., 2016; Millar et al., 2019). Fermentation is considered a suitable method to improve the nutritive quality of pulses (Adeyemo & Onilude, 2013; Bartkiene et al., 2016; Kapravelou et al., 2015; Rizzello et al., 2014). Fermentation is reported to increase the total phenolic content resulting in higher antioxidant activity of pulses, particularly for black soybean (Cheng et al., 2013), black bean (Lee et al., 2008) and soybean (Lin et al., 2006).\n\n\nNegative impact of addition of pulses\n\nAlthough pulse flour significantly improves the nutritive value of bread, the addition of raw pulse flour is restricted because of the anti-nutritional compounds present in pulses. Anti-nutritional compounds induce gastrointestinal difficulties due to non-digestible oligosaccharides, which reduce mineral absorption and protein digestibility (Millar et al., 2019; Roopashri & Varadaraj, 2014). Nutritional and anti-nutritional effects in pulses are demonstrated in two groups shown in Table 4. Anti-nutrients are also responsible for developing a bitter and unacceptable taste for fortified bread (Rizzello et al., 2014). The protein digestibility is decreased because of trypsin along with protease inhibitors that hinder the action of the amylase, lipase, and protease (Sathya & Siddhuraju, 2015). Inhibitors of phytic acid, and lectin are responsible for limiting protein readily available and easily digestible (Adenekan et al., 2018; Jin et al., 2017; Ohizua et al., 2017).\n\nThe indigestible oligosaccharides like raffinose are liable for flatulence, bloating (Adeyemo & Onilude, 2013; Winham & Hutchins, 2011) and develop intestinal gas when hydrolyzed by anaerobic micro-organisms (Hallén et al., 2004). Tannins adversely affected iron bioavailability (Prasad & Singh, 2015; Sotelo et al., 2010) while oxalate is responsible for decreasing the absorption of calcium (Massey & Kynast-Gales, 2001). Beany off-flavor and aroma were reported for the pulse fortified whole bread particularly for pigeon pea (Olagunju et al., 2020) and soy flour (Ndife et al., 2011). The lipoxygenase enzyme activity is responsible for off-flavors as it causes disintegration of polyunsaturated fatty acids to hydroperoxides that degraded into grassy-beany off-flavors compounds (Fahmi et al., 2019).\n\nHowever, these problems can be solved by treating pulses before incorporating them into wheat flour, which also promotes the nutritional content of pulses (Angulo-Bejarano et al., 2008; Shrivastava & Chakraborty, 2018). Dehulling of pulses can give a better look, texture, cooking quality, and digestibility by removing the hulls that contain a high amount of anti-nutrients (Egounlety & Aworh, 2003; Stantiall et al., 2018). Moreover, beany off-flavor produced by pulse can be effectively decreased by heat treatment, such as blanching or dry heating (Roland et al., 2017).\n\nSoaking chickpea and fava bean can improve the sensory characteristics of pulses as it reduces the saponin content (Barakat et al., 2015). Extrusion processing of cowpea destroys anti-nutritional compounds as well as prevents off-flavor development by inactivating lipoxygenase enzymes (McWatters et al., 2004). Thermal processing of pulses, particularly roasting/toasting significantly increase the digestibility of nutrient by inactivating heat-labile anti-nutritional factors (Millar et al., 2019; Ouazib et al., 2016). Cooking increases the bean protein digestibility by inactivating protease inhibitors and lectins (Baik & Han, 2012). Thermal processing further strengthens the handling capabilities of the pulse supplemented dough by lowering the solubility of the protein, rendering it nonfunctional and resulting in minimal gluten formation interference (Baik & Han, 2012). Because of changes in the structure of the starch and protein during thermal processing and germination of pea flour, it has better emulsifying and foaming capabilities (Benítez et al., 2013; Ouazib et al., 2016). Germination decreases anti-nutritional compounds and increases the quantity of crude fiber, fat and protein in the flour (Hallén et al., 2004). Prior fermentation of cereals increases amino acid and vitamin, improves the availability of starch and protein and decreases the anti-nutrients (Hallén et al., 2004).\n\n\nConclusions and future research scope\n\nThe consumption of pulse fortified whole wheat bread can play a significant role in preventing protein malnutrition among peoples in developing countries. The fortification of whole wheat with pulses can make it high nutritional food for all classes of people as the addition of pulses produced bread with balanced content of amino acids, vitamins, minerals, and a high fiber content. Although fortification with pulses undoubtedly promoted the nutritional content of bread, several adverse effects were observed at a higher level of substitution in dough rheology, particularly inferior stability, strength, elasticity, peak viscosity, resistance to deformation, handling characteristics and a rise in dough development time. Moreover, the addition of a higher level of pulses produced darker bread with a compact and dense structure characterized by lower bread volume, higher firmness, and longer baking time. Sensory characteristics of pulse fortified bread are also acceptable at a lower level while bread overall acceptability is very low above 10% of substitution as off-flavor compounds are developed because of antinutritional compounds. The addition of additives can be utilized to promote the dough characteristics, bread volume and sensory properties for bread with a higher level of pulses. The prior processing of pulses may also improve the nutritional value of bread, dough handling properties and inactivate anti-nutrient compounds responsible for lower mineral absorption and off-flavor.\n\nAlthough several studies were performed for pulses fortified white bread, a limited number of investigations were performed for pulse incorporated whole wheat bread. More research is needed to identify the permissible quantity of different pulses for manufacturing high-quality whole/entire wheat/grains bread. Moreover, whole/entire wheat/grains bread with good handling properties, dough stability, bread volume and sensory properties can be developed by utilizing a combination of additives and processed pulses while maintaining higher nutritional value. The prior processing method for different pulse types and specific structuring agents is required to determine for developing quality whole wheat bread with longer shelf life. More research is necessary to find an optimum bread formulation and processing method to produce high-quality pulse fortified whole wheat bread in the bread processing plant.\n\n\nData availability\n\nThere are no data associated with this article.\n\n\nAuthor contributions\n\nMH: Conceptualization, Methodology, Software, Validation, Investigation, Formal Analysis, Resources, Data curation, Writing – Original Draft, Writing – Review & Editing, Visualization\n\nRB: Software, Resources, Data curation, Writing – Original Draft, Writing – Review & Editing, Visualization\n\nMA: Methodology, Validation, Data curation, Writing – Original Draft, Writing – Review & Editing, Visualization, Supervision, Project Administration\n\nAS: Software, Resources, Data curation, Writing – Original Draft, Writing – Review & Editing, Visualization\n\nMMH: Software, Resources, Data curation, Writing – Original Draft, Writing – Review & Editing, Visualization\n\nMIH: Software, Resources, Data curation, Writing – Review & Editing, Visualization",
"appendix": "References\n\nAbedi E, Pourmohammadi K: The effect of redox agents on conformation and structure characterization of gluten protein: An extensive review. Food Sci. Nutr. 2020; 8(12): 6301–6319. PubMed Abstract | Publisher Full Text\n\nAdenekan MK, Fadimu GJ, Odunmbaku LA, et al.: Effect of isolation techniques on the characteristics of pigeon pea (Cajanus cajan) protein isolates. Food Sci. Nutr. 2018; 6(1): 146–152. PubMed Abstract | Publisher Full Text\n\nAdeyemo S, Onilude A: Enzymatic reduction of anti-nutritional factors in fermenting soybeans by Lactobacillus plantarum isolates from fermenting cereals. Nigerian Food Journal. 2013; 31(2): 84–90. Publisher Full Text\n\nAhmed IBH, Hannachi A, Haros CM: Combined effect of chia flour and soy lecithin incorporation on nutritional and technological quality of fresh bread and during staling. Foods. 2020; 9(4): 446. PubMed Abstract | Publisher Full Text\n\nAlasino MC, Osella CA, De La Torre MA, et al.: Use of sodium stearoyl lactylate and azodicarbonamide in wheat flour breads with added pea flour. Int. J. Food Sci. Nutr. 2011; 62(4): 385–391. PubMed Abstract | Publisher Full Text\n\nAltınel B, Ünal SS: The effects of amyloglucosidase, glucose oxidase and hemicellulase utilization on the rheological behaviour of dough and quality characteristics of bread. Int. J. Food Eng. 2017a; 13(2) Publisher Full Text\n\nAltınel B, Ünal SS: The effects of certain enzymes on the rheology of dough and the quality characteristics of bread prepared from wheat meal. J. Food Sci. Technol. 2017b; 54(6): 1628–1637. PubMed Abstract | Publisher Full Text\n\nAnderson JW, Gustafson N, Bryant C, et al.: Dietary fiber and diabetes: a comprehensive review and practical application. J. Am. Diet. Assoc. 1987; 87(9): 1189–1197. PubMed Abstract | Publisher Full Text\n\nAngulo-Bejarano PI, Verdugo-Montoya NM, Cuevas-Rodríguez EO, et al.: Tempeh flour from chickpea (Cicer arietinum L.) nutritional and physicochemical properties. Food Chem. 2008; 106(1): 106–112. Publisher Full Text\n\nAnil M: Using of hazelnut testa as a source of dietary fiber in breadmaking. J. Food Eng. 2007; 80(1): 61–67. Publisher Full Text\n\nBaik BK, Han IH: Cooking, roasting, and fermentation of chickpeas, lentils, peas, and soybeans for fortification of leavened bread. Cereal Chem. 2012; 89(6): 269–275. Publisher Full Text\n\nBarac MB, Pesic MB, Stanojevic SP, et al.: Comparative study of the functional properties of three legume seed isolates: adzuki, pea and soy bean. J. Food Sci. Technol. 2015; 52(5): 2779–2787. PubMed Abstract | Publisher Full Text\n\nBarakat H, Reim V, Rohn S: Stability of saponins from chickpea, soy and faba beans in vegetarian, broccoli-based bars subjected to different cooking techniques. Food Res. Int. 2015; 76: 142–149. Publisher Full Text\n\nBartkiene E, Bartkevics V, Rusko J, et al.: The effect of Pediococcus acidilactici and Lactobacillus sakei on biogenic amines formation and free amino acid profile in different lupin during fermentation. LWT. 2016; 74: 40–47. Publisher Full Text\n\nBenítez V, Cantera S, Aguilera Y, et al.: Impact of germination on starch, dietary fiber and physicochemical properties in non-conventional legumes. Food Res. Int. 2013; 50(1): 64–69. Publisher Full Text\n\nBoschin G, Arnoldi A: Legumes are valuable sources of tocopherols. Food Chem. 2011; 127(3): 1199–1203. PubMed Abstract | Publisher Full Text\n\nBoukid F, Zannini E, Carini E, et al.: Pulses for bread fortification: A necessity or a choice?. Trends Food Sci. Technol. 2019a; 88: 416–428. Publisher Full Text\n\nBoukid F, Zannini E, Carini E, et al.: Pulses for bread fortification: A necessity or a choice?. Trends Food Sci. Technol. 2019b; 88: 416–428. Publisher Full Text\n\nBoz H, Karaoğlu MM: Improving the quality of whole wheat bread by using various plant origin materials. Czech J. Food Sci. 2013; 31(5): 457–466. Publisher Full Text\n\nBressiani J, Oro T, Santetti GS, et al.: Properties of whole grain wheat flour and performance in bakery products as a function of particle size. J. Cereal Sci. 2017; 75: 269–277. Publisher Full Text\n\nCampos-Vega R, Loarca-Piña G, Oomah BD: Minor components of pulses and their potential impact on human health. Food Res. Int. 2010; 43(2): 461–482. Publisher Full Text\n\nCapriles VD, Arêas JAG: Novel approaches in gluten-free breadmaking: interface between food science, nutrition, and health. Compr. Rev. Food Sci. Food Saf. 2014; 13(5): 871–890. Publisher Full Text\n\nCheng K-C, Wu J-Y, Lin J-T, et al.: Enhancements of isoflavone aglycones, total phenolic content, and antioxidant activity of black soybean by solid-state fermentation with Rhizopus spp. Eur. Food Res. Technol. 2013; 236(6): 1107–1113. Publisher Full Text\n\nClemente A, del Carmen Arques M : Bowman-Birk inhibitors from legumes as colorectal chemopreventive agents. World J. Gastroenterol. 2014; 20(30): 10305–10315. PubMed Abstract | Publisher Full Text\n\nCollar C, Santos E, Rosell C: Assessment of the rheological profile of fibre-enriched bread doughs by response surface methodology. J. Food Eng. 2007; 78(3): 820–826. Publisher Full Text\n\nDabija A, Codină GG, Fradinho P: Effect of yellow pea flour addition on wheat flour dough and bread quality. Rom. Biotechnol. Lett. 2017; 22(5): 12888.\n\nde Almeida Costa GE , da Silva Queiroz-Monici K , Reis SMPM, et al.: Chemical composition, dietary fibre and resistant starch contents of raw and cooked pea, common bean, chickpea and lentil legumes. Food Chem. 2006; 94(3): 327–330. Publisher Full Text\n\nDewettinck K, Van Bockstaele F, Kühne B, et al.: Nutritional value of bread: Influence of processing, food interaction and consumer perception. J. Cereal Sci. 2008; 48(2): 243–257. Publisher Full Text\n\nDhingra S, Jood S: Physico-chemical and nutritional properties of cereal-pulse blends for bread making. Nutr. Health. 2002; 16(3): 183–194. PubMed Abstract | Publisher Full Text\n\nDuenas M, Sarmento T, Aguilera Y, et al.: Impact of cooking and germination on phenolic composition and dietary fibre fractions in dark beans (Phaseolus vulgaris L.) and lentils (Lens culinaris L.). LWT-Food Sci. Technol. 2016; 66: 72–78. Publisher Full Text\n\nEgounlety M, Aworh O: Effect of soaking, dehulling, cooking and fermentation with Rhizopus oligosporus on the oligosaccharides, trypsin inhibitor, phytic acid and tannins of soybean (Glycine max Merr.), cowpea (Vigna unguiculata L. Walp) and groundbean (Macrotyloma geocarpa Harms). J. Food Eng. 2003; 56(2-3): 249–254.\n\nElawad RMO, Yang TA, Ahmed AHR, et al.: Chemical composition and functional properties of wheat bread containing wheat and legumes bran. Int. J. Food Sci. Nutr. 2016; 1(5): 10–15.\n\nElleuch M, Bedigian D, Roiseux O, et al.: Dietary fibre and fibre-rich by-products of food processing: Characterisation, technological functionality and commercial applications: A review. Food Chem. 2011; 124(2): 411–421. Publisher Full Text\n\nErdaw M, Bhuiyan M, Iji P: Enhancing the nutritional value of soybeans for poultry through supplementation with new-generation feed enzymes. Worlds Poult. Sci. J. 2016; 72(2): 307–322. Publisher Full Text\n\nErtaş N, Bilgiçli N: Effect of different debittering processes on mineral and phytic acid content of lupin (Lupinus albus L.) seeds. J. Food Sci. Technol. 2014; 51(11): 3348–3354. PubMed Abstract | Publisher Full Text\n\nErukainure OL, Okafor JN, Ogunji A, et al.: Bambara–wheat composite flour: rheological behavior of dough and functionality in bread. Food Sci. Nutr. 2016; 4(6): 852–857. PubMed Abstract | Publisher Full Text\n\nEstrada-Martínez LE, Moreno-Celis U, Cervantes-Jimenez R, et al.: Plant lectins as medical tools against digestive system cancers. Int. J. Mol. Sci. 2017; 18(7): 1403. PubMed Abstract | Publisher Full Text\n\nFahmi R, Ryland D, Sopiwnyk E, et al.: Sensory and Physical Characteristics of Pan Bread Fortified with Thermally Treated Split Yellow Pea (Pisum sativum L.) Flour. J. Food Sci. 2019; 84(12): 3735–3745. PubMed Abstract | Publisher Full Text\n\nFeregrino-Pérez AA, Berumen LC, García-Alcocer G, et al.: Composition and chemopreventive effect of polysaccharides from common beans (Phaseolus vulgaris L.) on azoxymethane-induced colon cancer. J. Agric. Food Chem. 2008; 56(18): 8737–8744. PubMed Abstract | Publisher Full Text\n\nFicco DBM, Muccilli S, Padalino L, et al.: Durum wheat breads ‘high in fibre’ and with reduced in vitro glycaemic response obtained by partial semolina replacement with minor cereals and pulses. J. Food Sci. Technol. 2018; 55(11): 4458–4467. PubMed Abstract | Publisher Full Text\n\nFlight I, Clifton P: Cereal grains and legumes in the prevention of coronary heart disease and stroke: a review of the literature. Eur. J. Clin. Nutr. 2006; 60(10): 1145–1159. PubMed Abstract | Publisher Full Text\n\nFoschia M, Horstmann SW, Arendt EK, et al.: Legumes as functional ingredients in gluten-free bakery and pasta products. Annu. Rev. Food Sci. Technol. 2017; 8: 75–96. Publisher Full Text\n\nGhoshal G, Shivhare U, Banerjee U: Effect of xylanase on quality attributes of whole-wheat bread. J. Food Qual. 2013; 36(3): 172–180. Publisher Full Text\n\nGilani GS, Xiao CW, Cockell KA: Impact of antinutritional factors in food proteins on the digestibility of protein and the bioavailability of amino acids and on protein quality. Br. J. Nutr. 2012; 108(S2): S315–S332. Publisher Full Text\n\nGómez M, Oliete B, Rosell CM, et al.: Studies on cake quality made of wheat–chickpea flour blends. LWT-Food Sci. Technol. 2008; 41(9): 1701–1709. Publisher Full Text\n\nGómez M, Ronda F, Blanco CA, et al.: Effect of dietary fibre on dough rheology and bread quality. Eur. Food Res. Technol. 2003; 216(1): 51–56. Publisher Full Text\n\nGrausgruber H, Miesenberger S, Schoenlechner R, et al.: Influence of dough improvers on whole-grain bread quality of einkorn wheat. Acta Aliment. 2008; 37(3): 379–390. Publisher Full Text\n\nGupta RK, Gangoliya SS, Singh NK: Reduction of phytic acid and enhancement of bioavailable micronutrients in food grains. J. Food Sci. Technol. 2015; 52(2): 676–684. Publisher Full Text\n\nHadnađev TD, Torbica A, Hadnađev M: Rheological properties of wheat flour substitutes/alternative crops assessed by Mixolab. Procedia Food Sci. 2011; 1: 328–334. Publisher Full Text\n\nHallén E, İbanoğlu Ş, Ainsworth P: Effect of fermented/germinated cowpea flour addition on the rheological and baking properties of wheat flour. J. Food Eng. 2004; 63(2): 177–184. Publisher Full Text\n\nHan JJ, Janz JA, Gerlat M: Development of gluten-free cracker snacks using pulse flours and fractions. Food Res. Int. 2010; 43(2): 627–633. Publisher Full Text\n\nHossain M, Arafat M, Alam M, et al.: Effect of solvent types on the antioxidant activity and total flavonoids of some Bangladeshi legumes. Food Res. 2021; 5(4): 329–335. Publisher Full Text\n\nIndrani D, Soumya C, Rajiv J, et al.: Multigrain bread–its dough rheology, microstructure, quality and nutritional characteristics. J. Texture Stud. 2010; 41(3): 302–319. Publisher Full Text\n\nIndrani D, Swetha P, Soumya C, et al.: Effect of multigrains on rheological, microstructural and quality characteristics of north Indian parotta–An Indian flat bread. LWT-Food Sci. Technol. 2011; 44(3): 719–724. Publisher Full Text\n\nJenkins DJ, Kendall CW, Vuksan V, et al.: Effect of lowering the glycemic load with canola oil on glycemic control and cardiovascular risk factors: a randomized controlled trial. Diabetes Care. 2014; 37(7): 1806–1814. PubMed Abstract | Publisher Full Text\n\nJin X, Yang R, Guo L, et al.: iTRAQ analysis of low-phytate mung bean sprouts treated with sodium citrate, sodium acetate and sodium tartrate. Food Chem. 2017; 218: 285–293. PubMed Abstract | Publisher Full Text\n\nKapravelou G, Martínez R, Andrade AM, et al.: Improvement of the antioxidant and hypolipidaemic effects of cowpea flours (Vigna unguiculata) by fermentation: results of in vitro and in vivo experiments. J. Sci. Food Agric. 2015; 95(6): 1207–1216. PubMed Abstract | Publisher Full Text\n\nKohajdová Z, Karovičová J, Magala M: Effect of lentil and bean flours on rheological and baking properties of wheat dough. Chem. Pap. 2013; 67(4): 398–407. Publisher Full Text\n\nKumar A, Prasad N, Sinha SK: Nutritional and antinutritional attributes of faba bean (Vicia faba L.) germplasms growing in Bihar, India. Physiol. Mol. Biol. Plants. 2015; 21(1): 159–162. Publisher Full Text\n\nLee I-H, Hung Y-H, Chou C-C: Solid-state fermentation with fungi to enhance the antioxidative activity, total phenolic and anthocyanin contents of black bean. Int. J. Food Microbiol. 2008; 121(2): 150–156. Publisher Full Text\n\nLin C-H, Wei Y-T, Chou C-C: Enhanced antioxidative activity of soybean koji prepared with various filamentous fungi. Food Microbiol. 2006; 23(7): 628–633. PubMed Abstract | Publisher Full Text\n\nMamilla RK, Mishra VK: Effect of germination on antioxidant and ACE inhibitory activities of legumes. LWT. 2017; 75: 51–58. Publisher Full Text\n\nMassey LK, Kynast-Gales SA: Diets with either beef or plant proteins reduce risk of calcium oxalate precipitation in patients with a history of calcium kidney stones. J. Am. Diet. Assoc. 2001; 101(3): 326–331. Publisher Full Text\n\nMastromatteo M, Danza A, Guida M, et al.: Formulation optimisation of vegetable flour-loaded functional bread Part I: screening of vegetable flours and structuring agents. Int. J. Food Sci. Technol. 2012; 47(6): 1313–1320. Publisher Full Text\n\nMcWatters K, Phillips R, Walker S, et al.: Baking performance and consumer acceptability of raw and extruded cowpea flour breads. J. Food Qual. 2004; 27(5): 337–351. Publisher Full Text\n\nMillar K, Barry-Ryan C, Burke R, et al.: Dough properties and baking characteristics of white bread, as affected by addition of raw, germinated and toasted pea flour. Innov. Food Sci. Emerg. Technol. 2019; 56: 102189. Publisher Full Text\n\nMiñarro B, Albanell E, Aguilar N, et al.: Effect of legume flours on baking characteristics of gluten-free bread. J. Cereal Sci. 2012; 56(2): 476–481. Publisher Full Text\n\nMohammed I, Ahmed AR, Senge B: Dough rheology and bread quality of wheat–chickpea flour blends. Ind. Crop. Prod. 2012; 36(1): 196–202. Publisher Full Text\n\nMohammed I, Ahmed AR, Senge B: Effects of chickpea flour on wheat pasting properties and bread making quality. J. Food Sci. Technol. 2014; 51(9): 1902–1910. PubMed Abstract | Publisher Full Text\n\nMoktan K, Ojha P: Quality evaluation of physical properties, antinutritional factors, and antioxidant activity of bread fortified with germinated horse gram (Dolichus uniflorus) flour. Food Sci. Nutr. 2016; 4(5): 766–771. PubMed Abstract | Publisher Full Text\n\nMollard R, Luhovyy B, Panahi S, et al.: Regular consumption of pulses for 8 weeks reduces metabolic syndrome risk factors in overweight and obese adults. Br. J. Nutr. 2012; 108(S1): S111–S122. PubMed Abstract | Publisher Full Text\n\nNarina SS, Bhardwaj HL, Hamama AA, et al.: Seed protein and starch qualities of drought tolerant pigeonpea and native tepary beans. J. Agric. Sci. 2014; 6(11): 247. Publisher Full Text\n\nNdife J, Abdulraheem L, Zakari U: Evaluation of the nutritional and sensory quality of functional breads produced from whole wheat and soya bean flour blends. Afr. J. Food Sci. 2011; 5(8): 466–472.\n\nOhizua ER, Adeola AA, Idowu MA, et al.: Nutrient composition, functional, and pasting properties of unripe cooking banana, pigeon pea, and sweetpotato flour blends. Food Sci. Nutr. 2017; 5(3): 750–762. PubMed Abstract | Publisher Full Text\n\nOlagunju AI, Ekeogu PC, Bamisi OC: Partial substitution of whole wheat with acha and pigeon pea flours influences rheological properties of composite flours and quality of bread. Br. Food J. 2020; 122: 3585–3600. Publisher Full Text\n\nOlapade A, Oluwole O: Bread making potential of composite flour of wheat-acha (Digitaria exilis staph) enriched with cowpea (Vigna unguiculata L. walp) flour. Nigerian Food Journal. 2013; 31(1): 6–12. Publisher Full Text\n\nOuazib M, Garzon R, Zaidi F, et al.: Germinated, toasted and cooked chickpea as ingredients for breadmaking. J. Food Sci. Technol. 2016; 53(6): 2664–2672. PubMed Abstract | Publisher Full Text\n\nPasqualone A, De Angelis D, Squeo G, et al.: The Effect of the Addition of Apulian black Chickpea Flour on the Nutritional and Qualitative Properties of Durum Wheat-Based Bakery Products. Foods. 2019; 8(10): 504. PubMed Abstract | Publisher Full Text\n\nPenella JS, Collar C, Haros M: Effect of wheat bran and enzyme addition on dough functional performance and phytic acid levels in bread. J. Cereal Sci. 2008; 48(3): 715–721. Publisher Full Text\n\nPrasad SK, Singh MK: Horse gram-an underutilized nutraceutical pulse crop: a review. J. Food Sci. Technol. 2015; 52(5): 2489–2499. PubMed Abstract | Publisher Full Text\n\nPrevitali MA, Mastromatteo M, De Vita P, et al.: Effect of the lentil flour and hydrocolloids on baking characteristics of wholemeal durum wheat bread. Int. J. Food Sci. Technol. 2014; 49(11): 2382–2390. Publisher Full Text\n\nRibotta PD, Arnulphi SA, León AE, et al.: Effect of soybean addition on the rheological properties and breadmaking quality of wheat flour. J. Sci. Food Agric. 2005; 85(11): 1889–1896. Publisher Full Text\n\nRizzello CG, Calasso M, Campanella D, et al.: Use of sourdough fermentation and mixture of wheat, chickpea, lentil and bean flours for enhancing the nutritional, texture and sensory characteristics of white bread. Int. J. Food Microbiol. 2014; 180: 78–87.\n\nRoland WS, Pouvreau L, Curran J, et al.: Flavor aspects of pulse ingredients. Cereal Chem. 2017; 94(1): 58–65.\n\nRoopashri AN, Varadaraj MC: Hydrolysis of flatulence causing oligosaccharides by α-d-galactosidase of a probiotic Lactobacillus plantarum MTCC 5422 in selected legume flours and elaboration of probiotic attributes in soy-based fermented product. Eur. Food Res. Technol. 2014; 239(1): 99–115. Publisher Full Text\n\nRostamian M, Milani JM, Maleki G: Physical properties of gluten-free bread made of corn and chickpea flour. Int. J. Food Eng. 2014; 10(3): 467–472. Publisher Full Text\n\nRoy M, Imran MZH, Alam M, et al.: Effect of boiling and roasting on physicochemical and antioxidant properties of dark red kidney bean (Phaseolus vulgaris). Food Res. 2021; 5(3): 438–445. Publisher Full Text\n\nRysová J, Ouhrabková J, Gabrovská D, et al.: Food with addition of little-known legume varieties. Agron. Res. 2010; 8(2): 339–344.\n\nSathya A, Siddhuraju P: Effect of processing methods on compositional evaluation of underutilized legume, Parkia roxburghii G. Don (yongchak) seeds. J. Food Sci. Technol. 2015; 52(10): 6157–6169. PubMed Abstract | Publisher Full Text\n\nShivaani M: Characterization of Whole Wheat Bread Reformulated with Pea and Soy Protein Isolates. Int. J. Nutr. Pharmacol. Neurol. Dis. 2020; 10(3): 112.\n\nShrivastava C, Chakraborty S: Bread from wheat flour partially replaced by fermented chickpea flour: Optimizing the formulation and fuzzy analysis of sensory data. LWT. 2018; 90: 215–223. Publisher Full Text\n\nSilva CB d, Almeida EL, Chang YK: Interaction between xylanase, glucose oxidase and ascorbic acid on the technological quality of whole wheat bread. Ciência Rural. 2016; 46: 2249–2256. Publisher Full Text\n\nSingh B, Singh JP, Singh N, et al.: Saponins in pulses and their health promoting activities: A review. Food Chem. 2017; 233: 540–549. PubMed Abstract | Publisher Full Text\n\nSotelo A, González-Osnaya L, Sánchez-Chinchillas A, et al.: Role of oxate, phytate, tannins and cooking on iron bioavailability from foods commonly consumed in Mexico. Int. J. Food Sci. Nutr. 2010; 61(1): 29–39. PubMed Abstract | Publisher Full Text\n\nStantiall SE, Dale KJ, Calizo FS, et al.: Application of pulses cooking water as functional ingredients: the foaming and gelling abilities. Eur. Food Res. Technol. 2018; 244(1): 97–104. Publisher Full Text\n\nSulieman AME, Sinada EA, Ali AO: Quality characteristics of wheat bread supplemented with chickpea (Cicer arietinum) flour. Int. J. Food Sci. Nutr. Eng. 2013; 3(5): 85–90.\n\nTang X, Liu J: A comparative study of partial replacement of wheat flour with whey and soy protein on rheological properties of dough and cookie quality. J. Food Qual. 2017; 2017: 1–10. Publisher Full Text\n\nTebben L, Shen Y, Li Y: Improvers and functional ingredients in whole wheat bread: A review of their effects on dough properties and bread quality. Trends Food Sci. Technol. 2018a; 81: 10–24. Publisher Full Text\n\nTebben L, Shen Y, Li Y: Improvers and functional ingredients in whole wheat bread: A review of their effects on dough properties and bread quality. Trends Food Sci. Technol. 2018b; 81: 10–24. Publisher Full Text\n\nTronsmo K, Faergestad E, Schofield J, et al.: Wheat protein quality in relation to baking performance evaluated by the Chorleywood bread process and a hearth bread baking test. J. Cereal Sci. 2003; 38(2): 205–215. Publisher Full Text\n\nTuncel NB, Yılmaz N, Şener E: The effect of pea (Pisum sativum L.)-originated asparaginase on acrylamide formation in certain bread types. Int. J. Food Sci. Technol. 2010; 45(12): 2470–2476. Publisher Full Text\n\nTurfani V, Narducci V, Durazzo A, et al.: Technological, nutritional and functional properties of wheat bread enriched with lentil or carob flours. LWT. 2017; 78: 361–366. Publisher Full Text\n\nVan Hung P, Maeda T, Morita N: Dough and bread qualities of flours with whole waxy wheat flour substitution. Food Res. Int. 2007; 40(2): 273–279. Publisher Full Text\n\nWang J, Rosell CM, de Barber CB : Effect of the addition of different fibres on wheat dough performance and bread quality. Food Chem. 2002; 79(2): 221–226. Publisher Full Text\n\nWani IA, Sogi DS, Sharma P, et al.: Physicochemical and pasting properties of unleavened wheat flat bread (Chapatti) as affected by addition of pulse flour. Cogent Food Agric. 2016; 2(1): 1124486. Publisher Full Text\n\nWinham DM, Hutchins AM: Perceptions of flatulence from bean consumption among adults in 3 feeding studies. Nutr. J. 2011; 10(1): 128. PubMed Abstract | Publisher Full Text\n\nXu J, Zhang Y, Wang W, et al.: Advanced properties of gluten-free cookies, cakes, and crackers: A review. Trends Food Sci. Technol. 2020; 103: 200–213. Publisher Full Text\n\nYamsaengsung R, Schoenlechner R, Berghofer E: The effects of chickpea on the functional properties of white and whole wheat bread. Int. J. Food Sci. Technol. 2010; 45(3): 610–620. Publisher Full Text\n\nZannini E, Waters DM, Arendt EK: The application of dextran compared to other hydrocolloids as a novel food ingredient to compensate for low protein in biscuit and wholemeal wheat flour. Eur. Food Res. Technol. 2014; 238(5): 763–771. Publisher Full Text\n\nZhang Y, Hu R, Tilley M, et al.: Effect of Pulse Type and Substitution Level on Dough Rheology and Bread Quality of Whole Wheat-Based Composite Flours. Processes. 2021; 9(9): 1687. Publisher Full Text\n\nŽupunski V, Vasić M, Vozlič JŠ, et al.: Uncertainty of Trypsin Inhibitor Activity Measurement of Legume Crops Using Microtiter Plate Method. Food Anal. Methods. 2018; 11(4): 1034–1040. Publisher Full Text"
}
|
[
{
"id": "138272",
"date": "06 Jun 2022",
"name": "Rungsinee Sothornvit",
"expertise": [
"Reviewer Expertise Biopolymer films and coatings for food systems"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments: This manuscript was to review the effect of pulse fortified wheat bread on dough rheology, quality, and sensory properties. The manuscript is written quite well. However, it should introduce the definition of pulses which differ from other peas and nuts to provide an understanding to the readers. Some comments are below.\n\nAbstract\nPlease add or specify the optimum ratio of the pulse to whole wheat flour from the review.\n\nIntroduction\nWere any works done on the pulse flour itself to make bread?\n\nWhy would the authors like to emphasize utilizing pulse in the whole wheat bread, not the wheat bread? Please clarify.\n\nAre pea and soy protein isolates considered pulses?\n\nAre there any works fortified pulses in other types of flours?\n\nDough rheology:\nDid the pulse flour itself show the rheological behavior?\n\nDo different pulses provide different compositions resulting in different roles in rheology? Please clarify.\n\nDid the addition of pulse flour to the whole wheat flour vs. the wheat flour affect the quality of bread differently? Is it sufficient to add pulse flour into wheat flour with providing the desirable quality of bread and balanced nutrition?\n\nIs the multigrain considered as pulses? Please define the definition of multigrain at first. Did the rheology of multigrain differ from the others?\n\nFig. 2: Move the x-axis title to the y-axis title and add the other name for the x-axis. Did the data show any significant differences on all properties? Please clarify.\n\nAny work on the whole wheat flour?\n\nTable 2: Any significant differences on all results?\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "138273",
"date": "08 Jul 2022",
"name": "Dr. Rokeya Begum",
"expertise": [],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper is scientifically sound but a few changes that could be incorporated for the improvement of the manuscript are as follows:\nPage number 4 line number 16 and line number 22: 'protein digestibility improved by inactivating ant nutrient compounds; ant nutrients responsible for off flavour.' It should be anti-nutrient compounds or anti-nutrients.\n\nFigure 2 represents many parameters like water absorption capacity, dry gluten, protein content, protein recovery, albumin, globulin, glutelin, prolamin, lysine, etc. but few are discussed in the text. Please discuss other parameters.\n\nPage no 10 line 26: It was also permissible to replace 10% to >20%. Please indicate a specific range.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-536
|
https://f1000research.com/articles/11-535/v1
|
18 May 22
|
{
"type": "Data Note",
"title": "MapOSR - A mapping review dataset of empirical studies on Open Science",
"authors": [
"Jana Lasser",
"Jürgen Schneider",
"Thomas Lösch",
"Ronny Röwert",
"Tamara Heck",
"Clemens Bluemel",
"Maike Neufend",
"Isabel Steinhardt",
"Stefan Skupien",
"Jana Lasser",
"Jürgen Schneider",
"Thomas Lösch",
"Tamara Heck",
"Clemens Bluemel",
"Maike Neufend",
"Isabel Steinhardt",
"Stefan Skupien"
],
"abstract": "Research that investigates respective researchers’ engagement in Open Science varies widely in the topics addressed, methods employed, and disciplines investigated, which makes it difficult to integrate and compare its results. To investigate current outcomes of Open Science research, and to get a better understanding on well-researched topics and research gaps, we aimed at providing an openly accessible overview of empirical studies that focus on different aspects of Open Science in different scientific disciplines, academic groups and geographical regions. In this paper, we describe a data set of studies about Open Science practices retrieved following a PRISMA approach to compile a literature review. We included studies from the Scopus and Web of Science databases with keywords relating to Open Science between the years 2000 and 2020, as well as a snowball search for relevant articles. Studies that did not investigate any aspect of Open Science, or weren’t peer-reviewed were excluded, resulting in a total of 695 remaining studies. The data set was collaboratively annotated to ensure intercoder reliability of the coded data.",
"keywords": [
"Open Science",
"Open Access",
"Open Data",
"Open Education",
"Open Evaluation",
"Open Methods",
"Open Participation",
"Open Policies",
"Open Software",
"Open Tools"
],
"content": "Introduction\n\nOpen Science is still only vaguely defined. Different initiatives are subsumed under the label of Open Science, coming from different communities which share the goal of making sciences more open and transparent. The Open Science communities have made attempts to define key elements of Open Science - which are also referred to as the pillars of Open Science, that is, open access to publications, open data and open source (FOSTER Taxonomy of Open Science1). Findings from bibliometric studies indicate that research dealing with Open Science as a phenomenon either by exploring its concepts, by assessing Open Science initiatives both at the national or international level or by exploring Open Science research practices (Levin et al., 2016) have increased (Blümel & Beng, 2018). Yet, research that investigates engagement in Open Science varies widely in the topics addressed, methods employed, and disciplines investigated. This makes it difficult to integrate and compare results and get deeper insights on how Open Science and related practices evolved in science, or if the Open Science movement has any impact on research practices (Christensen et al., 2020). To get a better understanding of Open Science research and investigate aspects of Open Science, we are providing an openly accessible overview of peer-reviewed empirical studies that focus on the attitudes, assessments, and practices of Open Science among individuals, communities, and organizations.\n\nWith this approach, we intend to clarify the current understanding of Open Science. Empirical studies capture diverse aspects of Open Science: among others, different disciplines, practitioner groups, geographical scopes and user groups are investigated. For instance, numerous empirical survey-based studies have asked similar questions, but often to different groups of respondents. Therefore, a complementary overview of existing studies will allow us to identify which user groups are less covered in the current research landscape.\n\nEmpirical studies were collected following a Preferred Reporting Items for Systematic Reviews (PRISMA) workflow and then annotated along five categories. The collected data serves three purposes, among others: First, other researchers in the field of Open Science may use the data for further in-depth analysis and synthesize data in a systematic review or any other format synthesizing research. Second, the data can be used as an annotated literature corpus that allows for a curated introduction in literature on Open Science. Third, Open Science practitioners (e.g. librarians, Open Science officers at universities, funding bodies) can use the data as a source of information on Open Science studies.\n\n\nMethods\n\nWe designed the study as a mapping review. Our aim was to identify all empirical studies concerned with Open Science or any of its key elements, to be used as a basis for deeper investigations. Research on Open Science and its concrete concept varies, and the term “Open Science” is not new. However, Open Science as a movement of new research practices enabled by means of technical innovations on the Internet, has been discussed for over twenty years (Bartling & Friesike, 2014). Following the Foster taxonomy of Open Science, mapping in this study covered research related to key elements of Open Science (Open Data, Open Access, and Open Source) which also guided our search strategies. Our aim was to map research investigating these key elements of the Open Science movement, and not to identify the extent of Open Science concepts discussed, as a scoping review might aim for (cp. Grant & Booth, 2009). Moreover, in this first step, we did not synthesize any results like in a systematic review, but annotated the publications with five key features to give a better overview of the nature of the studies. With these settings and restrictions, we consider our study as a mapping review of empirical studies on defined Open Science elements.\n\nConsidering the recommendations on literature reviews (Gough et al., 2017), we carried out a systematic search, included and excluded publications based on factual criteria, and annotated the relevant publications to characterize main study design and the key features regarding the covered Open Science aspects, study method, disciplinary focus, targeted group and geographical scope. We did not pre-register the review because the idea was developed out of a research group that first collected Open Science studies, and then went on to expand the work with a systematic search and annotation. This first snowball search went over a period of six months. Researchers made an announcement on Twitter and researchgate.net in June 2020 and invited colleagues to contribute to the collection of empirical studies on Open Science. The results were included in the project’s publicly available Zotero-Library2. The first entry was made on 30 June 2020, the last on 16 March 2021. The snowball search yielded 126 publications.\n\nIn addition, we conducted a systematic literature search on January 26th and 27th, 2021. We searched in the Web of Science (all indices) and Scopus databases. The search query consists of two blocks: a) terms of the Open Science elements, b) terms describing any empirical study (see Table 1).\n\nWe deliberately excluded terms relating to open education, like open educational resources (OER) and open educational practices. Although OER are mentioned as part of Open Science (see e.g. FOSTER), research on them as well as educational practices span a different research field quite separated from discussions on Open Science (Scanlon, 2013). Including OER and similar research would therefore have resulted in a very large corpus, which was beyond the scope of this study. Similarly, we excluded citizen science from our search. Block b was necessary to limit the retrieved publications to a manageable number, as block a alone would have resulted in a large number of non-empirical studies discussing Open Science. After testing several search strings and checking the results, we decided to search Open Science elements in the title field only. Terms describing empirical studies were searched in title, abstract, and (author) keywords. Additionally, we limited results to the document types article, book, book chapter, and proceedings paper. As the term “Open Science” is rarely mentioned in the research literature before 2000 (Blümel & Beng, 2018), the date range was specified from 2000 to 2020. This search yielded 3651 publications. Table 1 shows the original queries for the Web of Science and Scopus.\n\nThe snowball search and the systematic search in the two databases resulted in 3777 publications. From these, we removed 842 duplicates (see Figure 1). The titles and abstracts of the remaining 2935 publications were independently screened by three coders (all authors of this study) according to the following inclusion criteria:\n\n• The publication deals with any aspect of Open Science (excluding OER and citizen science).\n\n• The study focused on Open Science inside academia (e.g. exclusion of topics such as open government data or industry-based research).\n\n• The study includes the collection of empirical data.\n\n• The publication is written in English, German, Italian, French or Spanish. Unfortunately, languages had to be limited according to the coders’ language skills.\n\nDisagreement was resolved through discussion. The screening resulted in 2101 publications being excluded.\n\nThe annotations of key features followed several iterative steps. The 834 publications were coded along five categories as described in the codebook (see Table 2 and mapOSR_codebook_V4.csv in the data repository, Extended data, Lasser et al., 2022) Action, method, discipline, group and geo scope. Within all categories, several labels could be awarded at the same time. We distributed the publications randomly across nine coders. These coders were trained in the codebook through joint development, refinement, and discussion in two rounds of coding.\n\nDuring the coding process, we excluded another 139 studies that did not meet the inclusion criteria upon closer inspection, e.g. for some of the studies the empirical design was not clear. Most exclusions resulted mainly from duplications between conference papers and corresponding publications. The final sample of coded publications therefore included n=695 publications. We adapted the codebook during our process with regard to the following aspects: In the action category we assessed which aspect of Open Science was targeted in the publication. We adapted the labels within the category based on the FOSTER taxonomy and added ‘open education’ and ‘open participation’ (categories are explained in Table 2). We note that while we did not include Open Education and Open Participation in our database search, we still included them in our codebook, to leave room for future extensions of our approach to these categories. Furthermore, we converted ‘open reproducible research’ into a broader ‘open methodology’. The second category describes the methods that are applied to empirically study the chosen aspect of Open Science, such as bibliometric studies or surveys. In the third category we coded the disciplines that are targeted with the study, such as engineering or social sciences. The selection of labels for this category is based on the OECD-Frascati Manual (OECD, 2015). The fourth category describes the group under investigation, such as researchers or librarians. In the last category we recorded the geographical scope of the empirical study according to design and included cases. The labels in this category were based on the ISO 3166-1 alpha-3 codes for countries.\n\n\nData validation\n\nAfter manual annotation, we performed an automated data cleaning step to correct misspelled labels. The code used to perform the data cleaning is publicly available (see file clean_data.ipynb in the code repository; Lasser & Schneider, 2022). This included replacing two-digit country codes with three-digit country codes where necessary, replacing “missing” and “none” with NaN values and unifying label names such as policies, which was mapped to “openpolicies”. A list of all encountered misspellings is provided in the data cleaning code accompanying this publication. In addition, the letter and “=” symbol preceding each label was stripped from the entries. The consistency of the data was then checked by comparing the labels present in each category (action, method, discipline and group) to the labels allowed by the coding scheme. Country codes in the data set were manually checked for consistency.\n\nSince each coded category was not exclusive, each entry could contain a list of labels, separated by a semicolon. Entries were first automatically split into a list of entries. Categories were then split into as many columns as possible, labels allowed in them and dummy-coded to only contain boolean values. For example, the category “method” was therefore split into five columns with the column names “method_biblio”,”method_documentreview”, “method_interview”, “method_survey”, and “method_other”. An entry that would originally read “m=biblio; m=survey” would be split into the following column entries: “method_biblio=True”, “method_documentreview=False”, “method_interview=False”, “method_survey=True”, “method_other=False”.\n\nAn overview of the development of publication numbers between the years 2000 and 2020 for the category “Action” is shown in Figure 2. The categories “Method”, “Discipline”, “Group” and “Geo Scope” are summarized in Figure 3. Code to reproduce the figure is publicly available (see file create_visualizations.ipynb in the code repository; Lasser & Schneider, 2022).\n\nThe top left panel shows the empirical study method, the top right panel shows the studied discipline, the bottom left panel shows the studied group, and the bottom right panel shows the distribution over the top 15 countries present in the dataset.\n\nInterrater agreement was calculated for each label within the five categories of the codebook. For this purpose, we double-coded 63 of the 697 publications (9%). The coders were evenly distributed across the data underlying the computation of the interrater agreement. The occurrence for several of the dichotomous labels (dummy transformed from the categories) was strongly imbalanced. An example of this is the occurrence frequency of certain countries in the geo category that were never or very rarely coded. Cohen’s kappa, the standard measure of agreement for dichotomous categorical variables, leads to biased values for skewed variables and was therefore not appropriate in this case (Xu & Lorber, 2014). We therefore resorted to simple percentage agreement values for all labels.\n\nBased on the results, we adapted category labels for geo and discipline, i.e. we recoded the labels of “geo=none” and “geo=all” to “geo=unspecific”, and “discipline=none” and “discipline=all” to “discipline=unspecific” again due to the skewed distribution. A reason for the coders’ disagreements for these category labels was that empirical studies do not always explicitly state their geographical or disciplinary focus. For example, bibliometric studies usually investigate publications from determined journals. Here, some coders labeled “geo=none” or “discipline=none” as they did not deviate geographical or disciplinary focus from a journal sample. Other coders annotated “all” to the categories for the same reason, i.e. the journal sample does not deliberately limit geo or discipline in any way.\n\nWe calculated the percent agreement for each of the 36 labels from the five categories that were double coded. In this section we are only reporting a summary of the agreement (see Table 3); details for the data transformation, recoding, and results are reported in the documentation (see file “reliability.html” in the code repository; Lasser & Schneider, 2022).\n\nThe following limitations should be considered with any use of the data set: despite the snowball search, which led to relevant results for the mapping review, we only did the systematic search in two databases, due to time constraints. As Web of Science and Scopus do not include all research literature and are biased towards specific criteria like publications (journal articles), languages (English-focused), and journals that are published in the United States, we lack other relevant peer-reviewed publications not covered in the two databases. We did not explicitly search for further gray literature to complement the results from the database search, therefore our data set may be susceptible to publication bias. Furthermore, in the inclusion criteria, we specify English, German, Italian, French or Spanish as the languages of publications due to the languages skills of the authors and coders involved in our study. This systematically excludes publications in other languages and thus regions investigated. Also, the terms used in the search query were not translated to German, Italian, French, Spanish. Therefore, the database search only returned publications in these languages if an abstract or title was available in English. We invite native speakers of other languages to apply the selection criteria and coding system to other databases and searches in their language and thus contribute to the expansion of the data set.\n\n\nLong-term data maintenance plans\n\nThe current review has the character of a pilot study, which we will build on. Three long term data maintenance plans are currently developed: first, annual data will be added following the year 2020 using the same selection criteria, coding and databases to keep the data and its value for research, teaching and science policy up to date, and to follow empirical research trends on Open Science practices. Second, we currently plan to include comparable data on literature about open educational resources and inclusive science practices such as citizen science or transdisciplinary approaches. Hence, the data will be expanded to further Open Science practices. Third, as a midterm goal a dashboard with visual analytical features will be programmed to allow for immediate usability of the data and to showcase the scoping efforts to a broader public.\n\n\nData and software availability\n\nZenodo: MapOSR - A Mapping Review Dataset of Empirical Studies on Open Science, https://doi.org/10.5281/zenodo.6491891 (Lasser et al., 2022)\n\nThis project contains the following underlying data:\n\n‐ mapOSR_data_V5_9_3_220419_coded_clean.csv\n\n‐ mapOSR_codebook_V4.csv\n\n‐ mapOSR_references.bib\n\n‐ mapOSR_interrater_reliability_clean.csv\n\n‐ mapOSR_info.csv\n\nPRISMA checklist and flow chart for”MapOSR - A Systematic Mapping Review of Empirical Studies on Open Science” are deposited on Zenodo: https://doi.org/10.5281/zenodo.6491891\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nAnalysis code available from: https://github.com/JanaLasser/mapping-open-science-research/tree/v1.0\n\nArchived analysis code as at time of publication: https://doi.org/10.5281/zenodo.6491829\n\nLicense: MIT",
"appendix": "References\n\nBartling S, Friesike S: Towards Another Scientific Revolution. Bartling S, Friesike S, editors. Opening science. New York: Springer Verlag; 2014; pp. 3–15. Publisher Full Text\n\nBlümel C, Beng F: Open Science – a loosely coupled discourse? Comparing Open Science and Open Innovation from a bibliometric point of view. STI 2018 Conference Proceedings. 2018; 369–377.\n\nChristensen G, Wang Z, Levy Paluck E, et al.: Open science practices are on the rise: The state of social science (3s) survey.2020. Reference Source\n\nGough D, Oliver S, Thomas J: Introducing Systematic Reviews. Gough D, Oliver S, Thomas J editors. An Introduction to Systematic Reviews. 2nd ed.London: Sage; 2017; pp. 1–17.\n\nGrant MJ, Booth A: A typology of reviews: an analysis of 14 review types and associated methodologies. Health Inf. Libr. J. 2009; 26(2): 91–108. PubMed Abstract | Publisher Full Text\n\nLasser J, Schneider J: mapOSR dataset 2000-2020 (v1.0).2022. Publisher Full Text\n\nLasser J, Schneider J, Lösch T, et al.: MapOSR - A Mapping Review Dataset of Empirical Studies on Open Science (V5_9_3_220419) [Data set]. Zenodo. 2022. Publisher Full Text\n\nLevin N, Leonelli S, Weckowska D, et al.: How do scientists define openness? Exploring the relationship between open science policies and research practice. Bull. Sci. Technol. Soc. 2016; 36(2): 128–141. PubMed Abstract | Publisher Full Text\n\nOSCD Frascati Manual: In The Measurement of Scientific, Technological and Innovation Activities. OECD; 2015. Publisher Full Text\n\nPage MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int. J. Surg. 2021; 88: 105906. PubMed Abstract | Publisher Full Text\n\nScanlon E: Scholarship in the digital age: Open educational resources, publication and public engagement. Br. J. Educ. Technol. 2013; 45(1): 12–23. Wiley. Publisher Full Text\n\nXu S, Lorber MF: Interrater agreement statistics with skewed data: Evaluation of alternatives to Cohen’s kappa. J. Consult. Clin. Psychol. 2014; 82(6): 1219–1227. PubMed Abstract | Publisher Full Text\n\n\nFootnotes\n\n1 See https://www.zotero.org/groups/2526436/meta-research_on_os-related_surveys/library\n\n2 http://www.fosteropenscience.eu/"
}
|
[
{
"id": "138248",
"date": "08 Jul 2022",
"name": "Katja M. Mayer",
"expertise": [
"Reviewer Expertise STS",
"critical data studies"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe \"data note\" assessed here is the first to provide an open annotated literature corpus that provides an overview of empirical studies on open science, specifically on open access, open data, and open source. The dataset has annotated references to 695 studies from 2000 to 2020 found through Web of Science searches, Scopus, and snowballing in the OS community. The rationale for creating the dataset is clearly described, protocols are appropriate and overall the work is technically sound. Datasets are in a useable and accessible format. The data paper describes in detail not only the dataset but also the annotation and category work, as well as the data validation processes. This is particularly noteworthy, as not common, and very helpful not only to reuse the dataset but also to learn about the process. The document is, therefore, also excellently suited for teaching. It is already apparent that I rate the paper and the dataset very highly in any case. Both also score well with regard to the dynamics of the field that is described: due to the excellent preparation for re-usability, as well as transparency of the production conditions, the dataset can be continued in versions and forms, a good starting point for an important repository of basic knowledge for further research.\nIt would be very interesting to know how the results of the search for studies differ between the indices and the answers from the community: were there significant differences along the five categories in terms of what could be found?\nRegarding the problem that perhaps more such studies can be found in the grey literature area: what outlook on this would the authors allow themselves on the basis of their experience? After all, Open Science is precisely about opening up the boundaries of traditional scientific communication channels, so a few more sentences on this would certainly be in order. The discussion of this dataset and papers could also contribute to the development of a metadata standard for precisely the recording of such \"grey literature\".\nPerhaps the article - although understandably not wanting to get into a discussion of the concepts around Open Science - could briefly note with regard to the search activities that it would probably also be possible to take up other terms such as \"data sharing\", \"e-infrastructures\" etc., especially with regard to the time before the widespread use of Open Science terms. Since this would certainly require a lot of additional effort, this dimension could be thought of in a further study or as an extension of the dataset in the future.\n\nThe Zotero list is quite wonderful, but it would be even more awesome if the 695 studies were tagged as such, and also the distinction of whether it was found from an index or through community snowballing could be tagged there. The Zotero Online group could then adopt these tags as well.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "154176",
"date": "17 Nov 2022",
"name": "Judith J. de Haan",
"expertise": [
"Reviewer Expertise Open science",
"preregistration",
"systematic reviews"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article describes a mapping of literature on various open science practices in the period of 2000 to 2020. There has been a lot of attention and progress in the open science movement, but there is no clear overview of the empirical studies that support open science practices. The authors of this paper made the first start by creating such an overview.\n\nThe strength of this paper is that they are trying to create a mapping of the empirical studies as a starting point for others to work on further and to add other papers as well. Though the dataset is now available in cvs format (accessible and reusable, which is great), it would be great if this would be available in a workable, open way. Like in a living library, where people can add and annotate papers, to start working on a richer and more complete overview. And more up-to-date because the newest studies can immediately be added as well. An example of such a living library can be found here: https://living-library-uu.web.app/. This is a prototype from the Freudenthal Institute. The manuscript of this library will be shared soon, as the open source code on github. For questions in the meantime, livinglibrary@uu.nl can be used.\n\nOpen science contains a lot of different practices and the authors state that they focus on only a part of these practices: open publications, open data, and open source. It could be described clearer which practices are included and which are not. In the search string in Table 1, it also includes 'open peer review' and 'open material'. On the other hand, it does not include the terms 'open source', 'open software', or 'FAIR data', which I think are also relevant if you want to search for open source and open data. The selection of the search terms is not clearly defined, this could be defined better and also state in the title and introduction better what the search includes. This is not about open science but about a selection of open science practices.\n\nThe authors also include a search block to narrow down the number of papers, because it would not be possible to go through that many papers. This does mean that it probably will miss studies on open science.\n\nSome small remarks, mostly about the extra explanation of the selection that was used for this search and how this paper was written:\nWhy online peer-reviewed? What about preprints, PCI, or preregistrations?\n\nIn the introduction it is written: 'Open Science is still only vaguely defined', maybe broadly defined would be a better term.\n\nThe goal of open science is not only to be more open and transparent, but this is a means to an end - improve the quality of research and improve the impact of the research.\n\nThe explanation for no preregistration is a bit limited. You can always still (pre)register your study design and follow-up steps, and state that you started data collection already.\n\nExplain better what is in this review, no OER, no citizen science, but also no public engagement, no open materials, no pre-prints, no pre-registration, no open proposals\n\nWhy is research from the industry removed? Mention this earlier and explain why.\n\nCan you specify the articles that were excluded (N=... for language, N=... not empirical data)\n\nHow many disagreements were there in the selection part?\n\n'We invite native speakers of other languages to apply the selection criteria and coding system to other databases and searches in their language and thus contribute to the expansion of the data set' - I think this is an important sentence. This study can become impactful if others contribute and it will be a living, annotated dataset.\n\n'The current review has the character of a pilot study, which we will build on.' - Mention this earlier. Relevant for the reader.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "154172",
"date": "18 Nov 2022",
"name": "Elena Šimukovič",
"expertise": [
"Reviewer Expertise Open Access",
"Open Science",
"research data management",
"Open Research Data",
"Science and Technology Studies",
"science policy",
"scholarly communication"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe aim of this data note, as outlined in the Methods section, was \"to identify all empirical studies concerned with Open Science or any of its key elements\", which is \"to be used as a basis for deeper investigations\". For this purpose, the authors compiled a list of peer-reviewed publications from two commercial databases and publicly shared the results of their collaborative coding exercise.\nIn summary, this approach tackles an important gap that might be useful for research and teaching alike, as well as for related policy work. However, in my view, the broad aims as announced in the Introduction section (e.g. \"to clarify the current understanding of Open Science\") are somewhat overestimated. In particular, this applies to the authors' choice to limit their literature search to a few elements of Open Science only (i.e. Open Data, Open Access, and Open Source) and to include only peer-reviewed publications from two particular databases. As the authors state themselves, there are plenty of risks and limitations related to the chosen approach, especially with regard to inherent biases inscribed in these methods. Since Open Science is a highly relevant topic to various practitioners (incl. professionals at libraries, funding bodies, publishers, science policy-makers, research consulting firms, etc.), which have produced a huge number of reports on related issues themselves, excluding grey literature entirely appears to me as highly problematic.\nBecause this contribution is meant as a \"data note\" and not a full research article (or other type of publication), it satisfies the requirements imposed on this type of work. However, I would suggest that the authors bring their announced (very broad) objectives into better accordance with the (necessarily limited) outcomes in their data note and related data sets. Also, the list of keywords might be misleading, since only a few of the named Open Science sub-areas are dealt with in more detail.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
},
{
"id": "154173",
"date": "28 Nov 2022",
"name": "Andrew M. Cox",
"expertise": [
"Reviewer Expertise Open data",
"research data management",
"open science from an information science perspective. I am not a scientometrician."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper explains the creation of a bibliometric dataset of peer reviewed publications about open science for 2000-2020. Exclusion of OER explained. Keywords used explained (I wonder if \"open research\" should have been a term?) A number of limits on the dataset are appropriately acknowledged, namely: limited range of databases searched, languages covered and exclusion of gray literature.\nIt would have been useful to discuss the implications of the database and language limitations. Given the quantity of material published in Chinese excluding material from this region is significant. Open access journals in South America would not be included in the search. Given the distinctive traditions around open science in that region this is again an issue. As an area of practice/policy I think including gray literature would have been helpful in increasing the value of the dataset.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-535
|
https://f1000research.com/articles/10-1261/v1
|
08 Dec 21
|
{
"type": "Research Article",
"title": "MSTCN: A multiscale temporal convolutional network for user independent human activity recognition",
"authors": [
"Sarmela Raja Sekaran",
"Ying Han Pang",
"Goh Fan Ling",
"Ooi Shih Yin",
"Sarmela Raja Sekaran",
"Goh Fan Ling",
"Ooi Shih Yin"
],
"abstract": "Background: In recent years, human activity recognition (HAR) has been an active research topic due to its widespread application in various fields such as healthcare, sports, patient monitoring, etc. HAR approaches can be categorised as handcrafted feature methods (HCF) and deep learning methods (DL). HCF involves complex data pre-processing and manual feature extraction in which the models may be exposed to high bias and crucial implicit pattern loss. Hence, DL approaches are introduced due to their exceptional recognition performance. Convolutional Neural Network (CNN) extracts spatial features while preserving localisation. However, it hardly captures temporal features. Recurrent Neural Network (RNN) learns temporal features, but it is susceptible to gradient vanishing and suffers from short-term memory problems. Unlike RNN, Long-Short Term Memory network has a relatively longer-term dependency. However, it consumes higher computation and memory because it computes and stores partial results at each level. Methods: This work proposes a novel multiscale temporal convolutional network (MSTCN) based on the Inception model with a temporal convolutional architecture. Unlike HCF methods, MSTCN requires minimal pre-processing and no manual feature engineering. Further, multiple separable convolutions with different-sized kernels are used in MSTCN for multiscale feature extraction. Dilations are applied to each separable convolution to enlarge the receptive fields without increasing the model parameters. Moreover, residual connections are utilised to prevent information loss and gradient vanishing. These features enable MSTCN to possess a longer effective history while maintaining a relatively low in-network computation. Results: The performance of MSTCN is evaluated on UCI and WISDM datasets using subject independent protocol with no overlapping subjects between the training and testing sets. MSTCN achieves F1 scores of 0.9752 on UCI and 0.9470 on WISDM. Conclusion: The proposed MSTCN dominates the other state-of-the-art methods by acquiring high recognition accuracies without requiring any manual feature engineering.",
"keywords": [
"human activity recognition",
"smartphone",
"temporal convolutional network",
"dilated convolution",
"one-dimensional inertial sensor"
],
"content": "Introduction\n\nHuman activity recognition (HAR) is extensively applied in various applications such as personal health monitoring,1,2 geriatric patient monitoring,3 ambient assisted living,4 etc. The widespread use of smartphone-based HAR is due to the ubiquity of smartphones and low-cost sensors. Additionally, sensor-based HAR provides a non-intrusive solution.\n\nNumerous HAR algorithms have been proposed, including handcrafted feature (HCF) methods5-7 and deep learning (DL) methods.8-10 HCF methods require complex data pre-processing and manual feature engineering. The manually extracted features are highly dependent on prior knowledge, leading to high bias and loss of essential implicit patterns. Hence, DL methods, such as convolutional neural network (CNN),8,9 recurrent neural network (RNN), and long-short term memory network (LSTM),10,11 are devised to overcome the downfalls of HCF methods. DL methods involve no complex data pre-processing, and features are automatically tuned for the desired outcome. Besides, the architecture is adaptable to different applications.\n\nAlthough CNN is good in extracting spatial features, it hardly learns temporal features, which are significant in motion analysis. RNN and LSTM are feasible for time-series data, but they suffer from several shortcomings. For example, RNN is prone to short-term memory problems, leaving out important information at the beginning if the input sequence is too long. LSTM prevails over RNN as the former has a longer-term dependency and is less susceptible to vanishing gradient. However, LSTM requires higher computation due to multiple gate operations and more memory to store partial results throughout the training phase.\n\nThis work proposes a multiscale temporal convolutional network, termed MSTCN. As illustrated in Figure 1, MSTCN is constituted by multiscale dilation (MSD) blocks, global average pooling and softmax. The contributions of this work are:\n\n- A deep analytic model, amalgamating the Inception model and Temporal Convolutional Network (TCN), is developed to extract spatial-temporal features from inertial data. MSTCN requires minimal data pre-processing and no manual feature engineering.\n\n- Multiple different-sized convolutions are incorporated in MSTCN to perform multiscale feature extraction. The scaled features encompass low-to-high level features of the data. The concatenation of multiscale features enables MSTCN for better data generalisation.\n\n- Dilated convolution is implemented to improve the convolution kernel's receptive fields. The dilation captures the global characteristics of the inertial data and retains a longer effective history.\n\n- A comprehensive experimental analysis is conducted using two popular public databases, UCI12 and WISDM.13 Subject independent protocol is implemented where the training and testing sets do not share the data from the same users.\n\nOne-dimensional inertial data undergoes a complicated pre-processing in HCF methods to extract salient statistical feature vectors in time and/or frequency domains. The manually extracted features are then fed into standard machine learning classifiers, such as support vector machine (SVM),7,12 ADA Boost,14 Random Forest,6 C4.5 decision tree,15 etc., for activity classification. He and Jin5 proposed a discrete cosine transform method to extract features and classify the features using multiclass SVM. Lara et al.,16 developed an additive logistic regression, boosting with an ensemble of 10 decision stump classifiers. In the works of Ronao and Cho,17,18 the authors explored the Continuous Hidden Markov Model (HMM) to perform activity recognition in two stages, where the first stage is for static and dynamic classification and the second stage is for course classification. Although these methods produce an adequate performance, they are highly dependent on the effectiveness of the manual feature engineering techniques.\n\nRecently, researchers leaned towards DL methods since DL requires minimal to zero pre-processing and feature engineering. Ronao et al.,8 Yazdanbakhsh et al.,9 and Huang et al.,18 proposed a CNN-based deep learning system to perform HAR. The reported empirical results show the feasibility of the CNN-based method in analysing motion data. Besides, three-layer LSTM was proposed to classify human activities.11 LSTM variant, known as Bidirectional LSTM, was employed in HAR.10 This model uses richer information, i.e. previous and subsequent information, to perform activity recognition. Nair et al. proposed two variations of TCN, namely Dilated-TCN and Encoder-Decoder TCN in HAR.19 In addition, another two TCN-based models are proposed in Ref. 20, namely TCN-FullyConnectedNetwork and deepConvTCN. Both works of Nair et al.,19 and Garcia et al.,20 concluded that the TCN-based models achieved better performance than existing recurrent models due to their longer-term dependencies.\n\n\nMethods and results\n\nThe raw inertial signals were first pre-processed to remove any null values. Next, the pre-processed signals were segmented using sliding window technique. In specific, the signals were partitioned into fixed-sized time windows and each window did not intersect with another window. Then, the segmented data was fed into seven MSD blocks in MSTCN (green box in Figure 1) for feature extraction. Figure 2 illustrates the structure of an MSD block. MSD block was designed based on the inception module structure for multiple scale feature extraction.21\n\nConvolutional unit in MSD block extracts spatial-temporal features of the motion data. The components of the convolutional unit are illustrated in Figure 3. First, the input channels are processed via one-by-one causal convolution for dimensionality reduction. This layer, known as bottleneck layer, adopts fewer filters to reduce the number of features maps while the salient features are retained. The causal padding preserves the input sequence's length and order, preventing information leakage from the future into the past. Next, the reduced feature maps are further processed parallelly by separable convolutions (SepConv) with three different-sized filters to extract features at multiple scales. Figure 4 shows the operation of SepConv. The reason for implementing SepConv in MSTCN is that it can produce fewer parameters and reduce computational complexity.\n\nDilated convolution prevails over classical convolution because it allows the model to have a larger receptive field, controlled by the dilation rate. This helps capture long-time sequences' global features without increasing the model's parameters and memory. Figure 5 shows the difference between the dilated convolution and the classical/standard convolution. Dilations are implemented in SepConv to increase the receptive fields of the convolution kernels.\n\nThe core difference between MSTCN and TCN is that the dilated convolutions are organised parallelly in MSTCN (green dotted circle in Figure 3) but in a serial form in TCN. With the proposed layout, each extracted multiscale feature from the SepConvs with differently sized filters is concatenated for a better model generalisation, see Figure 3.\n\nIn a MSD block, average pooling (brown box in Figure 2) down-samples the feature map to reduce noise and dimensionality. Additionally, it also preserves localisation. The pooling's output is fed into a one-by-one convolution. A residual connection is formed by passing the input into a one-by-one convolution, followed by a batch normalisation. This residual connection ensures longer-term dependencies and prevents information loss. Further, it also reduces the vanishing gradient effects. On the other hand, batch normalisations in MSD block are to reduce the internal covariance shift in the model during training. Furthermore, ReLU activation is chosen for its non-linearity, and the gradient vanishing is minimised.\n\nThe features extracted from the series of MSD blocks are further fed into the global average pooling (GAP). In MSTCN, GAP replaces the traditional fully connected layers because GAP is more suitable.22 This operation generates one feature map according to each activity from multi-dimensional feature inputs. Besides, GAP is also considered as a structural regulariser since it imposes the generated map as the confidence map for each class.22 With this, it better prevents overfitting by reducing the number of model parameters. Additionally, GAP does not require parameter optimisation.\n\nIn the classification stage, a simple softmax classifier is used. The softmax activation formula is defined:\n\nwhere z→ is the input vector, ezi is the exponential function of the input, K is the number of classes and ezj is the exponential function of the output. This function outputs probabilities of each class, ranging from zero to one, and the target class will have the highest probability.\n\nThe experiments were conducted on a desktop with Intel® Core™ i7-8750H CPU with 2.20 GHz, 16GB RAM and NVIDIA GeForce GTX 1050 Ti with Max-Q Design and 4GB memory. Two public databases, UCI12 and WISDM,13 were used to assess the reliability of the proposed model. In addition, subject independent protocol was implemented where there were no overlapping users between training and testing sets. Details of the databases are recorded in Table 1. The evaluation metrics used in this work include precision, recall, F1 score and classification accuracy.\n\nThree experiments were conducted on UCI dataset to study the effects of (1) convolution, (2) pooling and (3) regularisation on MSTCN's performance. Table 2 shows the proposed model's performances using dilated one-dimensional (1D) causal convolution (CC) and dilated 1D separable convolution (SC). From the empirical results, it was observed that the parameters of SC are approximately half of the parameters of CC. Usually, models with more parameters perform better since maximal data patterns are captured from the training samples. However, when the training sample size is limited, these models might tend to overfit and not generalise properly to the unseen data, leading to poor performance. In this study, SC obtains ~0.04 higher F1 score than CC.\n\nNext, the performances of max-pooling and average pooling were studied. From Table 3, average pooling dominates max-pooling by attaining F1 score of 0.9752. Average pooling performs better in this domain because it takes every value into account. With this, the information leakage is prevented, and feature localisation is preserved.\n\nTable 4 shows the performance of MSTCN with different regularisation settings. The regularisation is performed at the bottleneck layer in MSTCN. L1 is good at dealing with outliers and sparse feature spaces. Moreover, it also reduces the coefficient of the insignificant features to zero and removes them. It is a good feature selector. L2 learns complex patterns from the dataset and prevents overfitting. By combining the usage of L1 and L2, we can leverage the benefits from both. Hence, the best result of 97.5% accuracy is obtained with L1 and L2 regularisation.\n\nA performance comparison between MSTCN and other state-of-the-art methods was conducted. Tables 5 and 6 show the performance on UCI and WISDM datasets using subject independent protocol. The proposed MSTCN showed extraordinary performances against the existing methods by achieving 97.46% accuracy on UCI and 95.20% on WISDM. The experimental results will be discussed further in the following section.\n\n\nDiscussion\n\nFrom the empirical results, we observe that:\n\n1) MSTCN prevails over HCF methods on both datasets because the proposed model can better capture discriminating features from the motion data. Unlike handcrafted features, these deep features are less biased as they are not dependent on prior knowledge. This is crucial, especially for a subject independent solution.\n\n2) Generally, MSTCN outperforms most CNN-based approaches, with accuracy scores of ~97.5% in UCI and ~95.2% in WISDM. This performance exhibits that MSTCN can capture the global and local features that discriminate each activity. Besides, the implementation of GAP in MSTCN is less prone to overfitting.22 Hence, it is suitable for subject independent HAR.\n\n3) MSTCN dominates the recurrent model10 due to its ability in modelling longer-term dependencies via dilated convolution. Residual connection and ReLU activation in MSTCN allow the model to be less susceptible to gradient vanishing and exploding.\n\n4) MSTCN is a TCN-variant model. The obtained empirical results demonstrate that MSTCN outperforms the ordinary TCNs (Dilated TCN and Encoder-Decoder TCN).19 MSTCN learns features at multiple scales via different convolutions with differently sized filters. The concatenation of these multi-scaled features produces global feature maps encompassing each activity class low-to-high level features, leading to better recognition.\n\n\nConclusions\n\nA new deep analytic model, known as MSTCN, is proposed for subject independent HAR. MSTCN is based on the architectures of the Inception network and temporal convolutional network. In MSTCN, different-sized filters are adopted in dilated separable convolutions to extract multiscale features with the enlarged receptive field of each kernel for longer-term dependencies modelling. Besides, average pooling is performed for dimensionality reduction and locality preservation. The inclusion of residual connections in MSTCN prevents information leakage throughout the network. The efficiency of MSTCN is evaluated using UCI and WISDM datasets. The empirical results demonstrate the superiority of MSTCN over other state-of-the-art solutions by achieving 0.9752 and 0.9470 F1 scores, respectively, in UCI and WISDM.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "References\n\nLi H, Trocan M: Deep learning of smartphone sensor data for personal health assistance. Microelectronics J. 2019; 88(January 2018): 164–172. Publisher Full Text\n\nYang S, et al.: IoT structured long-term wearable social sensing for mental wellbeing. IEEE Internet Things J. Apr. 2019; 6(2): 3652–3662. Publisher Full Text\n\nChen X, Xue H, Kim M, et al.: Detection of Falls with Smartphone Using Machine Learning Technique. Proceedings - 2019 8th International Congress on Advanced Applied Informatics, IIAI-AAI 2019. 2019; pp. 611–616.\n\nWan J, Li M, O’Grady MJ, et al.: Time-Bounded Activity Recognition for Ambient Assisted Living. IEEE Trans. Emerg. Top. Comput. Jan. 2021; 9(1): 471–483. Publisher Full Text\n\nHe Z, Jin L: Activity recognition from acceleration data based on discrete consine transform and SVM. Conference Proceedings - IEEE International Conference on Systems, Man and Cybernetics. 2009; pp. 5041–5044.\n\nKee YJ, Shah Zainudin MN, Idris MI, et al.: Activity recognition on subject independent using machine learning. Cybern. Inf. Technol. Sep. 2020; 20(3): 64–74.\n\nSeto S, Zhang W, Zhou Y: Multivariate time series classification using dynamic time warping template selection for human activity recognition. Proceedings - 2015 IEEE Symposium Series on Computational Intelligence, SSCI 2015. 2015; 1399–1406.\n\nRonao CA, Cho SB: Human activity recognition with smartphone sensors using deep learning neural networks. Expert Syst. Appl. Oct. 2016; 59: 235–244. Publisher Full Text\n\nYazdanbakhsh O, Dick S: Multivariate Time Series Classification using Dilated Convolutional Neural Network. arXiv. 2019.\n\nYu S, Qin L: Human activity recognition with smartphone inertial sensors using bidir-LSTM networks. Proc. - 2018 3rd Int. Conf. Mech. Control Comput. Eng. ICMCCE 2018. 2018; pp. 219–224.\n\nPienaar SW, Malekian R: Human Activity Recognition using LSTM-RNN Deep Neural Network Architecture. 2019 IEEE 2nd Wireless Africa Conference, WAC 2019 - Proceedings. 2019.\n\nAnguita D, Ghio A, Oneto L, et al.: A public domain dataset for human activity recognition using smartphones. ESANN 2013 proceedings, 21st European Symposium on Artificial Neural Networks, Computational Intelligence and Machine Learning. 2013. [Accessed: 17-Sep-2021]. Reference Source\n\nKwapisz JR, Weiss GM, Moore SA: Activity recognition using cell phone accelerometers. ACM SIGKDD Explor. Newsl. 2011; 12(2): 74–82. Publisher Full Text\n\nKumar A, Gupta S: Human Activity Recognition through Smartphone’s Tri-Axial Accelerometer using Time Domain Wave Analysis and Machine Learning Simulation and Application performance evaluation using GPU through CUDA C & Deep Learning in TensorFlow View project Human Activi. Artic. Int. J. Comput. Appl. 2015; 127(18): 22–26. Publisher Full Text\n\nAnjum A, Ilyas MU: Activity recognition using smartphone sensors. 2013 IEEE 10th Consumer Communications and Networking Conference, CCNC 2013. 2013; pp. 914–919.\n\nLara ÓD, Prez AJ, Labrador MA, et al.: Centinela: A human activity recognition system based on acceleration and vital sign data. Pervasive and Mobile Computing. . 2012; 8(5): 717–729. Publisher Full Text\n\nRonao CA, Cho SB: Human activity recognition using smartphone sensors with two-stage continuous hidden markov models. 2014 10th International Conference on Natural Computation, ICNC 2014. 2014; pp. 681–686.\n\nHuang J, Lin S, Wang N, et al.: TSE-CNN: A Two-Stage End-to-End CNN for Human Activity Recognition. IEEE J. Biomed. Heal. Informatics. Jan. 2020; 24(1): 292–299. Publisher Full Text\n\nNair N, Thomas C, Jayagopi DB: Human activity recognition using temporal convolutional network. ACM Int. Conf. Proceeding Ser. 2018.\n\nGarcia FA, Ranieri CM, Romero RAF: Temporal approaches for human activity recognition using inertial sensors. Proc. - 2019 Lat. Am. Robot. Symp. 2019 Brazilian Symp. Robot. 2019 Work. Robot. Educ. LARS/SBR/WRE 2019. 2019; pp. 121–125.\n\nSzegedy C, et al.: Going deeper with convolutions. Proceedings of the IEEE Computer Society Conference on Computer Vision and Pattern Recognition. 2015; 07-12-June: 1–9.\n\nLin M, Chen Q, Yan S: Network in network. 2nd International Conference on Learning Representations, ICLR 2014 - Conference Track Proceedings. 2014.\n\nKim YJ, Kang BN, Kim D: Hidden Markov Model Ensemble for Activity Recognition Using Tri-Axis Accelerometer.Proceedings - 2015 IEEE International Conference on Systems, Man, and Cybernetics, SMC 2015. 2016; 3036–3041.\n\nKolosnjaji B, Eckert C: Neural network-based user-independent physical activity recognition for mobile devices. Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). 2015; vol. 9375 LNCS: pp. 378–386.\n\nRonao CA, Cho SB: Recognizing human activities from smartphone sensors using hierarchical continuous hidden Markov models. Int. J. Distrib. Sens. Networks. 2017; 13(1): 155014771668368. Publisher Full Text\n\nIgnatov A: Real-time human activity recognition from accelerometer data using Convolutional Neural Networks. Appl. Soft Comput. J. 2018; 62: 915–922. Publisher Full Text\n\nOgbuabor G, La R: Human activity recognition for healthcare using smartphones. ACM Int. Conf. Proceeding Ser. 2018; 41–46.\n\nSikder N, Chowdhury MS, Arif ASM, et al.: Human activity recognition using multichannel convolutional neural network.2019 5th International Conference on Advances in Electrical Engineering, ICAEE 2019. 2019; pp. 560–565.\n\nXu C, Chai D, He J, et al.: InnoHAR: A deep neural network for complex human activity recognition. IEEE Access. 2019; 7: 9893–9902. Publisher Full Text\n\nPeppas K, Tsolakis AC, Krinidis S, et al.: Real-time physical activity recognition on smart mobile devices using convolutional neural networks. Appl. Sci. 2020; 10(23): 1–25. Publisher Full Text"
}
|
[
{
"id": "102273",
"date": "10 Jan 2022",
"name": "Cheng-Yaw Low",
"expertise": [
"Reviewer Expertise Deep Learning",
"Computer Vision",
"Pattern Recognition",
"Biometric Recognition."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a poorly written manuscript, as many sections are unclear and most of the important information is missing.\nThe Inception model is recruited as the network backbone without any justifications. To be specific, why is Inception model useful for HAR?\n\nThe methodology section is difficult to read as it is incomplete. For example, the input dimension is unknown? and therefore I do not know why 1x1 conv is demanded for dimensionality reduction?\n\"First, the input channels are processed via one-by-one causal convolution for dimensionality reduction.\"\n\nFor clarity, the basic mathematical representation elaborating each operation should be included. On the other hand, I think the methods and results section should be separated into two.\n\nFigure captions contain no detail at all, and this makes the reading very difficult. For example, the authors do not provide in Fig. 3 (and the entire manuscript) the definition for d=[1, 2, 4, 5]? What are represented by 8x8, 16x16, 20x20? How was the feature concatenation is performed? By an arithmetic operation? Or stacking over different feature tensors?\n\nThere are a number of ambiguous or misleading statements throughout the manuscript.\n(a) In MSTCN, GAP replaces the traditional fully connected layers because GAP is more suitable. This operation generates one feature map according to each activity from multi-dimensional feature inputs.\n>> GAP generates one feature map according to each activity?\n\n(b) First, the input channels are processed via one-by-one causal convolution for dimensionality reduction. This layer, known as bottleneck layer, adopts fewer filters to reduce the number of features maps while the salient features are retained.\n>> The causal convolutional layer is not a bottleneck layer.\n\n(c) Subject independent protocol is implemented where the training and testing sets do not share the data from the same users.\n>> The training and the testing sets do not share the data from the same users always. I think the authors are claiming that the training and testing identities (instead of data) are disjoint. State also why this training protocol is important in HAR.\n(d) L2 learns complex patterns from the dataset and prevents overfitting.\n\n>> L2 is only a normalization technique, and L2 does not learn.\n(e) The pooling's output is fed into a one-by-one convolution. A residual connection is formed by passing the input into a one-by-one convolution, followed by a batch normalisation.\n>> There is no residual connection found from both Fig. 2 or 3?\n>> Dilated convolution captures global features? What are these global features? and by how the global features are captured?\n\nThis manuscript contains only ONE mathematical equation, but it is problematic. In the meantime, the definitions for each variable should also be provided, e.g., what is z_i? what is meant by \"simple\" softmax classifier? Cross-entropy?\n\nThe dataset information, the training procedures and the empirical hyperparameters are not disclosed?\n(a) What is the input dimension for each dataset? What is the data captured by accelerometer and gyroscope? What are the class number for each dataset?\n(b) What is feature dimension rendered by the MSTCN? and from which layer the feature representation is extracted for inference purposes?\n\n(c) The optimizer, learning rate, weight decay, batch size, etc., are unknown.\n(d) The measurement unit for segment size and segment interval in Table 1 should be indicated.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8203",
"date": "09 May 2022",
"name": "Sarmela Raja Sekaran",
"role": "Author Response",
"response": "First of all, we would like to convey our heartfelt thanks to the Editors and Reviewers who have provided us with the constructive comments which allowed us to improve our work. 1. The Inception model is recruited as the network backbone without any justifications. To be specific, why is the Inception model useful for HAR? Response: Thanks for the feedback. The main reason for recruiting the Inception model as the network backbone is because the Inception model allows multiscale feature extraction. The authors have revised the Methods section to include the justification of recruiting the Inception model for better clarification. 2. (a) The methodology section is difficult to read as it is incomplete. For example, the input dimension is unknown? and therefore I do not know why 1x1 Conv is demanded dimensionality reduction? Response: The Methods section has been revised for better clarification. In the revised version, the authors have included the input dimension in the Model configuration and experimental setup section. The reason for employing 1x1 Conv has also been included in the Method section. (b) I think the methods and results section should be separated into two. Response: Authors have separated the Methods and Results sections as suggested by the reviewer. 3. (a) Figure captions contain no detail at all, and this makes the reading very difficult. For example, the authors do not provide in Fig. 3 (and the entire manuscript) the definition for d=[1, 2, 4, 5]? What is represented by 8x8, 16x16, and 20x20?. Response: Authors have modified Figure 3 and provided a clearer explanation of the figure in the Methods section. (b) How was the feature concatenation is performed? By an arithmetic operation? Or stacking over different feature tensors? Response: Feature concatenation is performed by stacking over different feature maps. The Methods section has been revised to include the information for better clarification. 4. There are a number of ambiguous or misleading statements throughout the manuscript (a) GAP generates one feature map according to each activity? Response: Authors have revised the explanation in the Methods section for better clarification. (b) The causal convolutional layer is not a bottleneck layer. Response: Authors have revised the explanation in the Methods section for better clarification. (c) The training and the testing sets do not share the data from the same users always. I think the authors are claiming that the training and testing identities (instead of data) are disjoint. State also why this training protocol is important in HAR Response: For better clarification, the section on Model Configuration and Experimental Setup has been revised. The subject independent protocol is adopted in this work. In other words, there are no overlapping users between training and testing sets. This protocol is preferable for real-time HAR applications. (d) L2 learns complex patterns from the dataset and prevents overfitting. Response: Authors have revised the explanation in the Experiments section for better clarification. (e) There is no residual connection found from both Fig. 2 or 3? Response: Authors have revised Figure 2 and included more information regarding residual connection in the Methods section. (f) Dilated convolution captures global features? What are these global features? and by how the global features are captured? Response: Authors have revised the Methods section for better clarification. Confusing sentences have been revised. Dilated convolution enables longer-term time dependency of the proposed model by enlarging the convolution’s receptive fields. 5. This manuscript contains only ONE mathematical equation, but it is problematic. In the meantime, the definitions for each variable should also be provided, e.g., what is z_i? what is meant by \"simple\" softmax classifier? Cross-entropy? Response: Authors have revised and included equations (softmax activation and cross-entropy functions) as well as the definition for each variable of each equation in the Methods section for better clarification. Softmax classifier is implemented in the proposed model for classification purposes. Further, the categorical cross-entropy loss has been implemented to the softmax function output. 6. The dataset information, the training procedures and the empirical hyperparameters are not disclosed?? (a) What is the input dimension for each dataset? What is the data captured by the accelerometer and gyroscope? What is the class number for each dataset? Response: Authors have included detailed information about the datasets including input dimension, class number and data type in the Experiments and Results section. (b) What is the feature dimension rendered by the MSTCN? and from which layer the feature representation is extracted for inference purposes? Response: Softmax classifier is implemented for inference purposes. The authors have revised the Methods section for better clarification. (c) The optimizer, learning rate, weight decay, batch size, etc., are unknown Response: Authors have included information regarding optimizer, learning rate, batch size, etc., in the Model configuration and experimental setup section for better clarification. (d) The measurement unit for segment size and segment interval in Table 1 should be indicated. Response: Authors have provided the measurement unit for segment size and segment interval in the Model configuration and experimental setup section."
}
]
},
{
"id": "102276",
"date": "02 Feb 2022",
"name": "Sultan Daud Khan",
"expertise": [
"Reviewer Expertise Computer Vision"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this work, the authors proposed a framework for human activities recognition. The authors proposed a multi-scale temporal convolutional network that constituted multi-scale dilations block to capture multi-scale information. Overall, the paper is not well-written and organized and I have the following concerns the authors need to consider:\nThe contribution of the work is not clear. As there is a lot of literature on human activity recognition systems. How is the proposed framework different from its counterparts?\n\nWhat are the gaps the authors are trying to fill which are left behind by the previous approaches?\n\nFigure-1 should be improved, and more details should be incorporated.\n\nDiscussion section should not be in the bullets form. Please write detail in paragraph.\n\nThe authors should perform comparison with the following reference:\n\"Stacked lstm network for human activity recognition using smartphone data.\" In 2019 8th European workshop on visual information processing (EUVIP), pp. 175-180. IEEE, 2019.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "8204",
"date": "09 May 2022",
"name": "Sarmela Raja Sekaran",
"role": "Author Response",
"response": "First of all, we would like to convey our heartfelt thanks to the Editors and Reviewers who have provided us with constructive comments which allowed us to improve our work. 1. (a) The contribution of the work is not clear. As there is a lot of literature on human activity recognition systems. Response: Thanks for the feedback. The authors have revised the contribution of the work for better clarification. (b)How is the proposed framework different from its counterparts? Response: Thanks for the comment. For better clarification, the authors have revised the part of Contribution in the section Introduction to include the difference between the proposed model and the existing methods: Unlike the existing methods, the proposed method does not require either complex signal pre-processing or manual feature engineering by experts. Besides, the proposed MSTCN is capable of extracting features at multiple scales and concatenating them for a better representation of the overall features. Additionally, the adoption of the dilated convolutions enables the proposed model to preserve longer-term dependencies. 2. What are the gaps the authors are trying to fill which are left behind by the previous approaches? Response: Authors have revised the Introduction section and included the research gap in HAR. 3. Figure-1 should be improved, and more details should be incorporated. Response: Authors have revised Figure 1 and included more details for better clarification. 4. Discussion section should not be in the bullets form. Please write detail in paragraph. Response: Authors have revised the Discussion section. The discussion was written in paragraph form. 5. The authors should perform comparison with the following reference:\"Stacked lstm network for human activity recognition using smartphone data.\" In 2019 8th European workshop on visual information processing (EUVIP), pp. 175-180. IEEE, 2019. Response: Thanks for the suggestion. Authors have included the comparison with the suggested reference in Related Work section and the Experiments section."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1261
|
https://f1000research.com/articles/11-9/v1
|
06 Jan 22
|
{
"type": "Research Article",
"title": "Prediction of the Effects of Nonsynonymous Variants on SARS-CoV-2 Proteins",
"authors": [
"Boon Zhan Sia",
"Wan Xin Boon",
"Yoke Yee Yap",
"Shalini Kumar",
"Chong Han Ng",
"Boon Zhan Sia",
"Wan Xin Boon",
"Yoke Yee Yap",
"Shalini Kumar"
],
"abstract": "Background: SARS-CoV-2 virus is a highly transmissible pathogen that causes COVID-19. The outbreak originated in Wuhan, China in December 2019. A number of nonsynonymous mutations located at different SARS-CoV-2 proteins have been reported by multiple studies. However, there are limited computational studies on the biological impacts of these mutations on the structure and function of the proteins.\n\nMethods: In our study nonsynonymous mutations of the SARS-CoV-2 genome and their frequencies were identified from 30,229 sequences. Subsequently, the effects of the top 10 nonsynonymous mutations of different SARS-CoV-2 proteins were analyzed using bioinformatics tools including co-mutation analysis, prediction of the protein structure stability and flexibility analysis, and prediction of the protein functions.\n\nResults: A total of 231 nonsynonymous mutations were identified from 30,229 SARS-CoV-2 genome sequences. The top 10 nonsynonymous mutations affecting nine amino acid residues were ORF1a nsp5 P108S, ORF1b nsp12 P323L and A423V, S protein N501Y and D614G, ORF3a Q57H, N protein P151L, R203K and G204R. Many nonsynonymous mutations showed a high concurrence ratio, suggesting these mutations may evolve together and interact functionally. Our result showed that ORF1a nsp5 P108S, ORF3a Q57H and N protein P151L mutations may be deleterious to the function of SARS-CoV-2 proteins. In addition, ORF1a nsp5 P108S and S protein D614G may destabilize the protein structures while S protein D614G may have a more open conformation compared to the wild type.\n\nConclusion: The biological consequences of these nonsynonymous mutations of SARS-CoV-2 proteins should be further validated by in vivo and in vitro experimental studies in the future.",
"keywords": [
"SARS-CoV-2",
"nonsynonymous mutation",
"co-mutation",
"COVID-19"
],
"content": "Introduction\n\nA new coronavirus disease known as COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in Wuhan, China in December 2019.1 SARS-CoV-2 is a positive-sense single stranded RNA virus with a helical nucleocapsid. The genome size of SARS-CoV-2 is about 30 kilobases. There are 11 protein-coding genes from the SARS-CoV-2 genome including four structural genes (spike (S), envelope (E), membrane (M), and nucleocapsid (N) genes) and seven nonstructural genes (ORF1ab, ORF3a, ORF6, ORF7a, ORF7b, ORF8 and ORF10).2\n\nThe SARS-CoV-2 virus can rapidly mutate to bypass the immune response of the host.3 These mutations can be synonymous, nonsynonymous, deletions, insertions, or others. Nonsynonymous mutations are expected to have a greater impact than synonymous mutations since nonsynonymous mutations affect the amino acid sequences of a protein, subsequently they may change their structures and functions. According to Kim et al. (2020), a total of 767 synonymous and 1352 nonsynonymous mutations have been identified from SARS-CoV-2 genomes.4 In another study, a total of 119 SNPs were identified using 11,183 SARS-CoV-2 genomes, in which there were 74 nonsynonymous mutations and 43 synonymous mutations.5 From a study on the analysis of nonsynonymous mutations in structural proteins of SARS-CoV-2, it has been shown that S and N proteins have higher mutation rate per gene compared to that of E and M proteins.6 However, the biological consequences of these mutations on the functions and structures of SARS-CoV-2 proteins remain unclear. In our study, computational analysis of the nonsynonymous mutations of SARS-CoV-2 proteins were performed using different bioinformatics tools including co-mutation analysis, protein structure stability and flexibility analysis, and protein function analysis to predict the effects of the mutations on the structures and functions of proteins.\n\n\nMethods\n\nThe SARS-CoV-2 genomes data were downloaded from GISAID database (Global Initiative on Sharing All Influenza Data, RRID:SCR_018251).7 In this study, a total number of 30,229 SARS-CoV-2 virus genomes data with collection dates ranging from 2020-01-01 to 2021-03-21 were retrieved. To make sure that only high-quality sequences were used, the filters including complete genome, high coverage and patient status, excluding low coverage were applied. The reference strain NC_045512.2 with a total number of 29903 bases was retrieved from NCBI database (NCBI, RRID:SCR_006472). The wild type protein structures obtained from RCSB PDB (Research Collaboratory for Structural Bioinformatics Protein Data Bank, RRID:SCR_012820) are listed in Table 1.8 Since N protein R203 and G204 are located at a disordered region which does not have a well-defined three-dimensional structure, no experimental structural data was available for the prediction analysis. A predicted model of N protein model (QHD43423, estimate TM-score = 0.97) generated with D-I-TASSER/C-I-TASSER pipeline was used.9\n\nMultiple sequence alignment (MSA) was performed using rapid calculation in MAFFT (MAFFT, version 7.467, RRID:SCR_011811) which supports alignment for more than 20,000 sequences.10 After all SARS-CoV-2 sequences were aligned to the reference genome, the multiple sequence alignment file was visualized under MEGA X software, version 10.2.5 build 10210330 (MEGA Software, RRID:SCR_000667).\n\nThe 11 different coding sequences were extracted from these 30,229 strains according to their genomic positions in the reference strain (fasta file format) in NCBI, which is NC_045512.2. Inappropriate sequences of base calling errors, “N” unresolved nucleotides, and undefinable gaps were omitted. Then, the frequency and number of nonsynonymous mutations in these 30,229 strains were identified using a Python script.\n\nThe concurrence ratio of each nonsynonymous mutation in the SARS-CoV-2 genome was determined using GESS database (The Global Evaluation of SARS-CoV-2/hCoV-19 Sequences, RRID:SCR_021847)11 derived from GISAID web server. The concurrence search used for the analysis of the concurrence ratio in the top 10 nonsynonymous mutations is listed in Table 2. The frequency for each SNV in the concurrence search is greater than 0.1%. The chord diagram for co-mutations of nonsynonymous mutations in the SARS-CoV-2 genome was generated using Circos table viewer (Circos, RRID:SCR_011798).12\n\nTo predict the effects of the mutations on the stability and flexibility of the protein structure, the protein structures were analyzed with DynaMut server (DynaMut, RRID:SCR_021849).13 The free energy change between the wild type and mutant protein structure (ΔΔG) predicts the status of protein stability, in which the values of ΔΔG above zero indicate a good stabilization while any values below zero or negative indicate a destabilizing outcome. The difference in entropic energy between the wild type and mutant structures (ΔΔSVib ENCoM) predicts the status of protein flexibility, in which the values of ΔΔSVib ENCoM above zero indicate an increase in flexibility while any values below zero or negative indicate a decrease in flexibility.\n\nSIFT 4G (Sorting Tolerant From Intolerant For Genomes, RRID:SCR_021850)14 and PROVEAN (Protein Variation Effect Analyzer, RRID:SCR_002182)15 were used to predict the deleteriousness of the nonsynonymous single nucleotide polymorphisms (nsSNPs) on SARS-CoV-2 protein structure. SIFT 4G predicts the effects of the mutations based on the sequence conservation and amino acid properties. For SIFT 4G analysis, gene annotation files (GTF), fasta files containing the SARS-CoV-2 genome sequences, and a variant call format file (VCF) comprising all the SNP of SARS-CoV-2 were obtained. After that, the SARS-CoV-2 genome database, built with the SIFT 4G algorithm, was created. Lastly, SIFT 4G annotator was applied to annotate the VCF file with SARS-CoV-2 genome database. Mutations with a SIFT 4G score of less than 0.05 were considered deleterious. PROVEAN predicts the effects of the mutations based on the principle of alignment-based score. For PROVEAN analysis, the amino acid sequence along with the amino acid variation were processed in the PROVEAN server to get the prediction result. Mutations with a value less than −2.5 were considered as deleterious.\n\n\nResults\n\nFrom the multiple alignment analysis, we identified 231 nonsynonymous mutations from 30,229 SARS-CoV-2 genome sequences. Figure 1 shows the numbers of the nonsynonymous mutations found in 11 coding sequences of SARS-CoV-2 proteins. ORF1a has the highest numbers of nonsynonymous mutations, followed by S protein and N protein. The top 10 nonsynonymous mutations affecting 9 amino acids residues including ORF1a nsp5 P108S, ORF1b nsp12 P323L and A423V, S protein N501Y and D614G, ORF3a Q57H, N protein P151L, R203K and G204R are shown in Table 3.\n\nSome nonsynonymous mutations may be random and have no or little biological impact on viral transmission and pathogenesis. If a single nonsynonymous mutation co-mutates with other mutations, they may evolve together and interact functionally. To study co-mutation between different nonsynonymous mutations, the concurrence ratio of co-mutations in the top 10 nonsynonymous mutations was retrieved from GESS database website as shown in Table 2. The visualization of co-mutations in the top 10 nonsynonymous mutations generated with Circos table view is shown in Figure 2. In this chord diagram, connection ribbons represent co-mutations and each ribbon between row and column segments represents the value of concurrence ratio in each top 10 nonsynonymous mutations. Single colours encoded in circular arranged segments represent its own specific mutation whereas rainbow colours represent co-mutation in each mutation. The size of circular arrangement segments is proportional to the total value of concurrence ratio in a row or column. The circular size segment of ORF3a Q57H (G25563T) with the smallest segment size means the total value of concurrence ratio in row or column of ORF3a Q57H (G25563T) having the lowest concurrence ratio. A high concurrence ratio shows high co-mutation between each mutation with thicker ribbon size. S protein D614G (A23403G) with all other nine nonsynonymous mutations had concurrence ratios greater than 99%. On the other hand, low concurrence ratio shows low co-mutation with thinner ribbon size, for example, mutation ORF3a Q57H (G25563T) had the lowest concurrence ratio, only having a high concurrence ratio with S protein D614G (A23403G) and ORF1b nsp12 (P323L) C14408T, the top 2 nonsynonymous mutations which were present in more than 90% of the reported sequences.\n\nTable 4 summarizes the results of predicted effects of mutations on protein stability and flexibility obtained from DynaMut. Only two mutations, namely ORF1a nsp5 P108S and S protein D614G were predicted to be destabilizing with ΔΔG values of −0.288 and −0.072, respectively. For the prediction of protein flexibility, only S protein D614G was predicted to have an increase in flexibility with an ΔΔSVib ENCoM value of 0.523.\n\nThe prediction results of nonsynonymous mutations in the SARS-CoV-2 proteins using SIFT 4G and PROVEAN are shown in Table 5. SIFT 4G functional missense mutation score predicted that the P108S mutation in ORF1a nsp5 was deleterious (score 0.00) while four mutations S protein D614G, ORF3a Q57H, N protein R203K and G204R were tolerated (>0.05). However, the SIFT 4G results of ORF1b nsp12 P323L and A423V, S protein N501Y and N protein P151L mutations cannot be obtained due to missing data in the Ensembl database. For the PROVEAN score, three nonsynonymous mutations, namely ORF1a nsp5 P108S, ORF3a Q57H and N protein P151L were predicted to be deleterious (score < −2.5). However, six nonsynonymous mutations, namely ORF1b nsp12 P323L and A423V, S protein N501Y and D614G, N protein R203K and G204R were predicted to be neutral (score > −2.5).\n\n\nDiscussion\n\nThe top 10 nonsynonymous mutations of SARS-CoV-2 identified from 30,229 SARS-CoV-2 genome sequences were further analyzed with co-mutation analysis, prediction of the protein structure stability and flexibility analysis, and prediction of the protein function analysis. To determine if two nonsynonymous mutations of SARS-CoV-2 proteins co-mutate, concurrence ratio was calculated. Many nonsynonymous mutations showed a high concurrence ratio, suggesting these mutations may evolve together and interact functionally. The top 2 nonsynonymous mutations, S protein D614G and ORF1b nsp12 P323L (as known as RNA-dependent RNA polymerase) showed very high concurrence ratio with other mutations since they emerged in the early phase of the pandemic. Previously it has been shown that S protein D614G co-evolved with ORF1b nsp12 P323L.16 The combination of both mutations may enhance viral fitness based on epidemiological data, although the molecular mechanisms of this evolutionary advantage remain elusive.16 In another study, it has been predicted that multiple SARS-CoV-2 genes may have epistatic interactions linked to viral fitness.17 The effects of a mutation can be neutral, harmful, or beneficial to the virus. It is expected that most single mutations have a small effect on viral fitness. It remains an arduous task to associate a specific phenotype with a single viral mutation since it is possible that a specific phenotype is contributed to by the effects of multiple mutations.\n\nThere are huge numbers of single nucleotide polymorphisms (SNPs) present in the SARS-CoV-2 genome, hence evaluating the biological functions of all SNPs using experimental approaches is not feasible. Therefore, prediction of the effects of SNPs allows us to prioritize variants which may have some significant biological functions. Our study used the meta-prediction approach to perform functional predictions of nonsynonymous mutations to minimize the false positive rate. When two or three tools are combined, the prediction accuracy increases and reaches greater performance, however, the sensitivity is subsequently decreased as more tools are combined.18\n\nOf all these nine protein mutations, only two mutations namely ORF1a nsp5 P108S and S protein D614G were predicted to reduce their stability whereas only S protein D614G may have more a flexible conformation compared to the wild type. S protein binds to human ACE2 receptors to gain access to the host cell.19 D614G mutation is found at S1 domain which is involved in receptor binding.20 Two independent studies of S protein D614G mutant structures derived from cryo-electron microscopy analysis has demonstrated that the G614 mutant adopts a more open conformation compared to D614 wild type.21,22 Interestingly, an in vitro study has shown that S protein D614G mutation may enhance virus infectivity by promoting the packing of S protein into the virion, not by enhancing the binding of S protein to the ACE2 receptor.23 On the other hand, ORF1a nsp5, also known as 3C-like protease is responsible for cleaving viral polypeptides during replication.2 A study by Abe et al., (2021) has showed that ORF1a nsp5 protein P108S mutation diminished its activity, possibly leading to a reduction in disease severity.24\n\nSince the protein function depends directly on the three-dimensional structure of the protein, we wanted to see if these mutations may affect the function of the protein using SIFT 4G and PROVEAN prediction tools. The PROVEAN tool is applicable for all organisms. SIFT4G, instead of SIFT was used since it allows us to build a SARS-CoV-2 genome database with variant annotation. Interestingly ORF1a nsp5 protein P108S mutation was the only mutation found to be deleterious from both SIFT4G and PROVEAN functional analysis. Together with the DynaMut stability result, it has been demonstrated that this mutation may be harmful to the virus itself, and can be less damaging to the human host as reported by Abe et al., (2021).24 On the other hand, ORF3a Q57H and N protein P151L mutations are predicted to be deleterious by the PROVEAN tool only. ORF 3a is an ion channel (viroporin) which is involved in viral egress steps through lysosomal trafficking.25,26 ORF3a Q57H mutation not only causes a change in amino acid in ORF3a, but also produces a truncated ORF3b due to the overlapping protein-coding sequences shared by ORF3a and ORF3b.27 However, there are conflicting results about the effect of the ORF3a Q57H mutation on the human host immune response.27,28 N protein is involved in the liquid-liquid phase separation for the viral genome packaging.29 N protein P151L mutation is located at the RNA binding domain. It has been proposed that this mutation may disrupt the protein-drug interaction.30 Although another two N protein mutations, R203K and G204R were not predicted to be deleterious in our study, they have been identified in the alpha variant, B.1.1.7, gamma variant, P.1, lambda variant, C.37 and omicron variant, BA.1/B.1.1.529.31 While N protein, T205I mutation has been reported in the beta variant, B.1.351 and Mu variant, B.1.621.31 More recently, another N protein mutation, R203M has been reported in the delta variant, B.1.617.2.31 Interestingly mutants with N protein S202R or R203M mutations can pack more RNA material compared to the wild type based on in vitro studies.32 These observations and experimental results suggest that N protein residues, S202, R203, G204 and T205 may play some role on viral RNA replication.\n\n\nConclusion\n\nIn this study, ORF1a nsp5 P108S, S protein D614G, ORF3a Q57H and N protein P151L mutations have been predicted to alter their structures and/or functions. Since all the reported variants of concern contain multiple mutations present in multiple SARS-CoV-2 proteins, it is necessary to evaluate the impact of these mutations in combination on viral transmission and pathogenicity. The biological consequences of these nonsynonymous mutations of SARS-CoV-2 proteins should be further validated with in vivo and in vitro experimental studies in the future.\n\n\nEthics and dissemination\n\nNo ethical approval is required for data analysis in this study (EA0802021).\n\n\nAuthor contribution\n\nCHN contributes to the concept, design, supervision of the project. SBZ, WXB, YYY and SK contribute to the design, methodology, and data collection. SBZ, WXB, YYY and SK contributed to the analysis, and interpretation of data.\n\nAll authors were involved in drafting and revising the manuscript and approved the final version.\n\n\nData and software availability\n\nSARS-CoV-2 virus genome sequence data were downloaded from the GISAID Database. The additional multiple alignment data can be obtained from FigShare\n\nFigshare: MSA (SARS-CoV-2). https://doi.org/10.6084/m9.figshare.16681900.v433\n\nThis project contains the following underlying data.\n\n• MSA_0 (31-12-2019 to 31-05-2020).fasta file contains multiple sequence alignment data of SARS-CoV-2 genome sequences ranging between 31-12-2019 and 31-05-2020.\n\n• MSA_1 (01-06-2020 to 15-10-2020).fasta file contains multiple sequence alignment data of SARS-CoV-2 genome sequences ranging between 01-06-2020 and 15-10-2020.\n\n• MSA_2 (16-10-2020 to 31-01-2021).fasta file contains multiple sequence alignment data of SARS-CoV-2 genome sequences ranging between 16-10-2020 and 31-01-2021.\n\n• MSA_3 (01-02-2021 to 22-03-2021).fasta file contains multiple sequence alignment data of SARS-CoV-2 genome sequences ranging between 01-02-2021 to 22-03-2021.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nThe python script used for the identification of SARS-CoV-2 genome mutations can be obtained through GitHub (https://github.com/wxboon98/Mutations-Identification).\n\nThe same set of SARS-CoV-2 genomic data was also used to perform multiple sequence alignment analysis to identify the SARS-CoV-2 genomic mutations for another paper, titled “Prediction of the Effects of Synonymous Variants on SARS-CoV-2 Genome”.34 MEGA-X software was used to determine if the mutations are synonymous or nonsynonymous mutations for the subsequent prediction and other analyses.",
"appendix": "Acknowledgments\n\nThis research is supported by Multimedia University, Malaysia, IRFund 2.0 (grant number MMUI/210119 awarded to Chong Han, Ng). The funder has no role in study design, data analysis, decision to publish or manuscript preparation.\n\n\nReferences\n\nHuang C, et al.: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. Feb. 2020; 395(10223): 497–506. PubMed Abstract | Publisher Full Text\n\nMousavizadeh L, Ghasemi S: Genotype and phenotype of COVID-19: Their roles in pathogenesis. J. Microbiol. Immunol. Infect. 2020; 54(2): 159–163. Publisher Full Text\n\nHarvey WT, et al.: SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 2021; 19(7): 409–424. PubMed Abstract | Publisher Full Text\n\nKim J-S, Jang J-H, Kim J-M, et al.: Genome-Wide Identification and Characterization of Point Mutations in the SARS-CoV-2 Genome. Osong. Public Health Res. Perspect. 2020; 11(3): 101–111. PubMed Abstract | Publisher Full Text\n\nYuan F, Wang L, Fang Y, et al.: Global SNP analysis of 11,183 SARS-CoV-2 strains reveals high genetic diversity. Transbound. Emerg. Dis. Nov. 2021; 68(6): 3288–3304. PubMed Abstract | Publisher Full Text\n\nDas JK, Roy S: A study on non-synonymous mutational patterns in structural proteins of SARS-CoV-2. Genome. 2021; 64(7): 665–678. PubMed Abstract | Publisher Full Text\n\nGISAID Initiative: [Accessed: 23-Sep-2021]. Reference Source\n\nRCSB PDB: Homepage: [Accessed: 01-Dec-2021]. Reference Source\n\nModeling of the SARS-COV-2 Genome using D-I-TASSER: [Accessed: 01-Dec-2021]. Reference Source\n\nMAFFT - a multiple sequence alignment program: [Accessed: 23-Sep-2021]. Reference Source\n\nFang S, et al.: GESS: a database of global evaluation of SARS-CoV-2/hCoV-19 sequences. Nucleic Acids Res. Jan. 2021; 49(D1): D706–D714. PubMed Abstract | Publisher Full Text\n\nKrzywinski M, et al.: Circos: An information aesthetic for comparative genomics. Genome Res. Sep. 2009; 19(9): 1639–1645. PubMed Abstract | Publisher Full Text\n\nRodrigues CHM, Pires DEV, Ascher DB: DynaMut: Predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res. Jul. 2018; 46(W1): W350–W355. PubMed Abstract | Publisher Full Text\n\nVaser R, Adusumalli S, Leng SN, et al.: SIFT missense predictions for genomes. Nat. Protoc. Dec. 2015; 11(1): 1–9. PubMed Abstract | Publisher Full Text\n\nChoi Y, Chan AP: PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015; 31(16): 2745–2747. PubMed Abstract | Publisher Full Text\n\nIlmjärv S, et al.: Concurrent mutations in RNA-dependent RNA polymerase and spike protein emerged as the epidemiologically most successful SARS-CoV-2 variant. Sci. Rep. Jul. 2021; 11(1): 1–13. Publisher Full Text\n\nZeng H-L, Dichio V, Horta ER, et al.: Global analysis of more than 50,000 SARS-CoV-2 genomes reveals epistasis between eight viral genes. Proc. Natl. Acad. Sci. Dec. 2020; 117(49): 31519–31526. PubMed Abstract | Publisher Full Text\n\nSun H, Yu G: New insights into the pathogenicity of non-synonymous variants through multi-level analysis. Sci. Rep. Feb. 2019; 9(1): 1–11.\n\nWalls AC, Park YJ, Tortorici MA, et al.: Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020; 181(2): 281–292.e6. PubMed Abstract | Publisher Full Text\n\nKorber B, et al.: Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell. Aug. 2020; 182(4): 812–827.e19. PubMed Abstract | Publisher Full Text\n\nYurkovetskiy L, et al.: Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. Cell. Oct. 2020; 183(3): 739–751.e8. PubMed Abstract | Publisher Full Text\n\nBenton DJ, et al.: The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2. Proc. Natl. Acad. Sci. Mar. 2021; 118(9): e2022586118. PubMed Abstract | Publisher Full Text\n\nZhang L, et al.: SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity. Nat. Commun. Nov. 2020; 11(1): 1–9. Publisher Full Text\n\nAbe K, et al.: Pro108Ser mutant of SARS-CoV-2 3CLpro reduces the enzymatic activity and ameliorates COVID-19 severity in Japan. medRxiv. Feb. 2021; p. 2020.11.24.20235952.\n\nMiao G, et al.: ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation. Dev. Cell. Feb. 2021; 56(4): 427–442.e5. PubMed Abstract | Publisher Full Text\n\nGhosh S, et al.: β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway. Cell. Dec. 2020; 183(6): 1520–1535.e14. PubMed Abstract | Publisher Full Text\n\nLam JY, et al.: Loss of orf3b in the circulating SARS-CoV-2 strains. Emerg. Microbes Infect. 2020; 9(1): 2685–2696. PubMed Abstract | Publisher Full Text\n\nChu DKW, et al.: Introduction of ORF3a-Q57H SARS-CoV-2 Variant Causing Fourth Epidemic Wave of COVID-19, Hong Kong, China - Volume 27, Number 5—May 2021 - Emerging Infectious Diseases journal - CDC. Emerg. Infect. Dis. May 2021; 27(5): 1492–1495. PubMed Abstract | Publisher Full Text\n\nSavastano A, Ibáñez de Opakua A, Rankovic M, et al.: Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates. Nat. Commun. Nov. 2020; 11(1): 1–10. Publisher Full Text\n\nAzad GK: Identification and molecular characterization of mutations in nucleocapsid phosphoprotein of SARS-CoV-2. PeerJ. Jan. 2021; 9: e10666. PubMed Abstract | Publisher Full Text\n\nCoVariants: [Accessed: 03-Dec-2021]. Reference Source\n\nSyed AM, et al.: Rapid assessment of SARS-CoV-2 evolved variants using virus-like particles. Science (80-.). 2021; 6184.\n\nBoon WX, Ng CH: MSA (SARS-CoV-2). figshare. Dataset. 2021. Publisher Full Text\n\nBoon WX, Sia Z, Ng CH, et al.: Prediction of the Effects of Synonymous Variants on SARS-CoV-2 Genome. F1000Res. Oct. 2021; 10: 1053. Publisher Full Text"
}
|
[
{
"id": "123168",
"date": "28 Feb 2022",
"name": "Ujwal Ranjit Bagal",
"expertise": [
"Reviewer Expertise Genomics & Evolutionary Biology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors in this paper have tried to use an extensive set of SARS-COV-2 genomes to identify and select the top 10 non-synonymous mutations for analyzing the co-mutation effect, as well as its effect on the stability and flexibility of the protein structure. Overall, the paper is well written in terms of language and grammar, experiments were well conducted. The title suggests all the variants were analyzed. Hence, it can be modified to show that only the top 10 non-synonymous mutations were studied. Abstract is well written giving all details of the papers finding.\nSARS-COV-2 is an excellent example where there are public repositories with highly curated whole genome datasets and associated metadata are available for analysis. The authors need to use more data from 2020 to 2021 as the number of curated genomes available in GISAID is large (200,000+). This will make the analysis less obsolete.\n\nThe authors have applied meta-prediction methods for variant analysis. If relevant data in terms of genetic clade, and region where the sample was collected from, can be added to this analysis the results will be more relevant and can be verified using laboratory techniques. Hence, we suggest the authors try to incorporate these points and resolve a few issues mentioned below and resubmit the paper with additional tables and content.\nBelow are a few comments for the authors we as reviewers suggest:\nThe introduction seems too small. More details about the virus and work showing the effect of non-synonymous mutations affecting the viral efficacy need to be mentioned.\n\nIn the Methods section\nFor the downloaded datasets, what was the threshold used for coverage? A table showing the number of genomes with date (range should do), coverage above threshold, genetic nomenclature (clade name), and geographical information will be helpful to understand the diversity within the dataset.\n\nYou have performed a Co-mutation analysis using the GESS database. Does it provide information about the mutation frequency, which genetic nomenclature it was observed? If you can provide that information, it will be useful. The concurrence table is good, but with knowledge of the above information it will become more relevant.\n\nWhat was the criteria used for “top 10 nonsynonymous mutations”?\n\nFor prediction of mutation effect on protein function, where was the GTF file, as well as the VCF files, obtained from? There is no mention of whole genome SNP analysis. This part is a bit confusing. Clarification is required.\n\n“Mutations with a value less than-2.5 were considered as deleterious”. Can you provide a reference showing why -2.5 is used as a threshold? Same with the SIFT 4G score threshold of 0.05.\n\nIn the Results section:\nFigure 2: Is it possible to add the amino acid changes (e.g., D614G) instead of just nucleotide mutations for better understanding?\n\nIs it possible to show the genetic nomenclature associated with the top 10 nonsynonymous mutations?\n\nAlso, if possible, can you add figures showing the domain or the position on a 3D protein structure? This is optional as you have discussed the domain for few proteins in the discussion section.\n\nIn the Discussion section:\nYou write “showed very high concurrence ratio with other mutations since they emerged in the early phase of the pandemic”. How did you come to this conclusion? With reference to our comments in the results and methods section, if you can add this information in a tabular format it will be more informative.\n\n“The combination of both mutations may enhance viral fitness based on epidemiological data”. There is no mention of the epidemiological data in the results section. If it's in the supplementary files, mention it.\n\n“P108S mutation diminished its activity, possibly leading to a reduction in disease severity.” Can you mention in which genetic clade it was observed?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8209",
"date": "09 May 2022",
"name": "Chong Han Ng",
"role": "Author Response",
"response": "\"The authors in this paper have tried to use an extensive set of SARS-COV-2 genomes to identify and select the top 10 non-synonymous mutations for analyzing the co-mutation effect, as well as its effect on the stability and flexibility of the protein structure. Overall, the paper is well written in terms of language and grammar, experiments were well conducted. The title suggests all the variants were analyzed. Hence, it can be modified to show that only the top 10 non-synonymous mutations were studied. Abstract is well written giving all details of the papers finding.\" RE: To reflect the scope of the study better, the title of paper has been revised to “Prediction of the effects of the top 10 nonsynonymous variants from 30229 SARS-CoV-2 strains on their proteins.” \"SARS-COV-2 is an excellent example where there are public repositories with highly curated whole genome datasets and associated metadata are available for analysis. The authors need to use more data from 2020 to 2021 as the number of curated genomes available in GISAID is large (200,000+). This will make the analysis less obsolete.\" RE: We used SARS-CoV-2 virus genome data ranging from 1st January 20 to 22 March 21. The first draft of the manuscript was prepared in late June 21 and submitted in late August 21. Due to some delay in the editorial review, the paper was only published on 6th January 2022. Five nonsynonymous mutations, including ORF1b nsp12 P323L, S protein N501Y, S protein D614G, N protein R203K and N protein G204R identified in this study were also part of the defining mutations in the alpha variant. The mutational profile of SARS-CoV-2 genome is changing very rapidly. However, we are not aiming to monitor the mutational changes of SARS-CoV-2 genome since it is impossible to keep up with the exponential growth of these data. As of 26 April 2022, there are more than 10 million SARS-CoV-2 virus genomes sequences deposited in GISAID database. Although it is useful to get more recent dataset, it is out of the scope of our study to update the data. Both identification of the SARS-CoV-2 mutations and the prediction analysis of the biological consequences of these mutations are very time-consuming processes. Additional paragraph in the discussion section has been added to discuss the impact of our study and to explain why the study of some of the identified mutations remain relevant for the newer variants. \"The authors have applied meta-prediction methods for variant analysis. If relevant data in terms of genetic clade, and region where the sample was collected from, can be added to this analysis the results will be more relevant and can be verified using laboratory techniques. Hence, we suggest the authors try to incorporate these points and resolve a few issues mentioned below and resubmit the paper with additional tables and content.\" RE: We included the information on primary lineages for the past and present VOCs associated with the top 10 nonsynonymous mutations and their mutation frequency in Table 3. We also included the information about the geographical distribution of the SARS-CoV-2 dataset with the date range summarized in a table as extended data. We are not performing extra experiments to verify the prediction data since our work is primarily focused on prediction analysis of the mutations. The lab work is out of the scope of this paper, and it is too time-consuming and labour-intensive to perform experimental works. \"Below are a few comments for the authors we as reviewers suggest: The introduction seems too small. More details about the virus and work showing the effect of non-synonymous mutations affecting the viral efficacy need to be mentioned.\" RE: The introduction section with the examples of the effect of non-synonymous mutations affecting the viral efficacy has been included in the last paragraph. \"In the Methods section For the downloaded datasets, what was the threshold used for coverage? A table showing the number of genomes with date (range should do), coverage above threshold, genetic nomenclature (clade name), and geographical information will be helpful to understand the diversity within the dataset.\" RE: For the downloaded dataset, high coverage filter has been applied. The high coverage is defined as only entries with <1% Ns and <0.05% unique amino acid mutations (not seen in other sequences in database) and no insertion/deletion unless verified by submitter, according to GISAID. We included the information on primary lineages for the past and present VOCs associated with the top 10 nonsynonymous mutations and their mutation frequency in Table 3. We have the information about the geographical distribution of the SARS-CoV-2 dataset with the date range summarized in a table as extended data. While we observe a diverse genome dataset coming from different regions, we don’t know if there is a good correlation between the reported COVID case number and the number of SARS-CoV-2 genome data deposited to GISAID database. There may be some disparity in genomic surveillance in different countries due to these possible reasons, such as the quality of the sequencing data, the accessibility to the research funding resource, the socioeconomic status, the government policy. Therefore, it is less relevant for our study since we are not aimed to monitor the SARS-CoV-2 mutation profile in different regions. \"You have performed a Co-mutation analysis using the GESS database. Does it provide information about the mutation frequency, which genetic nomenclature it was observed? If you can provide that information, it will be useful. The concurrence table is good, but with knowledge of the above information it will become more relevant.\" RE: The GESS database doesn’t have the information about the mutation frequency of the mutations associated with the lineages or clades. However, we included the information obtain from COVID CG database on primary lineages for the past and present VOCs associated with the top 10 nonsynonymous mutations and their mutation frequency in Table 3. In addition, we expand the discussion part on co-mutation analysis based on the information of mutation frequency percentage by the lineages. \"What was the criteria used for “top 10 nonsynonymous mutations”?\" RE: The top 10 nonsynonymous mutations are identified based on the mutations with the highest frequency identified from this study. \"For prediction of mutation effect on protein function, where was the GTF file, as well as the VCF files, obtained from? There is no mention of whole genome SNP analysis. This part is a bit confusing. Clarification is required.\" RE: Additional information on GTF and VCF files are added in the methods. The GTF and VCF files are deposited in Figshare and the related information are included in Data and software availability section. It is a whole genome SNP analysis, but the SIFT 4G results of ORF1b nsp12 P323L and A423V, S protein N501Y and N protein P151L mutations cannot be obtained due to missing data in the Ensembl database. “Mutations with a value less than-2.5 were considered as deleterious”. Can you provide a reference showing why -2.5 is used as a threshold? Same with the SIFT 4G score threshold of 0.05. RE: Both references for the scoring method of SIFT4G and PROVEAN have been included. In the Results section: \"Figure 2: Is it possible to add the amino acid changes (e.g., D614G) instead of just nucleotide mutations for better understanding?\" RE: Figure 2 has been revised with the additional information on amino acid changes. \"Is it possible to show the genetic nomenclature associated with the top 10 nonsynonymous mutations?\" RE: The information on the mutation frequency percentage in the primary lineages associated with the past and present variant of concern (VOC) have been updated in Table 3. \"Also, if possible, can you add figures showing the domain or the position on a 3D protein structure? This is optional as you have discussed the domain for few proteins in the discussion section.\" RE: There are multiple SARS-CoV-2 proteins mentioned in the paper. We are not doing any work on protein structure modelling. The readers should refer to Protein Data Bank if they want to know more specific information on the protein domains. \"In the Discussion section: You write “showed very high concurrence ratio with other mutations since they emerged in the early phase of the pandemic”. How did you come to this conclusion? With reference to our comments in the results and methods section, if you can add this information in a tabular format it will be more informative.\" RE: Table 3 shows that S protein D614G and ORF1b nsp12 P323L mutations have the top 2 highest frequency. They are found in more than 90% of 30229 SARS-CoV-2 genome sequences, which are from the early batch of SARS-CoV-2 genome data. A similar finding has been reported by S. Ilmjärv et al., “Concurrent mutations in RNA-dependent RNA polymerase and spike protein emerged as the epidemiologically most successful SARS-CoV-2 variant,” Sci. Rep., vol. 11, no. 1, pp. 1–13, Jul. 2021. “The combination of both mutations may enhance viral fitness based on epidemiological data”. There is no mention of the epidemiological data in the results section. If it's in the supplementary files, mention it. RE: We are referring to the study published by S. Ilmjärv et al., “Concurrent mutations in RNA-dependent RNA polymerase and spike protein emerged as the epidemiologically most successful SARS-CoV-2 variant,” Sci. Rep., vol. 11, no. 1, pp. 1–13, Jul. 2021. “P108S mutation diminished its activity, possibly leading to a reduction in disease severity.” Can you mention in which genetic clade it was observed? RE: The genetic clade associated with ORF1a nsp5 P108S is 20B-T (lineage B.1.1.284). However, it is unknown if this mutation is associated with the past and current of variants of concern since the data is unavailable from COVID CG database."
}
]
},
{
"id": "125647",
"date": "10 Mar 2022",
"name": "In-Hee Lee",
"expertise": [
"Reviewer Expertise Genomics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors examined 10 selected nonsynonymous mutations in SARS-CoV-2 genome for their predicted effect on protein stability as well as their co-mutations. Overall the paper is written well to understand the experiments and analysis results.\nMethods:\n1. Authors mentioned that there were 231 nonsynonymous mutations from the 30,229 SARS-CoV-2 genome sequences used in the analysis. However, only 10 were intensively investigated throughout the paper. Can you explain the criteria why these mutations were selected?\n2. The number of nonsynonymous mutations in coding sequences (Figure 1) may need to be adjusted by the length of each coding sequence.\nResults:\n3. Given the diverse nature of sequences collected by GISAID, it would be helpful to understand if authors could provide more details about 30,229 sequences used in the study: geographic information for the origin of collection, genetic nomenclature (Nextstrain clade, PANGO lineage, variants of concern or interest by WHO).\n4. Co-mutation analysis was particularly intriguing because the co-mutation frequencies were high for most mutations. Can you discuss more about this in the Discussion? Also, I wonder if it will persist when co-mutation analysis were done by genetic nomenclature.\n5. Mutations are as both nucleotide changes and amino acid changes in most figures and tables, but Figure 2 only shows nucleotide changes while Table 4 and 5 show only amino acid changes. Can you put amino acid changes on Figure 2 for easy cross-match with other figures and tables?\nOthers:\n6. Specifying 10 nonsynonymous variants in the title may help readers from misinterpreting that the paper conducted an intensive investigation of all possible nonsynonymous variants.\n7. The findings reported by the paper might have been limited to the sequences collected from a time-period almost a year ago (2020-01-01 ~ 2021-03-21). Adding discussion about the impact of the study with the advent of omicron variants would be interesting to readers of wide backgrounds.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8210",
"date": "09 May 2022",
"name": "Chong Han Ng",
"role": "Author Response",
"response": "The authors examined 10 selected nonsynonymous mutations in SARS-CoV-2 genome for their predicted effect on protein stability as well as their co-mutations. Overall the paper is written well to understand the experiments and analysis results. Methods: 1. Authors mentioned that there were 231 nonsynonymous mutations from the 30,229 SARS-CoV-2 genome sequences used in the analysis. However, only 10 were intensively investigated throughout the paper. Can you explain the criteria why these mutations were selected? RE: The 10 nonsynonymous mutations are identified based on the mutations with the top 10 highest frequency identified from this study. 2. The number of nonsynonymous mutations in coding sequences (Figure 1) may need to be adjusted by the length of each coding sequence. RE: Figure 1 shows the total number of the mutations in each gene, eg D614G, N501Y in S protein. It is not relevant to include extra information. Results: 3. Given the diverse nature of sequences collected by GISAID, it would be helpful to understand if authors could provide more details about 30,229 sequences used in the study: geographic information for the origin of collection, genetic nomenclature (Nextstrain clade, PANGO lineage, variants of concern or interest by WHO). RE: We included the information on primary lineages for the past and present VOCs associated with the top 10 nonsynonymous mutations and their mutation frequency in Table 3. We also included the information on the geographical distribution of the SARS-CoV-2 dataset with the date range summarized in a table as extended data. While we can see diverse genome dataset coming from different regions, we don’t know if there is a good correlation between the reported COVID case number and the number of SARS-CoV-2 genome data deposited to GISAID database. There can be some disparity in genomic surveillance in different countries due to these possible reasons, such as the quality of the sequencing data, the accessibility to research funding resource, the socioeconomic status, the government policy. Therefore, it is less relevant for our study since we are not aimed to monitor the SARS-CoV-2 mutation profile in different regions. 4. Co-mutation analysis was particularly intriguing because the co-mutation frequencies were high for most mutations. Can you discuss more about this in the Discussion? Also, I wonder if it will persist when co-mutation analysis were done by genetic nomenclature. RE: The GESS database we used does not support co-mutation analysis by the clades or lineages. If we use other tools, we may get different results. Therefore, we didn’t do co-mutation analysis by the clades or lineages. However, we expand the discussion part on co-mutation analysis based on the information of mutation frequency percentage by the lineages derived from COVID CG database. 5. Mutations are as both nucleotide changes and amino acid changes in most figures and tables, but Figure 2 only shows nucleotide changes while Table 4 and 5 show only amino acid changes. Can you put amino acid changes on Figure 2 for easy cross-match with other figures and tables? RE: Figure 2 has been revised with the additional information on amino acid changes. Others: 6. Specifying 10 nonsynonymous variants in the title may help readers from misinterpreting that the paper conducted an intensive investigation of all possible nonsynonymous variants. RE: To reflect the scope of the study better, the title of paper has been revised to “Prediction of the effects of the top 10 nonsynonymous variants from 30229 SARS-CoV-2 strains on their proteins.” 7. The findings reported by the paper might have been limited to the sequences collected from a time-period almost a year ago (2020-01-01 ~ 2021-03-21). Adding discussion about the impact of the study with the advent of omicron variants would be interesting to readers of wide backgrounds. RE: Different SARS-CoV-2 variants of concern have specific sets of defining mutations; some are common among these VOCs while some are unique. Additional paragraph in the discussion section has been added to discuss the impact of our study and to explain why the study of some of the identified mutations remain relevant for the newer variants."
}
]
}
] | 1
|
https://f1000research.com/articles/11-9
|
https://f1000research.com/articles/10-1001/v1
|
04 Oct 21
|
{
"type": "Research Article",
"title": "Modelling sentiments based on objectivity and subjectivity with self-attention mechanisms",
"authors": [
"Hu Ng",
"Glenn Jun Weng Chia",
"Timothy Tzen Vun Yap",
"Vik Tor Goh",
"Glenn Jun Weng Chia",
"Timothy Tzen Vun Yap",
"Vik Tor Goh"
],
"abstract": "Background: The proliferation of digital commerce has allowed merchants to reach out to a wider customer base, prompting a study of customer reviews to gauge service and product quality through sentiment analysis. Sentiment analysis can be enhanced through subjectivity and objectivity classification with attention mechanisms. Methods: This research includes input corpora of contrasting levels of subjectivity and objectivity from different databases to perform sentiment analysis on user reviews, incorporating attention mechanisms at the aspect level. Three large corpora are chosen as the subjectivity and objectivity datasets, the Shopee user review dataset (ShopeeRD) for subjectivity, together with the Wikipedia English dataset (Wiki-en) and Internet Movie Database (IMDb) for objectivity. Word embeddings are created using Word2Vec with Skip-Gram. Then, a bidirectional LSTM with an attention layer (LSTM-ATT) imposed on word vectors. The performance of the model is evaluated and benchmarked against classification models of Logistics Regression (LR) and Linear SVC (L-SVC). Three models are trained with subjectivity (70% of ShopeeRD) and the objectivity (Wiki-en) embeddings, with ten-fold cross-validation. Next, the three models are evaluated against two datasets (IMDb and 20% of ShopeeRD). The experiments are based on benchmark comparisons, embedding comparison and model comparison with 70-10-20 train-validation-test splits. Data augmentation using AUG-BERT is performed and selected models incorporating AUG-BERT, are compared. Results: L-SVC scored the highest accuracy with 56.9% for objective embeddings (Wiki-en) while the LSTM-ATT scored 69.0% on subjective embeddings (ShopeeRD). Improved performances were observed with data augmentation using AUG-BERT, where the LSTM-ATT+AUG-BERT model scored the highest accuracy at 60.0% for objective embeddings and 70.0% for subjective embeddings, compared to 57% (objective) and 69% (subjective) for L-SVC+AUG-BERT, and 56% (objective) and 68% (subjective) for L-SVC. Conclusions: Utilizing attention layers with subjectivity and objectivity notions has shown improvement to the accuracy of sentiment analysis models.",
"keywords": [
"Sentiment analysis",
"subjectivity",
"objectivity",
"attention mechanism",
"neural nets."
],
"content": "Introduction\n\nThe proliferation of digital commerce, especially in Malaysia, has allowed many local merchants to reach out to a wider customer base. In order to attract customer’s attention, merchants always compete to offer better price and higher quality of services. Besides that, they also seriously consider the customer feedback or reviews in order to gauge service and product quality.1\n\nBy exploring the sentiment tendency of customer reviews, it can provide a good reference for other customer before the purchasing decision is made. Besides, it helps merchants to improve service quality and customer satisfaction.\n\nSentiment analysis is aimed to determine the sentiment as well as polarity on part of a text. Normally, language terms are under two form of statements, namely fact statement and a non-fact statement, which are known as objective and subjective in categorical terms.2 Facts are objective terms likes events entities and their properties. On the other hand, a non-fact statement is subjective and usually related to an individual’s sentiments, personal beliefs, opinion, perspective, feelings or thoughts.\n\nThis paper adopted attention segment3 to a neural network, LSTM, by creating attention-weighted features, namely Long Short Term Memory with Attention (LSTM-ATT)4 to create attention-weighted features. It aims to introduce these features at the input level to the neural network, so that the performance of sentiment can be increased.\n\nIn business operations, sentiment classification is the automated process of classifying customer reviews in text and labeling them as positive, negative, or neutral. It employs Natural Language Processing (NLP) routine to interpret subjective data, so that it can help merchants to understand how customers feel about their products or services. In this paper, sentiment classification is performed by non-deep neural network classifiers, namely Logistic Regression (LR) and Linear SVC (L-SVC) together with Deep Learning (Artificial Neural Networks) classifier by adopting attention mechanisms (LSTM-ATT).\n\nWord embeddings are a scheme to convert human language to a word representation that is understandable by computers. The word representation is in the form of a real-valued vector that encodes the meaning of the word, so that the words that are closer in the vector space are expected to be similar in meaning.\n\nCollobert5 declared that a distinction word vector and proper training can increase the performance of NLP works especially the sentiment analysis. Word embedding can be classified into two types; contextual and non-contextual embeddings. Non-contextual embedding does not consider the effects of arrangement of words in a particular sentence, while contextual embedding does the opposite.\n\nFor non-contextual embedding, Mikolov et al. initiated Word2Vec.6 The word2vec algorithm uses a neural network model to learn word associations from a large corpus of text. Once trained, such a model can detect synonymous words or suggest additional words for a partial sentence. Bengio et al.7 and Collobert et al.8 enhanced it by implementing Neutral Net Language Model (NNLM). Bojanowski et al.9 made enhancement on Word2Vec by applying n-grams and cables to obtain higher performance in Word Similarity assignments that involved various types of languages and was able to show big enhancements on morphology rich languages, in particular, German datasets such as GUR350 and GUR6510 and ZG222.11 Bhagat et al.12 applied unigrams to extra individual words from Twitter messages and multiple machine learning techniques to perform sentiment analysis. Ebner et al.13 employed three simple bag-of-words representations, where a text is represented as the bag (multiset) of its words, namely pooling encoders, pre-trained word embeddings, and unigram generative regularization to regularize incorporating auxiliary discriminative tasks that managed to reduce training time and model size while maintaining high performance. Gayatry14 employed Count Vectorizer to convert each word into its corresponding vectors.\n\nFor context embedding, Peters et al.15 modified LSTM neural nets to create Embedding from Language Models (ELMo) that were able to show better results than the Stanford Tree-bank model (SST-5) from the research work by Socher et al.16 Devlin et al.17 constructed BERT along with Transformers and Attention Mechanism.3 The role of BERT is not limited to embedding functions but also become a language model that is capable to exceed ELMo on General Language Understanding Evaluation assignments (GLUE) from the research outcomes by Wang et al.18 Liu et al.19 enhanced BERT by developing A Robustly Optimized BERT Pre-Training Approach (RoBERTa). RoBERTa omits the Next Sentence Prediction task and applies an unfixed masking configuration rather than static Masked Language Modelling (MLM). Sangeetha20 proposed multi-head attention fusion model of word and context embedding for sentiment analysis of student feedback.\n\n\nMethods\n\nEthical Approval Number: EA1602021 (From Technology Transfer Office (TTO), Multimedia University).\n\nThree large corpora datasets were chosen to denote objectivity and subjectivity datasets correspondingly. IMDb21 and Wiki-en22 were chosen as the objectivity datasets while ShopeeRD23 was chosen as the subjectivity dataset.\n\nIMDb consists of 50K of movie reviews with contents based on the true plot and written with a neutral point of view (NPOV). Wiki-en consists of 4677K of records based on Wikipedia that forced the articles to be factual and follow the NPOV policy. ShopeeRD consists of 208K customer reviews taken from the Shopee Code League 2020 Data Science and Data Analytics competition. ShopeeRD’s entries are based on customer experiences, which are potentially judgemental and opinionated.\n\nWiki-en was used as the objectivity corpus for word embedding, while IMDb was used for objectivity sentiment analysis. 70% of the ShopeeRD was used as the subjectivity corpus for word embedding and the remaining 30% for subjectivity sentiment analysis. Figure 1 displays the mapping of datasets.\n\nThe reviews and records from the datasets underwent a set of data cleaning steps which included emoji cleaning, text cleaning such as repeated character elimination, punctuation (e.g., ?, ! or,) elimination, stop word (e.g., becomes, against, or at) elimination, lemmatization, case lowering and normalization (normalizing non-English writing into English writing).\n\nWord embedding is carried out to transform the reviews into floating-point numbers that are stored in a high dimension array, which forms a dictionary that the computer is able to obtain word vectors from. The word embedding must be large enough to represent millions of words and for each word is denoted as a high dimension vector. In this paper, one word is represented as a 300-dimension vector.\n\nWord2Vec by Mikolov et al.24 is a word embedding method that consist of two structural design, namely Skip-gram and Continuous Bag-of-Words (CBOW). In the CBOW model, the distributed representations of context (or surrounding words) are combined to predict the word in the middle, while in the Skip-gram model, the distributed representation of the input word is used to predict the context. It has been proven that the Skip-gram structure has been shown better results in comparison to Continuous Bag-of-Words.25-27 Hence, this paper utilizes Word2Vec Skip-Gramm structure to perform word embedding.\n\nShopeeRD and Wiki-en were trained into embeddings of 300d (300-dimension), with a factor of five negative examples, window dimension of five tokens, and elimination of small sentences. The two embeddings (subjectivity and objectivity) were trained for ten repetitions.\n\nTo prevent over-fitting or one model favouring towards a particular embedding, two models (LR and L-SVC) were applied for this paper. In general, a sentence vector is produced from the formation of word vectors.28 Nevertheless, this paper assumes that certain letterings might not apply any weight or produce any consequence, therefore an attention layer, which is adopted from Vaswani et al.3 was produced as a substitute. Self-attention is capable of allocating ‘attention’ to an important vector (keyword). This permits the structural design in a way to highlight attention-ed vectors.29\n\nFor that reason, a model integrating attention segments was recommended, and the structural design is presented in Figure 2. The word vectors worked through the attention layer, creating attention-weighted features. By adapting LSTM neural nets, both the original embedding and the attention-weighted embedding are concatenated to create sentiment features.\n\nThis paper adopted attention-weighted features model is called Long Short Term Memory with Attention (LSTM-ATT)4 with intention to improve the sentiment performance. These features at the input level to the neural network and go through a few dense layers to flatten the output. Finally, Rectified Linear Unit (RELu), a non-linear activation function is applied to produce the sentiment results. The model, LSTM-ATT, is then evaluated against LR and L-SVC. The workflow of the sentiment analysis on IMDb and ShopeeRD with multiple models is illustrated in Figure 3.\n\n\nResults and discussion\n\nThe experiments were performed in Python, utilizing the scikit-learn library for machine learning as well as the BERT model architecture. Three models (LR, L-SVC and LSTM-ATT) were trained with the objectivity (Wiki-en) and subjectivity (70% of ShopeeRD) embeddings. Ten-fold cross-validation was applied during the training. After that, the models were tested against the objectivity (IMDb) test set and the subjectivity (20% of ShopeeRD) test set to eliminate bias.\n\nThe experiments were based on benchmark comparison, embedding comparison and model comparison with 70-10-20 train-validation-test splits. The validation was carried out to perform parameter tuning, so that the best results among the models could be obtained.\n\nFigures 4 and 5 demonstrate the t-distributed Stochastic Neighbor Embedding (t-SNE) plots for Wiki-en and ShopeeRD embeddings on the top 15 nearest words to the word ‘happy’. The t-SNE for both datasets revealed that word similarities are discovered in the embeddings, for instance, ‘glad’, ‘pleased’, ‘excited’ are grouped together with ‘happy’.\n\nThe words ‘very’ and ‘good’ having closeness to ‘happy’ were only found in t-SNE for Wiki-en only. Meanwhile the words ‘satisfied’ and ‘wonderful’ having closeness to ‘happy’ were found in t-SNE for ShopeeRD. Furthermore, outliers like ‘everyone’ and ‘everybody’ were found to appear in the t-SNE for Wiki-en. This shows that the two embeddings are different in nature.\n\nThe three models namely LR, L-SVC and LSTM-ATT were evaluated in terms of their performance in sentiment analysis. The accuracy of the three models is presented in Table 1. L-SVC obtained the highest accuracy (56.9%) for objectivity embedding, whereas LSTM-ATT obtained the highest accuracy (69.0%) for subjectivity embedding. L-SVC performed better than LR properly due to L-SVC attempting to exploit the margin between the closest support vectors whereas LR exploits the posterior class probability.30\n\nFrom Table 1, there is possible limitation factor cause by the capacity of the training data, therefore the size of the dataset is increased through the data augmentation technique.31 As LR has a simpler architecture, data augmentation is not considered, and the focus is made on L-SVC and LSTM-ATT. Table 2 presents the outcome of data augmentation.\n\nFrom Table 2, it is found that the accuracy of models with the augmented data are found to be better than the models, although not by much. The LSTM-ATT+AUG-BERT was able to beat L-SVC+AUG-BERT on both objective and subjective embeddings.\n\nTo the best of our knowledge, there is only one sentiment analysis result from Gayatry’s work14 that accepted by Shopee Code League 2020 Data Science.32 Table 3. shows the comparison of our models with Gayatry’s work on ShopeeRD.\n\nTo the best of our knowledge, there is no research work on objectivity sentiment analysis on IMDB without any involvement of pre-train data from taken IMDB, as all of them used 50% of total dataset for training and another 50% for testing. In this paper, we trained the models by Wiki-en and test on IMDB.\n\n\nConclusions\n\nThis paper has presented word embeddings for both objectivity and subjectivity contexts by applying Word2Vec. Analyzing the embedding using the t-distributed stochastic neighbour embedding plot shows that there are some similarities between the two embeddings，but a majority of them are dissimilar. Three models namely, LR, L-SVC and LSTM-ATT were employed to evaluate the performance of the adopted embedding technique. The attention model adopted was able to perform sentiment analysis well with the requirement of more data was fed into the model utilizing AUG-BERT data augmentation. Models with differing architectures will be explored in future work.\n\n\nData availability\n\n\n\n- Compiled Movie reviews from the Internet Movie Database (IMDb) : https://datasets.imdbws.com/,21 cited on 6 August 2021.\n\nThe data are available for personal and non-commercial use, as stipulated by the owner (IMDb).\n\n- A complete copy of all Wikimedia wikis, in the form of wikitext source and metadata embedded in XML: https://dumps.wikimedia.org/backup-index.html,22 cited on 6 August 2021.\n\nThe data are available under the terms of the Creative Commons Attribution-Share-Alike 3.0 License.\n\n- Product reviews from the Shopee e-commerce platform, created for the Shopee Code League 2020 Data Science and Data Analytics competitions: https://www.kaggle.com/davydev/shopee-code-league-20,23 cited on 6 August 2021.\n\nThe data are available for personal and non-commercial use, as stipulated by the owner (Shopee).",
"appendix": "References\n\nVanaja S, Belwal M: Aspect-level sentiment analysis on e-commerce data. 2018 Int Conf Inventive Res Computing Applications (ICIRCA). IEEE; 2018, July; (pp. 1275–1279).\n\nSahu I, Majumdar D: Detecting factual and non-factual content in news articles. Proc fourth ACM IKDD conferences on data sciences. 2017, March; (pp. 1–12). Publisher Full Text\n\nVaswani A, Shazeer N, Parmar N, et al.: Attention is all you need. In Advances in neural information pro-cessing systems. 2017; (pp. 5998–6008). arXiv preprint arXiv:1706.03762.\n\nLee WS, Ng H, Yap TTV, et al.: Attention Models for Sentiment Analysis Using Objectivity and Subjectivity Word Vectors. In: Alfred R, Iida H, Haviluddin H, et al. (eds) Computational Science and Technology. Lecture Notes in Electrical Engineering. Singapore: Springer; 2021; vol 724. . Publisher Full Text\n\nCollobert R, Weston J, Bottou L, et al.: Natural language processing (almost) from scratch. J Machine Learn Res. 2011; 12(ARTICLE), 2493–2537.\n\nMikolov T, Sutskever I, Chen K, et al.: Distributed representations of words and phrases and their compositionality. arXiv preprint arXiv:1310.4546. 2013.\n\nBengio Y, Ducharme R, Vincent P, et al.: A neural probabilistic language model. J Machine Learning Res . 2003; 3: 1137–1155.\n\nCollobert R, Weston J: A unified architecture for natural language processing: Deep neural networks with multitask learning. Proc 25th Int Con Machine learning. 2008, July; (pp. 160–167). Publisher Full Text\n\nBojanowski P, Grave E, Joulin A, et al.: Enriching word vectors with subword information. Transactions of the Association for Computational Linguistics . 2017; 5: 135–146.\n\nGurevych I: Using the structure of a conceptual network in computing semantic relatedness. Int Conf Natural Language Processing. Berlin, Heidelberg: Springer; 2005, October; (pp. 767–778).\n\nZesch T, Gurevych I: Automatically creating datasets for measures of semantic relatedness. Proc Workshop Linguistic Distances. 2006, July; (pp. 16–24).\n\nBhagat A, Sharma A, Chettri S: Machine Learning Based Sentiment Analysis for Text Message. Int J Computing Technol. 2020.\n\nEbner S, Wang F, Van Durme B: Bag-of-Words Transfer: Non-Contextual Techniques for Multi-Task Learning. Proc 2nd Workshop Deep Learning Approaches for Low-Resource NLP (DeepLo 2019). 2019, November; (pp. 40–46).\n\ncited on 6 August 2021. Reference Source\n\nPeters ME, Neumann M, Iyyer M, et al.: Deep contextualized word representations. arXiv preprint arXiv:1802.05365. 2018.\n\nSocher R, Perelygin A, Wu J, et al.: Recursive deep models for semantic compositionality over a sentiment treebank. Proc 2013 Conf Empirical methods in natural language processing. 2013, October; (pp. 1631–1642).\n\nDevlin J, Chang MW, Lee K, et al.: Bert: Pre-training of deep bidirectional transformers for language understanding. arXiv preprint arXiv:1810.04805. 2018.\n\nWang A, Singh A, Michael J, et al.: GLUE: A multi-task benchmark and analysis platform for natural language understanding. arXiv preprint arXiv:1804.07461. 2018. Publisher Full Text\n\nLiu Y, Ott M, Goyal N, et al.: Roberta: A robustly optimized bert pretraining approach. arXiv preprint arXiv:1907.11692. 2019.\n\nSangeetha K, Prabha D: Sentiment analysis of student feedback using multi-head attention fusion model of word and context embedding for LSTM. J Ambient Intelligence Humanized Computing. 2020; 1–10.\n\nIMDB movie review data. IMDB.com. cited on 6 August 2021. Reference Source\n\nWikimedia.org: Wikimedia Downloads. Wikimedia.org. n.d. cited on 6 August 2021. Reference Source\n\nShopee Code League 2020 Data Science. kaggle.com. cited on 6 August 2021. Reference Source\n\nMikolov T, Sutskever I, Chen K, et al.: Distributed representations of words and phrases and their compositionality. arXiv preprint arXiv:1310.4546. 2013.\n\nJang B, Kim I, Kim JW: Word2vec convolutional neural networks for classification of news articles and tweets. PloS one . 2019; 14(8): e0220976. Publisher Full Text\n\nCaselles-Dupré H, Lesaint F, Royo-Letelier J: Word2vec applied to recommendation: Hyperparameters matter. In Proc 12th ACM Conf Recommender Systems. 2018, September; (pp. 352–356).\n\nLi B, Drozd A, Guo Y, et al.: Scaling word2vec on big corpus. Data Science and Engineering . 2019; 4(2): 157–175. Publisher Full Text\n\nLiu H: Sentiment analysis of citations using word2vec. arXiv preprint arXiv:1704.00177. 2017.\n\nChorowski J, Bahdanau D, Serdyuk D, et al.: Attention-based models for speech recognition. In Advances in neural information processing systems. 2015; (pp. 577–585). arXiv preprint arXiv:1506.07503.\n\nSa'id AA, Rustam Z, Wibowo VVP, et al.: Linear Support Vector Machine and Logistic Regression for Cerebral Infarction Classification. 2020 Int Conf Decision Aid Sciences Application (DASA). 2020, pp. 827–831. Publisher Full Text\n\nShi L, Liu D, Liu G, et al.: AUG-BERT: An Efficient Data Augmentation Algorithm for Text Classification. Int Conf Communications, Signal Processing Systems. Singapore: Springer; 2019, July; (pp. 2191–2198). Publisher Full Text\n\ncited on 6 August 2021. Reference Source"
}
|
[
{
"id": "123733",
"date": "28 Feb 2022",
"name": "Ashima Yadav",
"expertise": [
"Reviewer Expertise Sentiment analysis",
"deep learning",
"machine learning",
"attention mechanism"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper has presented word embeddings for both objectivity and subjectivity contexts by applying Word2Vec. Analyzing the embedding using the t-distributed stochastic neighbour embedding plot shows that there are some similarities between the two embeddings, but a majority of them are dissimilar. Three models namely, LR, L-SVC and LSTM-ATT were employed to evaluate the performance of the adopted embedding technique. The attention model adopted was able to perform sentiment analysis well with the requirement of more data was fed into the model utilizing AUG-BERT data augmentation. The authors have very well addressed the problem. However, I still have following suggestions for them:\nThe authors should give a more detailed description of the deep learning based methods used in sentiment analysis. (Sentiment analysis using deep learning architectures: a review1) (A Weighted Text Representation framework for Sentiment Analysis of Medical Drug Reviews2)\n\nAlso, they should tell how their proposed model is different from the other baseline models (apart from giving higher accuracy) as the area of sentiment classification have many popular models.\n\nExplain the role of attention mechanism in sentiment analysis. Can word-level and sentence level attention give better accuracy as explained in (A Language-independent Network to Analyze the Impact of COVID-19 on the World via Sentiment Analysis3)?\n\nIn the Introduction section, a bullet-wise summary of the significant contribution of this work is required, which could highlight the motivation for this study.\n\nThere should be a Related work section in the manuscript which should explain how their proposed model differs from baseline methods or the advantages of their model over the baseline ones.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8234",
"date": "17 May 2022",
"name": "Hu NG",
"role": "Author Response",
"response": "Dear Prof Yadav, We are greatly appreciative of the insightful comments and helpful suggestions that you have provided. The following are our response on the issues that you have highlighted: Your Comment 1. The authors should give a more detailed description of the deep learning based methods used in sentiment analysis. Our Response Additional papers have been cited to provide more context on the deep learning based methods in the Literature Review. Your Comment 2. Also, they should tell how their proposed model is different from the other baseline models (apart from giving higher accuracy) as the area of sentiment classification have many popular models. Our Response This model places emphasis on attention mechanisms which in this context perform better than other baseline models. Remarks about this is added to the Methods. Your Comment 3. Explain the role of attention mechanism in sentiment analysis. Can word-level and sentence level attention give better accuracy as explained in (A Language-independent Network to Analyze the Impact of COVID-19 on the World via Sentiment Analysis3)? Our Response The attention mechanism allows the model to utilize the most relevant parts of the input sequence in a flexible manner, by a weighted combination of all of the encoded input vectors, with the most relevant vectors being attributed the highest weights. We have not looked into sentence level attention as the focus of this paper is on word-level, and sentence-level will be explored in future work. Your Comment 4. In the Introduction section, a bullet-wise summary of the significant contribution of this work is required, which could highlight the motivation for this study. Our Response A new paragraph has been added to highlight the contribution of this research work. We believe the paragraph format is more appropriate as follow the format of the journal Your Comment 5. There should be a Related work section in the manuscript which should explain how their proposed model differs from baseline methods or the advantages of their model over the baseline ones. Our Response The use of attention mechanisms in this context proves to be beneficial, and this is the advantage over baseline methods. Our Response New references added Yadav, A., & Vishwakarma, D. K. (2020). Sentiment analysis using deep learning architectures: a review. Artificial Intelligence Review, 53(6), 4335-4385. Yadav, A., & Vishwakarma, D. K. (2020, September). A weighted text representation framework for sentiment analysis of medical drug reviews. In 2020 IEEE Sixth International Conference on Multimedia Big Data (BigMM) (pp. 326-332). IEEE. Yadav, A., & Vishwakarma, D. K. (2021). A Language-independent Network to Analyze the Impact of COVID-19 on the World via Sentiment Analysis. ACM Transactions on Internet Technology (TOIT), 22(1), 1-30."
}
]
},
{
"id": "126992",
"date": "23 Mar 2022",
"name": "Hien D. Nguyen",
"expertise": [
"Reviewer Expertise Intelligent system",
"knowledge engineering",
"data science",
"automated reasoning",
"machine learning"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper introduced an architecture to adopt attention segment to a neural network, called LSTM-ATT, to create attention-weighted features. Through that, sentiment classification is performed by non-deep neural network classifiers, this method is called Logistic Regression (LR) and Linear SVC (L-SVC) together with Deep Learning classifier by LSTM-ATT. The results show that L-SVC scored the highest accuracy with 56.9% for objective embeddings (Wiki-en) and LSTM-ATT scored 69.0% on subjective embeddings. The authors also experimented by integrating the proposed method with data augmentation using AUG-BERT. The LSTM-ATT+AUGBERT model scored the highest accuracy at 60.0% for objective embeddings and 70.0% for subjective embeddings, and 57% (objective) and 69% (subjective) for L-SVC+AUG-BERT.\nThis paper is well organized. However, the authors should revise as follows:\nThe authors should explain more the importance about modeling sentiment based on objectivity and subjectivity.\n\nThis study has to present more the architectures in Figure 2 and Figure 3.\n\nThe results need to be explained more their meaning. The authors should compare the proposed method with other similar methods, such as:\nNguyen, H., Huynh, T., Hoang, S., et al. (2020). Language-oriented Sentiment Analysis based on the Grammar Structure and Improved Self-attention Network. ENASE 2020, pp. 339-3461\nZainuddin, N., Selamat, A., Ibrahim, R. (2018). Hybrid sentiment classification on twitter aspect-based sentiment analysis. Applied Intelligence 48(5): 1218 – 12322\n\nThe references [14] and [32] should be added their titles.\nIn my opinion, this paper need to be revised before the final decision.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8235",
"date": "17 May 2022",
"name": "Hu NG",
"role": "Author Response",
"response": "Dear Prof Nguyen, We are greatly appreciative of the insightful comments and helpful suggestions that you have provided. The following are our response on the issues that you have highlighted: Your Comment 1. The authors should explain more the importance about modeling sentiment based on objectivity and subjectivity. Our Response We are of the opinion that once subjectivity is identified the sentiment accuracy can be further increased as objective statements should not contribute to this. Your Comment 2.This study has to present more the architectures in Figure 2 and Figure 3. Our Response The references have also been corrected. Your Comment 3.The results need to be explained more their meaning. The authors should compare the proposed method with other similar methods, such as: Nguyen, H., Huynh, T., Hoang, S., et al. (2020). Language-oriented Sentiment Analysis based on the Grammar Structure and Improved Self-attention Network. ENASE 2020, pp. 339-3461 Zainuddin, N., Selamat, A., Ibrahim, R. (2018). Hybrid sentiment classification on twitter aspect-based sentiment analysis. Applied Intelligence 48(5): 1218 – 12322 Our Response As we are using different datasets, we could not compare the results as is. However, we will perform this in future work. In addition, we take these papers into consideration and have cited them in the paper. Nguyen, H. D., Huynh, T., Hoang, S. N., Pham, V. T., & Zelinka, I. (2020, May). Language-oriented Sentiment Analysis based on the Grammar Structure and Improved Self-attention Network. In ENASE (pp. 339-346). 4. The references [14] and [32] should be added their titles. Our Response The references have also been corrected."
}
]
},
{
"id": "126996",
"date": "08 Apr 2022",
"name": "Marco Polignano",
"expertise": [
"Reviewer Expertise Natural Language Processing",
"Machine Learning",
"Sentiment Analysis",
"Recommender Systems"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present an approach to performing sentiment analysis by comparing different embeddings and classification strategies.\n\nSeveral weaknesses need to be addressed by the authors to enable publication:\nInsufficient detail is provided on the motivations for the article. Why is what is presented relevant to scientific research?\n\nNumerous approaches in the literature use an attention level LSTM model to do sentiment analysis. What does this work present that is innovative?\n\nTechnical and implementation details are not provided. Source code is not shared. This makes the proposed contribution non-replicable.\n\nIt is unclear why non-contextual embeddings were used and not the newer ones based on BERT and ELMO. It is unclear how the data is used in the two phases of embedding space creation and sentiment analysis. Further details on the experimental protocol should be reported.\n\nThe authors show accuracy as the only metric. This metric is not applicable if the datasets are unbalanced. Unfortunately, such analysis is not performed by the authors. I suggest including the scores of additional metrics such as precision, recall, and f1 measure.\n\nA statistical validation of the results has not been conducted, so the differences obtained are not supported by real-world evidence and may be due to chance.\nTherefore, it is suggested to further investigate these issues to make the contribution more robust and relevant to the community.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1001
|
https://f1000research.com/articles/11-534/v1
|
17 May 22
|
{
"type": "Research Article",
"title": "Political, economic, and psychological barriers to an effective climate treaty and sustainable energy: The PEP triangle",
"authors": [
"Urs Steiner Brandt",
"Gert Tinggaard Svendsen",
"Urs Steiner Brandt"
],
"abstract": "The climate change issue has constituted an ongoing political struggle since the first formal international climate negotiations were initiated in 1992 in Rio. It is crucial to understand and solve this collective action problem to pave the road for an effective climate treaty in the future. Thus, we raise the following main research question: How should the political, economic and psychological barriers to an effective climate treaty and sustainable energy be modelled? This 'PEP Triangle' may be applied to better understand and thus improve the ongoing climate negotiations and sustainability. For example, the PEP Triangle may be used in green diplomacy and assist the European External Action Service (EEAS) in accomplishing an effective Paris Treaty.",
"keywords": [
"climate treaty",
"barriers",
"sustainable energy",
"Paris Treaty",
"EU",
"EEAS."
],
"content": "Introduction\n\nFor more than four decades, climate scientists have expressed their worries about climate change in numerous reports and journal articles, most notably in the reports by the Intergovernmental Panel on Climate Change (IPCC). The First Assessment Report (FAR) of the IPCC was completed in 1990. It served as the basis of the United Nations Framework Convention on Climate Change (UNFCCC). Since then, the reports have been updated every four to five years and, in each round, drawing more unequivocal conclusions that climate change is happening (mostly human induced), that climate change constitutes a huge and increasing challenge to humans and ecosystems globally, and that immediate and significant cuts in greenhouse gas (GHG) emission are all-important. Consequently, the climate change issue has constituted an ongoing political struggle since the first formal international climate negotiations were initiated in 1992 in Rio.\n\nThe Stern Review on the Economics of Climate Change stated the following:\n\n“Climate change is a global issue that requires a global response. The science tells us that emissions have the same effects from wherever they arise. The implication for the economics is that this is clearly and unambiguously an international collective action problem with all the attendant difficulties of generating coherent action and of avoiding free riding. It is a problem requiring international cooperation and leadership.” (Stern 2007, IV).\n\nThus, climate change and its potential adverse effects, if not properly dealt with, are well recognized. The World Economic Foundation (WEF) (2020) global risk evaluation identifies lack of climate action and extreme weather events as the most likely risks and lack of climate action as the largest global risk in terms of impact.\n\nIn December 2015, at the ‘Conference of the Parties’ (COP21) in Paris, 195 countries agreed on the long-term goal of limiting global warming to less than 2 °C compared to the pre-industrial level (UN, 2015). As argued by Brandt and Svendsen (2021a), the effectiveness of this Paris Treaty is questionable since real progress is slow and the target level most likely to be exceeded (IPCC, 2021). The implementation of effective national climate policies represents a gap in the literature (Brandt and Svendsen, 2016). The political acceptability also depends on the economics involved and perceived psychological legitimacy of the risk involved in the climate change issue. One crucial problem is the presence of political, economic and psychological barriers, hindering sufficient progress and sustainability. Thus, this paper set out to model these three main barriers that may reduce the likelihood of successful climate negotiations. The main research question is as follows: How should the political, economic and psychological (PEP) barriers to an effective climate treaty and sustainable energy be modelled?\n\nMost barriers still undermine the potential of real progress, and, to simplify a complex reality, our conceptual PEP triangle can, in this way, be used to explain, analyse, and determine how progress is most effectively achieved in the future. Such insights within political, economic, and psychological barriers can be used by central institutional actors as a tool in green diplomacy. For example, the EU aims to be climate neutral by 2050 in the European Green Deal (EU, 2022a). Here, the European External Action Service (EEAS) has expressed strong ambitions to promote the international climate leadership by the EU through its ‘Green Diplomacy Network’ (EEAS, 2018a). EEAS has chaired the Green Diplomacy Network since 2012. It “consists of officials dealing with international environment and sustainable development issues in the EU’s Ministries of Foreign Affairs and their diplomatic missions including the European External Action Service (EEAS) and the EU Delegations” (CEU, 2019).\n\nIn this way, the EEAS can navigate the foreign policy of a global climate change paradigm. A paradigm can incorporate the worldviews in external policy actions by diplomats, for example, within the Green Diplomacy Network. Such conceptual frameworks for thinking about promoting climate change action can be very operational indeed as policy views may be changed from isolationist to having a global scope (Jørgensen et al., 2020).\n\n\nMethods\n\nOur conceptual PEP model is based on the idea that the overall success of international climate policies can be inferred as a function of contextual barriers. More generally, several papers address the issue that contextual barriers influence the likelihood of success of a treaty (Sandler, 2017; Young, 2011; Barrett, 2003). Overall, these barriers can determine and explain major differences between the non-cooperative and cooperative behavioural outcome.\n\nOur conceptual model is based on a multi-criteria decision analysis approach. Here, we have an overarching objective of reaching an effective low-emission agreement. We argue that three major barriers exist, namely political, economic, and psychologic barriers. In total, they overall define how likely success is. As no natural scale exists to measure the severity of these barrier, we identify, for each barrier, three underlying factors that together define the level of each barrier.\n\nThese three underlying factors for each barrier are measured on a three-point scale (high, middle, and low). In sum, they give an indication of the severity of the barrier in question. We have not specified precisely which level of the underlying factor that exactly determines the interval on the scales (high, middle, low) as we are only interested in how to achieve total progress and generate a general model for doing so. We do stress, however, that all factors need to be at a low level, i.e., the best score for reducing the specific barrier, in order to increase the likelihood of achieving an effective treaty. Since we do not have data to estimate (1), we use theory and literature review to identify factors that are observable and can determine the level of the barriers\n\nAn effective climate treaty has to secure that the target levels stated by politicians are achieved, such as the 1.5-degree target level from the Paris Treaty (CEU, 2022b). Such treaty has to ensure that the necessary tools are taken into use. This is possible if the main political, economic and psychological barriers are minimized. As shown in Equation 1, the effectiveness of the climate treaties (E) can be controlled by addressing the barriers in all three domains:\n\nWe add an error term (ε), signifying those factors outside the control of decision makers that might also affect the effectiveness of a treaty (such as the financial crisis in 2008 or COVID-19). Furthermore, the three main barriers are depicted as a three-dimensional PEP model. Each dimension represents the main barriers and measures the likelihood of an effective climate treaty. The fewer barriers, the higher the likelihood of an effective treaty.\n\nAll three barriers in Figure 1 below are measured on a scale from low—at the centre of the PEP model triangle—to high—in the three corners of the PEP triangle.\n\nA high level implies that either many or severe barriers exist in that domain. The traffic light colours in Figure 1 thus identify a minimum level of barriers to overcome to move from red to green in each dimension. Moving from red to yellow and green increases the likelihood of reaching an effective treaty. In the following, we consider each of the three main barriers in the PEP triangle, identifying three sub-barriers under each main barrier and their impact on the likelihood of success.\n\n\nResults\n\nPolitical sub-barriers\n\nLobbying\n\nConcerning political barriers, a country is not a monolith but represents different and often conflicting interests (Putnam, 1988). Two commonly mentioned stakeholders in environmental problems are industrial interests and environmental interests.\n\nIt is well documented that lobbying influences the decisions of policymakers. Svendsen (1999) argues that all eight existing US permit market programmes have been distorted politically through lobbying activities. Here, the environmental groups (EGs) try to maximize their influence by maximizing membership. Increasing membership increases payments and, hence, enables these groups to increase their lobbying activities. The industrial groups (IGs) often use international competitiveness, rising unemployment, and reduction in export as arguments against environmental regulation, focusing entirely on the costs imposed on its members by the proposed regulation, and have no preferences for the environment as such.\n\nThe EGs, interested in securing the environmental assets, are not concerned about the likely costs from such regulation. The more resources the EGs and the IGs control, the more influential they are because of their lobbying capacity. The government will respond to this political demand side pressure resulting in a policy that accommodates the interests of the dominant political actors (Downs, 1957; Hillman, 2019). The higher the relative strength of the EGs over the IGs in a country, the more environmental protection reduction this country will accept. Sometimes, non-traditional coalitions between environmentalists and industrialists may occur when the latter produce renewable energy, such as wind turbine industries (Brandt and Svendsen, 2004).\n\nIn a similar vein, industrial lobbying from fossil fuel-based producers has arguably distorted the design of the European emissions trading system (Markussen and Svendsen, 2005). Another example is lobbying from green industries in Denmark, such as the relatively small group of wind turbine producers who, because of concentrated benefits from favourable regulation, have been better able to promote their interests than, for example, organic farmers, with their much larger group size and more dispersed benefits (Svendsen, 2011).\n\nBrandt and Svendsen (2016) argue how high-quality institutions are important to counterbalance economically harmful lobbying. Lobbying may be illegal in terms of bribing bureaucrats and politicians. Lobbying may also be legal when interest groups try to inform decision makers about the consequences of their potential decisions. In both cases, the formal institutions have to address corruption or any asymmetries in the political arena where producer groups are in a relatively stronger position to promote their interest at the expense of taxpayers and consumers.\n\nThe relative strength of lobbying can be affected by changes in incentives, either by exogenous barriers, such as the positive selective incentive of subsidizing the development in renewable energy sources, or negative selective incentives, such as punishment for emitting too much, matching mechanisms, or taxation of GHG (Svendsen, 2020a, 2020b).\n\nFairness\n\nA political complication arises when fairness becomes an important measure to reach an agreement. There are no commonly accepted definitions of fairness, but fairness typically relates to equity. According to Hillman (2019), an equity principle refers to more general concepts of fairness. A specific equity principle implies a burden-sharing rule, that is, operational formulas implying a specific burden-sharing scheme, which is here defined as based on one or more criteria.\n\nKeohone (2016) argues that fairness considerations are potential distractions from addressing climate change and could undermine collective action in the face of urgent public goods crises. Klinsky et al. (2017), on the other hand, argue that equity questions are central to the climate negotiations in that reciprocity is inevitably connected to actors’ perceptions of fairness. Moreover, cooperating actors are less inclined to behave in a reciprocal manner if they consider the institution unjust or the outcomes it is expected to provide inequitable (Ostrom and Ahn, 2009).\n\nDiplomatic network\n\nInstitutions can also be informal, including different types of social networks. In particular, the absence of climate diplomacy within such networks is relevant in our setting. As the Italian diplomat Daniele Vare once put it, diplomacy is the art of letting someone else have your way. In this way, these informal networks can increase the likelihood of cooperation and the win-win situations that Vare hinted at.\n\nIn the EU, EEAS could play a decisive role in this process and in how to identify operational ways forward within climate diplomacy. One option could be simply to use the existing diplomatic infrastructure of EU delegations. By the end of 2019, the EU had 141 delegations around the world, employing almost 6,000 staffers. This diplomatic infrastructure could furthermore be supplemented by the Green Diplomacy Network (as chaired by the EEAS).\n\nIn the same vein, the European Council (2019) has emphasized the importance of diplomatic networks, stating that the EU will continue to lead global climate action and the enhancement of international climate cooperation. For example, the EU may practice informal climate diplomacy in relation to China, the world’s largest greenhouse gas emitter. Such flexible climate partnerships could mean more green technology exports from the EU to China and other developing countries. For example, the EU has comparative advantages within the wind turbine industry, and in this way, the EEAS could facilitate relatively low-cost cooperation with large CO2 emitters outside the EU and address their differentiated interests (Mathiasen and Svendsen, 2020). These bilateral agreements are more bottom up, following informal talks between diplomats in their networks, and may be a decisive strategy if the stated target levels in the EU and the Paris Agreement are to be achieved (Jørgensen et al., 2020).\n\nSummary: Political barriers\n\nAn important fairness pillar of the UNFCCC is the principle of common but differentiated responsibility and respective capabilities. The Paris Agreement reaffirms the obligations of developed countries to continue to take the lead in mobilizing climate finance.\n\nThe actual mechanism in place is the Global Environment Facility (GEF), which has served as an operating entity of the financial mechanism since the Convention’s entry into force in 1994. At COP 16 in 2010, parties established the Green Climate Fund (GCF) and, in 2011, also designated it as an operating entity of the financial mechanism. The financial mechanism is accountable to the COP, which decides on its policies, programme priorities and eligibility criteria for funding (UNFCCC, 2011). The main purpose of the GCF is to finance and facilitate climate-related projects and governance structures in developing countries to help accelerate transitions to low-carbon societies.\n\nUntil now, the financial mechanism has not delivered. As of 31 July 2020, the GCF has raised $10.3b, which is far below the expectation of $100b when the fund was established in 2011 (Green Climate Fund, 2020). This view is supported by Cui et al. (2020), who argue that the efforts of the GCF to mobilize finance have failed to meet the needs of developing countries for addressing climate change. Based on an intensive study of projects, they argue that co-financing could be a useful solution.\n\nIn the same line of thought, Brandt and Svendsen (2021b) argue for more direct climate-friendly technology transfers to the global south countries and that technology development should be tailored to the specific circumstances, enabling a ‘leap-frogging effect’, which again leads to sustainability. Lobbying for non-climate policies can be counteracted by incentivizing private firms and investors to invest in climate-friendly and sustainable practices, technologies and innovations.\n\nFor instance, in its strategy for financing the transition to a sustainable economy, the EU (European Commission, 2021) has emphasized enabling frameworks to shift the focus of financial and non-financial companies to sustainability and long-term development. Including a voluntary European Green Bond standard and the adaption of disclosure policy, which requires financial and non-financial companies to provide information to investors about the environmental performance of their assets and economic activities.\n\nThe EU has already established a wide-ranging web of bilateral and multilateral climate partnerships and initiatives with other countries and regions. In the European Green Deal, the EU proclaims that it will step up bilateral engagement with partner countries and, where necessary, establish innovative forms of engagement (EU, 2019). Stepping up the level of climate action taken by international partners will require tailor-made geographic strategies that reflect different contexts and local needs (Brandt and Svendsen, 2021). Finally, the EU emphasizes that it will intensify working with global partners to develop international carbon markets as a key tool to create economic incentives for climate action.\n\nThe EU has established a long-lasting bilateral partnership with China and India on climate change-related issues. In 2005, the first EU-China declaration on climate change was signed (European Commission, 2005). Subsequently, several programmes for joint initiatives have been agreed on, such as long-term development strategies on low greenhouse gas emission, emissions trading and investment in climate and clean energy projects (European Commission, 2018). The newest strategic cooperation agenda is formulated in 2020 (EEAS, 2020). EU has also recently intensified its partnership with India. This partnership includes EU support for renewable energy projects (solar and offshore wind), support for implementation of smart grid, but also policies aiming at accelerating clean energy innovation and global deployment and meeting their respective NDCs.1\n\nThe EU has also developed cooperation with Canada (cooperation regarding efficiency in the energy sector) (Government of Canada, 2016), South Korea (technological cooperation and facilitating implementation of emissions trading scheme) (EEAS, 2018b), Brazil and Mexico (deforestation and forest management) (European Commission, 2007, 2008), and South Africa (assisting in implementation of climate policy and helping South Africa become a regional climate leader) (EUR-Lex, 2007).\n\nMultilateral partnerships include the EU-African Union partnership. In the 2020 comprehensive EU Strategy for Africa, it is stated that the EU underlines the importance of strengthening the cooperation with the African Union on, among other things, climate change adaptation and mitigation (European Parliament, 2020). Other multilateral partnerships include the 2019 EU-Central Asia strategy, including cooperation on the implementation of the Paris Agreement on Climate Change (European Commission, 2019) and the EU-Eastern Neighbourhood partnership. In the latter, areas of cooperation are to increase the resource efficiency of economies, develop new green jobs and economic opportunities linked to the green transition and develop local and renewable sources of energy (European Commission, 2016, 2020a).\n\nThe EU also engages in non-partnership efforts through trade or international institutions. Regarding the climate cooperation through trade agreements, the EU trade agreements contain rules on trade and sustainable development (European Commission, 2020b). Finally, established in 2019 partly by the EU, the International Climate Finance, an international platform on sustainable finance, is a forum for facilitating exchange and coordinating efforts in support of green financing. The main aim is to scale up the mobilization of private capital towards environmentally sustainable investments (European Commission, 2020c, 2020d).\n\nWhile this is an impressive list of partnerships, a weakness of all these partnerships is the lack of stated quantitative objectives, such as the amount of greenhouse gas emissions reductions, making it difficult to evaluate their potential and actual achievement. Given that none of the partnerships seemingly involve immediate large-scale policy changes, there is a barrier from the absence of effective diplomatic network (see Figure 2).\n\nThe effectiveness of these policies and the potential for such policies to be adapted have yet to be seen, but the partnerships mark an important first step towards reducing the barriers from lack of climate network diplomacy.\n\nEconomic sub-barriers\n\nFree-rider incentives\n\nClimate change problems have a distinct global public goods character. Reducing emissions will provide a public good as 1) each country can enjoy this benefit in terms of smaller damages, although the benefits will differ, and 2) no country can be excluded from this enjoyment. The fundamental issue here is that for climate change, the contribution to this public good is voluntary, meaning that self-enforcement is an overarching condition for a climate policy to be effective.\n\nMost experts assert that for an individual country, the marginal per capital return of a climate policy is less than one, after some initial policies that may coin a net benefit (Barrett, 2006; Nordhaus, 2019). Moreover, the theory of international relations assumes that individual countries will try to maximize their national benefits when choosing a national climate policy. In his seminal work, Barrett (1994) concludes that very little cooperation can be sustained. Moreover, Barrett (2003) claims that most agreements do not work in the sense that they only require that parties do what they would have done anyway. Out of more than 200 existing agreements, only few require significant reductions compared to what countries would have done without an agreement (Sandler, 2015, 2017). Thus, free riding is a first and major economic obstacle to solving the collective action problem.\n\nWhat characterizes the incentives to free ride? First, pure economic costs and benefits are important. The temptation to free ride is generally higher the larger the difference between the costs of abatement and damage costs, both total and marginal (Finus and Tjøtta, 2003). Higher reduction costs increase the gain from non-participation, and this is especially severe the more sharply the costs of abatements are likely to increase, so that countries have a great deal to gain by reducing their abatement. This implies that the more demanding the reduction obligations, the higher the resulting free-rider incentives. Low damage costs, and especially low marginal damage costs, also increase free riding, since the loss of free-rider incentives because of smaller environmental protection is limited.\n\nObviously, the greater the free-rider incentives, the more complicated the negotiations. Barrett (1997) notes that when countries interact only in providing a public good (the reduction of transboundary dispersed pollutants), then cooperation in the provision of this good can only be sustained by a self-enforcing international environmental agreement if the threat of failing to provide the good in the event that others do so is credible. In order to handle or eliminate such incentives, more complicated mechanisms must be employed, possibly with built-in punishment structures. Barrett (2003) remarks that credible enforcement mechanisms and effective monitoring systems are essential. However, in addition to complicating negotiations, such punishments may be non-credible, for instance, if they cannot be implemented. In such cases, free-rider incentives are non-manageable.\n\nTrade sanctions against free-riding countries seem to be the most likely type of sanctions (Barrett, 1997; Brandt and Svendsen, 2002). What are the possibilities of punishment via trade sanctions? The prospects of effective sanctions are higher when they are credible. Trade sanctions are arguably more effective against small countries than large regions or countries such as the EU, China, and USA. Nordhaus (2015) introduces the idea of climate clubs, where club member countries agree on a uniform domestic carbon price, while non-participants are penalized, for instance, by a uniform percentage tariff on the imports of non-participants into the club region.\n\nLacking the ability to influence the behaviour of other countries\n\nThe next economic sub-barrier deals with the possibility that countries may unilaterally undertake climate policies without engaging in any formal international climate negotiations. Unilateral climate actions will be any credible climate actions made by a country implying a significantly larger effort than comparable countries in comparable situations with the intention – at least partially – to trigger a positive response among other countries or groups of agents.\n\nConsequently, unilateral actions can be viewed as voluntary contributions to a public good having the potential to trigger positive reciprocal behaviour (Bernauer et al., 2016). However, such a climate leadership may not work and may even trigger fewer climate actions in other countries that free ride on the contributor (Hoel, 1991). Another risk is that a country that acts unilaterally is excessively overoptimistic and a victim to the winner’s curse; the country that takes the lead may also be the one who most optimistically misjudges the costs of mitigation (Eskeland, 2013). Finally, it might be politically difficult to justify a costly policy for which the consequences are uncertain (Facchini, 2016).\n\nIn a seminal paper on unilateral climate actions, Hoel (1991) argues that the motivation for engaging in unilateral action is setting a good example for others to follow. However, no mechanisms were specified on how to create incentives for other countries to follow the good example. Recently, several papers have proposed such mechanisms, coming up with manifold motivations based on identified positive responses of other countries, including Schwerhoff (2016) and Buchholz and Sandler (2017). Schwerhoff and Kornek (2018) more specifically identify positive responses related to motivational effects, learning effects, and knowledge spillover effects.\n\nMotivations could be centred on morally based arguments, such as a sense of responsibility because of previous high historic emissions or distributional issues (Brandt and Svendsen, 2016). Furthermore, expressive behaviour as a performance comparison contest with comparable or neighbouring countries may play a role (Hillman, 2019). The motivational effects may also stimulate more ambitious climate policies abroad.\n\nLearning effects may exactly be enhanced through knowledge spillovers to other countries (Keller, 2010; Klarl, 2014; European Union, 2017). Knowledge spillovers exist in situations where the social benefit from new knowledge is larger than the private returns to their innovator. As with national spillovers, knowledge, and information spillover can also propagate to other countries and have impacts of increased human capital, such as increased knowledge in sustainable production and production processes, but also cleaner local air pollution, potentially leading to less greenhouse gas emissions. Unintentional technological benefits to firms that come from the research and development efforts of other firms or countries without the costs being shared can also create spillover effects and increase sustainable production.\n\nInvestments in climate innovations either provide a lowering of costs through better learning rates and/or larger efficiency of existing technologies (such as wind or solar photovoltaic (PV)) or produce new and more competitive and reliable technological solutions. Learning is not necessarily restricted to renewable energy technologies but could also include reduced food waste, recycling practices, or different sharing arrangements (Shipan and Volden, 2008; Bertoldi et al., 2018).\n\nTechnology and knowledge spillover can be both an advantage and a disadvantage for the developing country. The technology spillovers impact the developing country’s economy through two main channels: 1) negative impact through the reduction of first-mover advantage, and 2) positive impact through stimulating world demand for its products. When other countries adopt a technology, new learning effects will occur, and some of these will then drive forward with even more adoption as a reinforcement of the initial technology diffusion process. Note that the larger the extent of technology adoption, the more additional learning effects will be generated, producing a positive feed-back mechanism. Over time, these effects will reduce the overall global GHG emissions and provide additional benefits for the acting country (Brandt and Svendsen, 2016).\n\nThe effect of a unilateral action in terms of, for instance, producing actual learning advantages is therefore most uncertain. How much will the costs of the new technology be, how effective will it be to reduce emissions, how good will it be to substitute more polluting technologies, how likely is it that following countries will find it worthwhile to also use the new technology, and what about political learning? Is such learning transferable to other countries? The latter part of the uncertainty related to the response depends on the costs and effectiveness of the new technology and policies but also on how it fits into the responding countries’ socio-economic, geographic, and current infrastructure. In real life, uncertainty surrounds how costly an abatement effort will be for a yet not developed technology. We might have an idea about the learning rate of a new technology but are uncertain about technical details, but also about the application possibilities and public acceptance. Finally, even if costs are lowered in the developing country, it is not automatically converted into the same cost saving in other countries.\n\nFirst-mover disadvantages\n\nIn a business context, first-mover advantages refer to the benefit enjoyed by firms as the consequence of early entry into a new market (Lieberman, 2016). In an environmental context, Przychodzen et al. (2020) argue for first-mover advantages of being a green innovator. Such actions may build stronger preference formations for consumers by the green leader and produce unique products/services that appeal to environmentally aware customers. Green research and development can also increase productivity and technological strength.\n\nHowever, Cleff and Rennings (2012) claim that such first-mover advantages should not be taken for granted, for example due to lack of protection of intellectual property rights, competitors learning from first-mover’s mistakes etc. Aragon-Correa and Leyva-de-la Hiz (2016) show that firms exploiting well-known technologies perform better than those who develop innovations.\n\nFrom the perspective of the country engaging in unilateral climate actions, regulation is needed to change behaviour to achieve the climate goals. According to the Porter hypothesis, strict environmental regulations can induce efficiency and encourage innovations that help improve commercial competitiveness (Porter and van der Linde, 1995). Both Ramanathan et al. (2017) and Weiss and Anisimova (2019) show that this is the case for well-designed regulation providing sufficient incentives for the regulated firms to invest in green innovation.\n\nThe EU (2017) has analysed the direct benefits from being a first mover on technology development. Obvious first-mover advantages from being a climate leader are here identified, such as new green jobs, better practices, new technologies, and overall improved competitiveness. If a first mover is successful, it is possible to enjoy the monopoly rent. The size of the first-mover advantages depends on the demand for the product in markets abroad and the speed of the catch-up by companies in other countries. This must be compared with the initial investment costs.\n\nSummary: Economic barriers\n\nCurrently, free-riding incentives are still massive (B/C<1 of own emissions). However, costs of reducing emissions are constantly falling. As an example, the near-future learning rates for wind and solar electricity are expected to be 3-5% for wind and about 12% for solar PV (Samadi, 2018).\n\nWhether investments in innovation of clean technologies produce a net gain or net loss (first-mover disadvantages) and, therefore, acts a barrier for such investments depends on the size of demand for such technologies abroad. This again depends on the development of climate policies abroad, the learning curve effects and – as argued by Brandt and Svendsen (2021a) – since each country has a specific threshold for applying a new, cleaner technology, whether or not lowering costs of technologies might trigger adaptation and changes in country preferences that change the threshold. As seen in Table 1, the EU, the US, Japan, and the UK have recently announced larger Paris Agreement targets.\n\nAccording to scenarios presented in IEA (2020), cost reductions and sustained policy support are expected to drive strong renewables growth beyond 2022. Overall, renewables are set to account for 95% of the net increase in global power capacity through 2025. Moreover, recent policy momentum has the potential to give renewable energy an extra boost. Finally, net zero emissions targets in key markets (EU, Japan, South Korea, 2050 and China, 2060) are expected to accelerate their deployment of renewables.\n\nHuge investment costs and supportive policies have been needed to advance the development and deployment of clean technologies, clearly indicating a first-mover disadvantage. The trend is now changing as the demand for renewable technologies is soaring. The results of this combination are continued learning curve effects on renewable energy systems and demand shifts because of expectedly more stringent climate policies and changes in public preferences.\n\nThis provides the necessary pull and push factors for creating large first-mover advantages when investing in such systems, with the caveat that fierce competition is to be expected. Finally, the ability to influence other countries’ climate policies has also been increased, both via technology export and an increase in partnerships. These results are summarized in Figure 3.\n\nPsychological sub-barriers\n\nUnderestimating the risk of climate change\n\nThe psychological domain relates to how climate change is perceived by the public and politicians. The underlying characteristics of climate changes are that they evolve slowly with significant delays and that future damages are uncertain and mostly related to existing but elevated extreme weather events (IPCC, 2021). Until recently, the implication of climate change has often been perceived as a potentially severe but not immediate threat.\n\nHere, we identify three main barriers from a psychological domain perspective: the direct perceived risk of climate change, the level of abstraction defined as the relevance that climate change is perceived to have on an individual, and the net costs to individuals when considering changes toward more climate-friendly behaviour.\n\nThe relevance of risk perception is described by Capstick et al. (2015), who state that the ways in which individuals, societies, and polities respond to climate change are in many cases contingent on public perceptions of its causes, consequences and wider implications. Risk perception of climate change, as it relates to individuals’ perception of the risk of climate change, is part of the psychology of climate change, which addresses human perception, impacts, and responses regarding climate change (Clayton and Manning, 2018).\n\nNon-scientists typically rely more on the more readily available associative and affective processing of climate-related information that comes their way (Slovic et al., 2004; Weber, 2006) and engage in risk perception; that is, how large a risk a potential threat is perceived to be, which often differs from scientific evaluations. Sunstein (2006) observes that if people answer the question, ‘should we be fearful of climate change’ by using the logic of the availability heuristic, then they assess the magnitude of the risk by asking whether examples of harm can readily be brought to mind. If people can easily recall such an example, then they are more likely to be frightened, as shown by several examples in Tversky and Kahneman (1982). If relevant events are not available, the unavailability bias will predominate, leading to inaction in taking the necessary precaution (Sunstein and Zeckhauser, 2011; Weber, 2010).\n\nAs evidence of the adverse effects of accelerated global warming mounts, and both media and political discourse focus increasingly on climate change, the availability of climate change is increasing. Capstick et al. (2015) present a four-decade trend in risk perceptions and conclude that in many parts of the world, there has been growing concern about climate change in recent years, while a more recent survey in YouGov (2019) found that a majority of people in 28 countries think climate change is likely to cause serious economic damage, destroy cities, and start wars.\n\nThe level of abstraction\n\nHere, we define two concepts related to abstraction: distance and control, both affecting the individual person’s sense of identification and relevance. Sunstein (2006) points out that for risk perception, salience is important as well. He notes that the impact of seeing a house burning on the subjective probability of such accidents is probably greater than the impact of reading about a fire in the local paper. Hence, in terms of identifying with the risk of climate change, the disaster needs to be close in order to be personalized fear. Based on actual studies, Whitmarsh (2009) and Spence et al. (2011) conclude that experience seems like a filter through which the many risks we face daily are evaluated and ranked. This phenomenon is part of the concept of psychological distance, which refers to the distance between an individual and the occurrence of an adverse event (Schuldt et al., 2018).\n\nThe general notion is that the larger the distance on any of the four distances, the less likelihood that the problem is related to, identified as relevant and coped with by an individual. Sambrook et al. (2021) review recent findings on the empirical evidence on the relationship between personal experience of extreme weather events and climate change concern and action. The relationship remains mixed. Howe (2021) quotes several recent studies trying to establish a positive relationship between metrics of experiences of extreme weather and measures of opinions on climate change. Although some evidence exists, it is not conclusive. However, other recent studies find that households experiencing climate change, change their voting behaviour, which fits the findings of Sambrook et al. (2021). According to Downs (1957), political parties will also listen to voters’ demand for efficient climate policy. Popular support will decrease political justification costs when climate action is undertaken (Facchini, 2016).\n\nIf people feel they cannot change a situation, they are very likely to retreat into apathy and resignation and, thus, less likely to address environmental issues (Moser and Dilling, 2004; Brandt, 2014). Tobler et al. (2012) find that one concept for measuring the feeling of powerlessness is the locus of control, which describes the degree to which individuals believe they can influence outcomes through their actions.\n\nThe net costs of climate-friendly behaviour\n\nFrom a public perspective, when considering changing to a more climate-friendly behaviour or consumption pattern, key factors are ease of substitutability and convenience, such as switching to an electrical vehicle (EV) only if it has the same functionality, price and convenience as an internal combustion engine car (ICE), including charging possibilities. A second important factor is the environmental benefits that such behaviour creates.\n\nTobler et al. (2012) define cost in this context not merely based on direct economic consequences but also include factors such as the requirement of additional time, discomfort, or effort. They argue that while recycling is a low-cost domain, mobility and shifts in consumption are considered high-cost domains. They found that perceived costs and perceived climate benefits turned out to be the strongest predictors for the willingness to support climate policy measures. These findings are supported by Jakučionytė-Skodienė and Liobikienė (2021), who refer to several recent studies claiming that the relationship between climate change concern and behaviour depends on the cost of the behavioural changes and that costs and inconvenience level can reduce the likelihood of individuals mitigating climate change.\n\nSummary: Psychological barriers\n\nPublic perception of climate change hinges on availability, which is affected by whether climate change is considered as having a catastrophic potential (which drastically increases death risks) and on its identification, which depends on personal impact, both from experienced and non-delayed consequences. According to the IPCC (2021), human-induced climate change is already affecting many weather and climate extremes in every region across the globe.\n\nBehaviour is also shaped by societal norms, narratives, and discourses, such as the emergence of intensified information flow and catastrophic risk framing. In 2019, climate scientists and organizations from the UN changed their terminology and began using stronger language to describe the situation we are in. For instance, the UN Secretary-General, António Guterres, talked of the ‘climate crisis’ in September, adding, “We face a direct existential threat” (Guardian, 2019).\n\nA catastrophe narrative for climate change emerged in 2018, exemplified here by a quote from Extinction Rebellion’s (2021) website: “The Truth: We are facing an unprecedented global emergency. Life on Earth is in crisis: scientists agree we have entered a period of abrupt climate breakdown, and we are in the midst of a mass extinction of our own making”.\n\nIn accordance with this, most people globally no longer systematically underestimate the risk of climate change. The United Nations Development Program (UNDP) (2021) shows that public belief in climate emergency ranges from 72% in Western Europe and North America to 61% in Sub Saharan Africa. According to Pew research (2020), 63% Americans said that climate change is affecting their local community.\n\nRegarding the solutions, the net costs of climate actions remain problematic. For instance, individual solutions such as substituting an ICE car with an EV remains expensive and inconvenient. Food with less climate footprint is still low in supply or unattractive. According to Stankuniene et al. (2020), households exhibit behavioural stickiness regarding changes in, for instance, energy savings, even in cases where it would be economically preferable to switch to energy-saving measures.\n\nLikewise, Thøgersen (2021) states that the relationship between consumer behaviour and climate change is complex and that most consumers are not capable of determining which behavioural changes are worth making. He concludes that consumers need considerable assistance to make the right climate-related choices. This fits with the findings that a majority want their governments to be the main driver of the changes. According to Pew research (2020), 65% of American citizens say that the federal government is taking too little action on climate change.\n\nFinally, a comprehensive, recent study identifies views on priorities for limiting climate change. People in China (35%) and the US (34%) believe technological improvements are most effective, while in Europe, 29% name this option as the most effective. In Europe, 39% cite a radical change in their habits (consumption, transport etc.) as the most appropriate way to fight climate change. For Chinese (32%) and American (31%) respondents, this option is ranked as the second-most effective way to limit climate change (EIB, 2021).\n\nGiven these assessments, we evaluate the current strength of the psychological barriers to be as described in Figure 4 below.\n\n\nDiscussion\n\nOur main research question addressed how to model the political, economic, and psychological barriers to an effective climate treaty and sustainable energy. We argued that such a tool could be helpful to policy makers on a global level, for example, considering the international climate leadership by the EU and the potential diplomatic role of the EEAS. The EU is on the right track with ambitious initiatives such as the Green Deal but focusing on barriers could help turn policy output into outcome.\n\nThus, we developed the PEP triangle tool by considering the barriers that have the largest impact on the likelihood of success. This was done in a general setting, and for each set of political, economic, and psychological barriers, the difficulty of reaching an effective treaty was analysed further. Consider, for example, the Paris Treaty and what would happen if one relevant barrier suddenly changed. The fewer sub-barriers, the more likely the climate treaty is to succeed. Overall, the implications for making effective climate treaties can now be summarized in the PEP triangle below in Figure 5. Reducing sub-barriers simply means a movement from blue to red circles, thus, approaching the green area, where a given climate treaty is most likely to succeed.\n\n\nConclusion\n\nOverall, the PEP triangle can be used to define a unique set of challenges and opportunities for achieving effective climate treaties such as the Paris Treaty. A limitation of this study is, however, that it is mainly theoretical. How to implement the PEP triangle in practice and pave the road for successful green diplomacy in the ongoing climate negotiations? An important recommendation for future research is therefore how the PEP triangle can assist diplomatic institutions, for example the European External Action Service (EEAS). Here, the EEAS may pave the way for efficient climate policies and a sustainable future, for example, by enabling a leap-frogging effect when transferring climate-friendly technologies to global south countries. Thus, policy intervention by institutions may establish a positive tipping point where a sustainable development becomes even more profitable. When the EEAS stimulates innovation and transfer of new technology that makes low-cost production of, for example, EVs feasible. In this way, countries will have economic incentives to cooperate and choose sustainable energy solutions rather than free ride.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "References\n\nAragón-Correa JA, Leyva-de la Hiz DI: The influence of technology differences on corporate environmental patents: A resource-based versus an institutional view of green innovations. Bus. Strateg. Environ. 2016; 25: 421–434.\n\nBarrett S: Self-enforcing International Environmental Agreements. Oxf. Econ. Pap. 1994; 46: 878–894.\n\nBarrett S: The Strategy of Trade Sanctions in International Environmental Agreements. Resour. Energy Econ. 1997; 19: 345–361.\n\nBarrett S: Environment and Statecraft: The Strategy of Environmental Treaty-Making. New York: Oxford University Press; 2003.\n\nBarrett S: Climate Treaties and “Breakthrough” Technologies. Am. Econ. Rev. 2006; 96: 22–25.\n\nBernauer T, Dong L, McGrath LF, et al.: Unilateral or reciprocal climate policy? Experimental evidence from China. Politics and Governance. 2016; 3: 152–171.\n\nBertoldi P, Kona A, Rivas S, et al.: Towards a global comprehensive and transparent framework for cities and local governments enabling an effective contribution to the Paris climate agreement. Curr. Opin. Environ. Sustain. 2018; 30: 67–74.\n\nBrandt US: Unilateral actions, the case of international environmental problems. Resour. Energy Econ. 2004; 26: 373–391.\n\nBrandt US: The implication of extreme events on policy responses. J. Risk. Res. 2014; 17: 221–240.\n\nBrandt US, Svendsen GT: Hot air in Kyoto, cold air in The Hague: the failure of global climate negotiations. Energy Policy. 2002; 30: 1191–1199.\n\nBrandt US, Svendsen GT: Fighting windmills: The Coalition of Industrialists and Environmentalists in the Climate Change Issue. International Environmental Agreements: Policy, Law and Economics. 2004; 4: 327–337.\n\nBrandt US, Svendsen GT: The Politics of Persuasion: Should Lobbying be Regulated in the EU?. Cheltenham, UK: Edward Elgar Publishing; 2016.\n\nBrandt US, Svendsen GT: A new tool to measure the effectiveness of climate agreements? The Paris Agreement and the role of the EEAS. Submitted.2021a.\n\nBrandt US, Svendsen GT: ‘Technology diffusion and climate action: A leader-follower model’. Submitted.2021b.\n\nBuchholz W, Sandler T: Successful leadership in global public good provision: incorporating behavioural approaches. Environ. Resour. Econ. 2017; 67: 591–607.\n\nCapstick S, Whitmarsh L, Poortinga W, et al.: International trends in public perceptions of climate change over the past quarter century. WIREs Climate Change. 2015; 6: 35–61.\n\nCEU: Green diplomacy. International Issues. European Commission; 2019. (accessed 10 January 2022). Reference Source\n\nCEU: A European Green Deal. European Commission; 2022a. (accessed 10 January 2022). Reference Source\n\nCEU: Paris Agreement. European Commission; 2022b. (accessed 26 March 2022). Reference Source\n\nClayton S, Manning C: Introduction: Psychology and climate change.Clayton S, Manning C, editors. The psychology and climate change: human perception, impacts and responses. London: Academic Press, Elsevier; 2018.\n\nCleff T, Rennings K: Are there any first-mover advantages for pioneering firms? Lead market orientated business strategies for environmental innovation. Eur. J. Innov. Manag. 2012; 15: 491–513.\n\nClimate Action Tracker: Climate target update tracker.2021. Reference Source\n\nCui L, Sun Y, Song M, et al.: Co-financing in the green climate fund: lessons from the global environment facility. Clim. Pol. 2020; 20: 95–108.\n\nDowns A: An Economic Theory of Democracy. New York: Harper & Row; 1957.\n\nEEAS: Climate, environment & energy. Policy – Activity.2018a. (accessed 9 April 2021). Reference Source\n\nEEAS: Delegation of the European Union to the Republic of Korea. Emissions Trading System; 2018b. Reference Source\n\nEEAS: EU-China 2020 Strategic Agenda for Cooperation.2020. Reference Source\n\nEIB: European Investment Bank: What is the best way to fight climate change? 2020-2021, EIB Climate Survey, part 3 of 3.2021. Reference Source\n\nEskeland GS: ‘Leadership in Climate Policy: Is there a case for Early Unilateral Unconditional Emission Reductions?’, Discussion paper 6-2013, Department of business and management science, Norwegian School of Economics.2013.\n\nEUR-Lex: Strategic partnership with South Africa.2007. Reference Source\n\nEuropean Commission: EU and China Partnership on Climate Change.2005. Reference Source\n\nEuropean Commission: EU-Brazil: Commission proposes strategic partnership.2007. Reference Source\n\nEuropean Commission: EU-Mexico: Commission proposes strategic partnership.2008. Reference Source\n\nEuropean Commission: Declaration on cooperation on environment and climate change in the eastern partnership.2016. Reference Source\n\nEuropean Commission: European Commission and China hold first policy dialogue.2018. Reference Source\n\nEuropean Commission: The EU and Central Asia: New Opportunities for a Stronger Partnership.2019. Reference Source\n\nEuropean Commission: Sustainable development.2020a. Reference Source\n\nEuropean Commission: Eastern Partnership policy beyond 2020. Reinforcing Resilience - an Eastern Partnership that delivers for all.2020b. Reference Source\n\nEuropean Commission: International platform on sustainable finance.2020c. Reference Source\n\nEuropean Commission: International platform on sustainable finance. Annual report.2020d. Reference Source\n\nEuropean Commission: Strategy for financing the transition to a sustainable economy.2021. Reference Source\n\nEuropean Council: Joint declaration between the European Union and the Republic of India on a clean energy and climate partnership.2016. Reference Source\n\nEuropean Council: Climate diplomacy: Council adopts conclusions. Press Release.2019. Retrieved June 15, 2021. Reference Source\n\nEuropean Parliament: A Comprehensive EU strategy for Africa.2020. Reference Source\n\nEuropean Union: A technical case study on R&D and technology spillovers of clean energy technologies. European commission; 2017. Reference Source\n\nExtinction Rebellion: Tell the truth.2021. Reference Source\n\nFacchini F: Political ideological shift: A theoretical approach. Soc. Sci. Inf. 2016; 55: 589–602.\n\nFinus M, Tjøtta S: The Oslo Protocol on sulfur reduction: the great leap forward?. J. Public Econ. 2003; 87: 2031–2048.\n\nGovernment of Canada: Strategic partnership agreement between Canada, of the one part, and the European Union and its member states, of the other part.2016. Reference Source\n\nGreen Climate Fund: 2020. Reference Source\n\nGuardian: Why the Guardian is changing the language it uses about the environment.2019. (accessed 10 January 2022). Reference Source\n\nHillman AL: Public Finance and Public Policy. Responsibilities and Limitations of Government. 3rd ed.Cambridge: Cambridge University Press; 2019.\n\nHoel M: Global environmental problems: The effects of unilateral actions taken by one country’. J. Environ. Econ. Manag. 1991; 20: 55–70.\n\nHowe PD: Extreme weather experiences and climate change opinion. Curr. Opin. Behav. Sci. 2021; 42: 127–131.\n\nIEA: Renewables 2020 Analysis and forecast to 2025.2020. (accessed 10 January 2022). Reference Source\n\nIPCC: AR6 Climate Change 2021: The Physical Science Basis.2021. (accessed 10 January 2022). Reference Source\n\nJakučionytė-Skodienė M, Liobikienė G: Climate change concern, personal responsibility and actions related to climate change mitigation in EU countries: Cross-cultural analysis. J. Clean. Prod. 2021; 281: 125189.\n\nJørgensen KEJG, Kaas TB, Knudsen GTS, et al.: The EEAS navigating foreign policy paradigms. Eur. Politics Soc. 2020. Publisher Full Text\n\nKeller W: ‘International trade, foreign direct investment, and technological spillovers’, Chapter 19 in Handbooks in Economics, Volume 02. Elsevier B.V; 2010.\n\nKeohane RO: Climate change politics after Paris as a two-level game: implications of pledge and review for social science research. Keynote Address at the 2016 Berlin Conference on Global Environmental Change, Transformative Global Climate Governance après Paris, Berlin, Germany, 24 May 2016.2016.\n\nKlinsky S, Roberts T, Huq S, et al.: Why equity is fundamental in climate change policy research’. Glob. Environ. Chang. 2017; 44: 170–173.\n\nKlarl T: Knowledge diffusion and knowledge transfer revisited: Two sides of the medal. J. Evol. Econ. 2014; 24: 737–760.\n\nLieberman M: First-Mover Advantage. Augier M, Teece D, editors. The Palgrave Encyclopedia of Strategic Management. Palgrave Macmillan; London: 2016.\n\nMarkussen P, Svendsen GT: Industry Lobbying and the Political Economy of GHG Trade in the European Union. Energy Policy. 2005; 33: 245–255. Reference Source\n\nMathiasen ES, Svendsen GT: Can public agencies facilitate efficient sustainable energy strategies? A climate partnership model. Int. J. Sustain. Energy. 2020; 8: 739–754. Publisher Full Text\n\nMinistry of External Affairs: India-EU Strategic Partnership: A Roadmap to 2025.2020. Reference Source\n\nMoser SC, Dilling L: Making climate hot: Communicating the urgency and challenge of global climate change. Environment. 2004; 46: 32–46.\n\nNordhaus WD: Climate clubs: Overcoming free-riding in international climate policy. Am. Econ. Rev. 2015; 105: 1339–1370.\n\nNordhaus WD: Climate change: The ultimate challenge for economics. Am. Econ. Rev. 2019; 109: 1991–2014.\n\nOstrom E, Ahn TK: The Meaning of Social Capital and Its Link to Collective Action.Svendsen GT, Svendsen GLH, editors. Handbook of Social Capital: The Troika of Sociology, Political Science and Economics. Cheltenham, UK: Edward Elgar; 2009; pp. 17–35\n\nPew Research Center: How Americans see climate change and the environment in 7 charts.2020. Reference Source\n\nPorter ME, van der Linde C : Toward a new conception of the environment–competitiveness relationship. J. Econ. Perspect. 1995; 73: 97–118.\n\nPrzychodzen W, Leyva-de la Hiz DI, Przychodzen J: First-mover advantages in green innovation – Opportunities and threats for financial performance: A longitudinal analysis. Corp. Soc. Responsib. Environ. Manag. 2020; 27: 339–357.\n\nPutnam RD: Diplomacy and Domestic Policies: The logic of Two-level Games. Int. Organ. 1988; 42: 427–460.\n\nRamanathan R, He Q, Black A, et al.: Environmental regulations, innovation and firm performance: A revisit of the Porter hypothesis. J. Clean. Prod. 2017; 155: 79–92.\n\nSamadi S: The experience curve theory and its application in the field of electricity generation technologies – A literature review. Renew. Sust. Energ. Rev. 2018; 82: 2346–2364.\n\nSambrook K, Konstantinidis E, Russell S, et al.: The Role of Personal Experience and Prior Beliefs in Shaping Climate Change Perceptions: A Narrative Review. Front. Psychol. 2021; 12: 1–7.\n\nSandler T: Collective action: fifty years later. Public Choice. 2015; 164: 195–216.\n\nSandler T: Environmental cooperation: Contrasting international environmental agreements. Oxf. Econ. Pap. 2017; 69: 345–364.\n\nSchuldt JP, Rickard LN, Yang ZJ: Does reduced psychological distance increase climate engagement? On the limits of localizing climate change. J. Environ. Psychol. 2018; 55: 147–153.\n\nSchwerhoff G: The economics of leadership in climate change mitigation. Clim. Pol. 2016; 16: 196–214.\n\nSchwerhoff G, Kornek U: Leadership in climate change mitigation: consequences and incentives. J. Econ. Surv. 2018; 32: 491–517.\n\nShipan RS, Volden C: The mechanisms of policy diffusion. Am. J. Polit. Sci. 2008; 52: 840–857.\n\nSlovic P, Finucane ML, Peters E, et al.: Risk as analysis and risk as feelings: Some thoughts about affect, reason, risk, and rationality. Risk Anal. 2004; 24: 311–322.\n\nSpence A, Poortinga W, Butlerog C, et al.: Perception of Climate Change and Willingness to Save Energy Related to Flood Experience. Nat. Clim. Chang. 2011; 1: 1–4.\n\nStankuniene G, Streimikiene D, Kyriakopoulos GL: Systematic Literature Review on Behavioral Barriers of Climate Change Mitigation in Households. Sustainability 2020. 2020; 12: 7369.\n\nStern N: Stern Review on the Economics of Climate Change. Cambridge University Press; 2007.\n\nSunstein CR, Zeckhauser R: Overreaction to fearsome risks. Environ. Resour. Econ. 2011; 48: 435–449.\n\nSunstein CR: The availability heuristics, intuitive cost-benefit analysis, and climate change. Clim. Chang. 2006; 77: 195–210.\n\nSvendsen GT: Olson, Mancur. Harris P, Bitonti A, Fleisher C, et al., editors. The Palgrave Encyclopedia of Interest Groups, Lobbying and Public Affairs. Cham: Palgrave Macmillan; 2020a. Publisher Full Text\n\nSvendsen GT: Collective Action Problem. Harris P, Bitonti A, Fleisher C, et al., editors. The Palgrave Encyclopedia of Interest Groups, Lobbying and Public Affairs. Cham: Palgrave Macmillan; 2020b. Publisher Full Text\n\nSvendsen GT: Evaluating and regulating the impacts of lobbying in the EU? The case study of green industries. Environ. Policy Gov. 2011; 21: 131–142.\n\nSvendsen GT: US Interest Groups Prefer Emission Trading: A New Perspective. Public Choice. 1999; 101: 109–128.\n\nThøgersen J: Consumer behavior and climate change: consumers need considerable assistance. Curr. Opin. Behav. Sci. 2021; 42: 9–14.\n\nTobler C, Visschers VHM, Siegrist M: Addressing climate change: Determinants of consumers' willingness to act and to support policy measures. J. Environ. Psychol. 2012; 32: 197–207.\n\nTversky A, Kahneman D: Judgment under uncertainty: Heuristics and biases. Kahneman D, Slovic P, Tversky A, editors. Judgment Under Uncertainty: Heuristics and Biases. Cambridge and New York: Cambridge Univ. Press; 1982. pp. 3–22.\n\nUnited Nations Development Program (UNDP): ‘Peoples’ Climate Vote.2021. (accessed 10 January 2022). Reference Source\n\nUNFCCC: Green Climate Fund.2011. Reference Source\n\nWeber EU: Experience-based and description-based perceptions of long-term risk. Why global warming does not scare us (yet). Clim. Chang. 2006; 77: 103–120.\n\nWeber EU: What shapes perceptions of climate change?. Wiley Interdiscip. Rev. Clim. Chang. 2010; 1: 332–342.\n\nWorld Economic Foundation (WEF): Risk report.2020. Reference Source\n\nWeiss JF, Anisimova T: The innovation and performance effects of well-designed environmental regulation: evidence from Sweden. Ind. Innov. 2019; 26: 534–567.\n\nWhitmarsh L: Behavioural responses to climate change: Asymmetry of intentions and impacts. J. Environ. Psychol. 2009; 29: 13–23.\n\nYouGov: International poll: most expect to feel impact of climate change, many think it will make us extinct.2019. (access date, 17 June 2021). Reference Source\n\nYoung OR: Effectiveness of international environmental regimes: Existing knowledge, cutting-edge themes, and research strategies. PNAS. 2011; 108: 19853–19860.\n\n\nFootnotes\n\n1 Two main documents describing this in detail are “Joint declaration on a clean energy and climate partnership” ( European Council 2016) and “India-EU Strategic Partnership: A Roadmap to 2025” (Ministry of External Affairs 2020)."
}
|
[
{
"id": "349403",
"date": "16 Jan 2025",
"name": "Delali Benjamin K Dovie",
"expertise": [
"Reviewer Expertise Global Environmental Change Studies"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript contributes to conceptual framework using the PEP triangle that integrates political, economic, and psychological barriers to assess the effectiveness of climate treaties and sustainable energy policies. Its multidisciplinary approach has the potential to bridge gaps between theory and practice, offering a structured lens for analyzing barriers in climate negotiations. The model’s adaptability to green diplomacy and policy-making contexts, particularly for institutions like the European External Action Service (EEAS), highlights its practical relevance. By focusing on overcoming collective action challenges, the work contributes actionable insights for fostering international cooperation and advancing sustainable energy transitions on a global scale. However, the following issues emerged that require intense redressing:\nMany sections, particularly the Results and Discussion, are overly descriptive and lack the depth needed to critically analyze the data or concepts presented. Key terms such as \"low,\" \"middle,\" and \"high\" on the barrier severity scale are not well-defined, which reduces the model's reproducibility. The lack of empirical data weakens the clarity and accuracy of claims regarding the efficacy and utility of the PEP triangle. In the methods section, the error term in the equation for treaty effectiveness is not adequately explained or contextualized, leaving the reader unclear on its role or significance. Some citations, such as Barrett (1997) and Svendsen (1999), are older and might not reflect the latest developments in climate policy or treaty-making. While the EU is a strong focus, there is insufficient engagement with literature and examples from non-EU countries or regions, such as China, the US, and the Global South. Recent advancements in climate modeling, behavioral psychology in climate change, and technology diffusion are underrepresented, missing critical perspectives. The reader comment from Sascha Samadi highlights an inaccuracy in citing learning rates for solar PV technology. This suggests insufficient attention to detail in integrating cited literature.\nHence authors must:\nProvide explicit definitions of terms and concepts to enhance clarity. Use case studies, simulations, or real-world examples to demonstrate the application of the PEP triangle. Include a detailed discussion on how the error term is quantified and managed. Incorporate more recent and globally diverse literature to provide a balanced perspective. Address the reader comment regarding inaccuracies in citing Samadi (2018) and correct the error. Include research on emerging topics, such as climate technology innovation, to enhance the manuscript’s relevance.\nIntroduction The introduction establishes the importance of climate change as a global issue, providing a historical overview of international climate negotiations and highlighting the ongoing challenges of collective action. It positions the PEP triangle as a response to these challenges. However,\nThe introduction does not clearly define the gap in existing literature that the PEP triangle seeks to fill. It relies heavily on EU-centric examples, potentially alienating non-EU readers or contexts. The narrative lacks depth in explaining why previous frameworks or models fail to address the outlined barriers.\nMethods\nThe absence of empirical validation weakens the model’s applicability and credibility. There is subjective classification of barriers (e.g., high, middle, low) lacking clear, measurable indicators. The error term (ε) in the effectiveness equation is not fully explained, leaving uncertainty about uncontrollable variables.\nResults\nThere is over-reliance on descriptive analysis without quantitative validation which undermines the robustness of the findings. Examples are primarily drawn from EU contexts, limiting the global applicability of insights. Figures (e.g., the PEP triangle and its dimensions) lack detailed annotations or contextual explanations, reducing their clarity.\nDiscussion\nThere are insufficient exploration of the real-world challenges in applying the PEP triangle, particularly in non-EU contexts. There is limited discussion of scalability and adaptability for different treaty sizes or contexts. The manuscript does not critically engage with alternative frameworks or potential criticisms of the PEP triangle.\nConclusion\nThe conclusion does not offer actionable policy recommendations or steps for operationalizing the PEP triangle. It also overlooks key limitations of the study, such as its theoretical nature and lack of empirical testing.\nEnhanced Recommendations\nThere is the need for author to supplement theoretical claims with real-world data, simulations, or case studies. The scope of examples must be broadened to include non-EU perspectives and contexts. There is need for clear, actionable recommendations for policymakers and diplomats. Authors must explore how the PEP triangle can be applied across different treaty sizes and political environments. It will be relevant to compare and contrast the PEP triangle with other frameworks to establish its unique contributions and address potential criticisms.\nAbstract The abstract seeks to present the research question, emphasizing the importance of understanding political, economic, and psychological barriers (PEP) for achieving effective climate treaties and sustainable energy policies. It introduces the PEP triangle as a conceptual tool for improving negotiations and informing green diplomacy but must address the ff:\nInclude a concise summary of the PEP triangle framework, outlining its components and application areas. Summarize key findings, such as the identification of sub-barriers and their implications for treaty success. Highlight the unique contributions of the research, such as specific insights for policymakers or the novel approach to modeling barriers.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-534
|
https://f1000research.com/articles/10-277/v1
|
06 Apr 21
|
{
"type": "Method Article",
"title": "Antibiotic Drug screening and Image Characterization Toolbox (A.D.I.C.T.): a robust imaging workflow to monitor antibiotic stress response in bacterial cells in vivo",
"authors": [
"Benjamin Mayer",
"Meike Schwan",
"Kai M. Thormann",
"Peter L. Graumann",
"Meike Schwan",
"Kai M. Thormann"
],
"abstract": "The search for novel drugs that efficiently eliminate prokaryotic pathogens is one of the most urgent health topics of our time. Robust evaluation methods for monitoring the antibiotic stress response in prokaryotes are therefore necessary for developing respective screening strategies. Besides advantages of common in vitro techniques, there is a growing demand for in vivo information based on imaging techniques that allow to screen antibiotic candidates in a dynamic manner. Gathering information from imaging data in a reproducible manner, robust data processing and analysis workflows demand advanced (semi-)automation and data management to increase reproducibility. Here we demonstrate a versatile and robust semi-automated image acquisition, processing and analysis workflow to investigate bacterial cell morphology in a quantitative manner. The presented workflow, A.D.I.C.T, covers aspects of experimental setup deployment, data acquisition and handling, image processing (e.g. ROI management, data transformation into binary images, background subtraction, filtering, projections) as well as statistical evaluation of the cellular stress response (e.g. shape measurement distributions, cell shape modeling, probability density evaluation of fluorescence imaging micrographs) towards antibiotic-induced stress, obtained from time-course experiments. The imaging workflow is based on regular brightfield images combined with live-cell imaging data gathered from bacteria, in our case from recombinant Shewanella cells, which are processed as binary images. The model organism expresses target proteins relevant for membrane-biogenesis that are functionally fused to respective fluorescent proteins. Data processing and analysis are based on customized scripts using ImageJ2/FIJI, Celltool and R packages that can be easily reproduced and adapted by users. Summing up, our approach aims at supporting life-scientists to establish their own imaging-pipeline in order to exploit their data as versatile as possible and in a reproducible manner.",
"keywords": [
"Combined workflow",
"ImageJ2",
"FIJI",
"cell shape modelling",
"R-statistics",
"machine learning",
"clustering",
"image processing",
"image analysis",
"automation",
"drug screening"
],
"content": "Introduction\n\nBioimage analysis is continuously changing our understanding about the world and how we see our environment. Bacteria are present at µm scale and physiological processes, like cellular signalling events, are even lower than nanometer scale. Cell shape is important for these non-compartmentalized, unicellular organisms. The question of how fast cells grow and divide is connected to tightly regulated intracellular processes like protein-biogenesis from which novel synthesized proteins are translocated along synthesis pathways to their target. Associated proteins play an important role in membrane biogenesis1–3. Membrane proteins are synthesized by ribosomes and usually co-translationally inserted into the cytoplasmic membrane. In this process, the signal recognition particle (SRP; composed of SRP RNA and of Ffh protein) recognizes the signal sequence of the nascent polypeptide at the ribosome4. This complex is recognized by the SRP receptor FtsY and is delivered to the translocon in the cytoplasmic membrane5–7. The nascent polypeptide can be inserted into the membrane or translocated across the membrane by the translocon8,9. Disruption of these processes results in dysregulation of essential networks followed by reduced viability, for instance, via chemically induced stress by antibiotic compounds. Susceptibility towards different antibiotics can vary from organism to organism depending on the mode of action of the compound. To further understand respective mechanisms of cellular stress response in bacteria, morphological feature changes are useful to monitor those in vivo. Our goal is to illustrate how an imaging based workflow can be efficiently deployed to monitor these processes as part of an antibiotic drug screening strategy involving cell morphology and viability. Further more, the presented combined workflow shows how to extract valuable information from imaging data in a reproducible manner using classic statistical approaches, as well as unsupervised machine learning algorithms.\n\n\nMethods\n\nOur model organism Shewanella putrefaciens CN-32 is a Gram-negative bacteria that occurs in aquatic environments10. Depending on its growth and division cycles, it has approximately 3 µm in length and 1 µm in width at exponential phase. Cell division occurs with peak rates at exponential phase represented by OD600 0.5. In our study, we use markerless insertions at the original gene locus functionally expressing fusion-proteins that are relevant for membrane protein-biogenesis: bacterial signal recognition particle Ffh, its receptor FtsY and ribosomal protein of large subunit L1. In order to monitor druginduced stress responses that affect protein-biogenesis, mVenus is used as a fluorescent protein for fluorescence microscopy. Recombinant strains are cultured at 30°C and 200 rpm in Lysogeny broth (LB) medium without antibiotics. This aspect is beneficial to avoid potential bias induced by compound interaction. To analyze antibiotic stress on membrane biogenesis, the protein synthesis inhibitor puromycin was used (200 µg/ml). Puromycin inhibits translation by preventing the release of the premature nascent polypeptide11.\n\nDrug screening time-course replicates are taken at different days. Cells are inoculated from an overnight culture and cultured at 30°C and 200 rpm until OD600 0.5. From this batch, 1 ml is sampled into a glass tube as steady-state (NC), 1 ml treated with antibiotics and is continuously incubated with same conditions. A sample of 3 µl is taken from the culture at steady state and mounted on slides using 1% ultrapure agarose for reduced background. During imaging of cells at steady-state, cells treated with antibiotics are incubated for a minimum of 30 minutes until image acquisition. Similar to this, samples from treated culture after a minimum of 60 minutes are taken accordingly. Viability assay is additionally performed after timecourse experiments. We assume that cells treated with the compound during the time-course experiment are sublethally impaired in cell-growth and division. In order to do so, cells at steady-state and treated with puromycin are 10 fold serially diluted and distributed on LB-agar plates for further incubation at 30°C overnight and imaged using a Fusion-Gel-Illuminator.\n\nImages are acquired using brightfield and photobleaching fluorescence microscopy. In our live-cell imaging pipeline, we use an Olympus IX 71 microscope (100x/NA 1.49/optovar 1.6) customized for slim field microscopy12, with a fast image acquisition conducted by an Andor iXON Ultra EMCCD camera. Brightfield images are acquired using 50 ms exposure time (see Figure 1). Live-cell time-lapse recordings are acquired using 16 ms exposure time. We take advantage of photobleaching steps through continuous slim field illumination until single particles can be localized (see Figure 2). Continuous slim field excitation for photobleaching of the samples is conducted using 514 nm laser line (50%). The microscope setup uses Andor Solis as camera software using at least 2000 frames with integration times of 17.76 ms.\n\nA) Brightfield images are transformed from 16-bit into 8-bit and smoothed by B) non-linear noise reduction using the Kuwahara filter option in FIJI (sampling window = 2). Noise reduced images are C) thresholded using ’Percentile’ thresholding algorithm and D) segmented using watershed for cell discrimination. E) Resulting binary images are finally corrected manually by correcting potential false positive cells through drawing options. F) ROI are extracted from appropriate binary images, stored as individual .zip folders which also involves measurement of cellular areas in an automated manner. This process can be repeated until the the correction is optimal and representative for further analysis. Further analysis always refer to the updated data base and corrections are automatically included when image analysis is reproduced accordingly in Celltool or R-statistics. Scale bar = 1 µm.\n\nData can be corrected and updated at every stage of the workflow to continuously improve the database until bias is minimized. Scale bar = 1 µm.\n\nImage processing in this workflow is conducted using ImageJ2/FIJI13–15. Binary images are sequentially and automatically annotated, transformed from 16-bit into 8-bit, non-linearily noise reduced using a Kuwahara filter and thresholded using ’Percentile’ thresholding algorithm and segmented using watershed segmentation for cell detection (see Figure 1). Resulting binary images are finally corrected manually using the paint function of ImageJ2/FIJI accordingly (see Figure 1). This process can be repeated until the correction is optimal and representative for further analyses (see Figure 2). Fluorescence time lapse recordings are automatically annotated, cropped after sufficient photobleaching steps and projected using the ’Standard deviation’ method. This method is used for tomographic representations and highlights areas of high fluorescent densities within a region of interest (ROI). Resulting fluorescence micrographs are background corrected using the math function ’substract’. All images are automatically scaled and stored in a database management system that is connected through a set of predefined folder operations within the automation script. Regions of interest (ROI) are automatically detected using ImageJ2/FIJI and further processed using scripts based on macro language implemented in ImageJ2/FIJI (see Figure 1). ROIs are extracted from binary images using the ROI-manager plugin and used as a mask for cell-measures of projected fluorescence micrographs (see Figure 2).\n\nAs a result, we receive comma separated value (.csv) tables that are merged using a custom script in R-statistics based on the ’dplyr’ package to organize and merge the tables to a final result-table. Cell shape analysis is conducted using Celltool developed by Pincus lab for cell shape modelling16. Scripts for extraction of polygonal contours, alignment statistical evaluation of probability density of cell areas or curvatures and modelling of shape modes are adapted according to the tutorial from Pincus labs (https://zplab.wustl.edu/celltool/) (see Figure 2). Statistical evaluation of cell areas collected from ROI and fluorescence measurements mean gray value (mgv) as well as integrated density (IntDen) (https://imagej.nih.gov/ij/docs/menus/analyze.html) are statistically analyzed with Rstudio using a customized markdown pipeline in R 3.6.117–28 (see Figure 2). To understand the context between mgv and IntDen, is important to know that:\n\n\n\n\n\nStatistical distributions resulting from measurements are tested for normality using the Shapiro-Wilk test. Non-parametric Wilcoxon rank sum test is used to test pairwise for significance (confidence level: 0.95 ; p < 0.05 = * ; p < 0.01 = ** ; p < 0.001 = ***). In order to establish an unsupervised machine learning approach using the ImageJ2/FIJI results tables, Density based clustering of applications with noise (dbscan) R-package is applied to cellular areas and mean gray value with the aim to evaluate clusters that distinguish between cellular amount of fusion proteins (indicated by fluorescence) and cellular areas29.\n\n\nProof of concept\n\nPuromycin treated cells show abnormal cell morphology regarding their size and shape over time (see Figure 3A). Cell shape changes can be modelled with Celltool. Generalized models according to time points show increased variation of cells explained by mode 1 and 2 (see Figure 4), if stressed with puromycin. Corresponding to these findings, probability plots show increasing cell size (see Figure 3C) and abnormal cell morphology reflected by normalized curvature in a quantitative manner during induction with puromycin (see Figure 3D). Depending on the acquisition of the time-interval, cell length increases which indicates cell division stress30. Differences between cellular areas grouped by condition times show clearly a significant time dependent increase (see Figures 5A and B). Although differences of cellular areas appear to be significant as well between L1, Ffh and FtsY if grouped by respective strains, there is no significant difference between Ffh and FtsY. Further more, these findings are strongly influenced by extreme values suggesting that these differences are not a result due to puromycin (see Figures 5C and D). The fluorescence intensity of Ffh and FtsY decreases over time because no new proteins can be translated caused by the protein synthesis inhibitor puromycin and the old proteins are degraded (see Figure 5E and F). From here, it can be only speculated why L1 amount is higher after 30 minutes of induction. One possible explanation could be that the compound does not affect ribosome formation itself. Furthermore, the autocatalytic nature of the ribosomes makes it even more complicated to address31. However, the increased integrated density (see Figure 5F) indicates that changes of the cellular area (in 2D space of course, which is actually a volumetric aspect in 3D) is the decisive parameter to monitor puromycin stress response in our approach. Our assumption that the cellular area is indeed the relevant indicator for puromycin induced stress is further supported by the fact that comparison of cellular areas and curvature with Celltool corresponds to the R-statistics analysis.\n\nA) Time-course of PUR stressed cells at different time points (NC, after >30 min., after >60 min. Viability assay with unstressed (NC) and puromycin stressed cells. B) Colonies on LB-agar show drastic effects between serial dilutions of steady-state and puromycin treated cells. Whilst viability is not impaired for steady-state, protein biosynthesis inhibitor puromycin shows sublethal impaired cell growth and division indicated by reduced colony density. C) CellTool area comparison shows increasing numbers of larger cells that can be quantified which corresponds to D) an increasingly abnormal cell curvature over time after puromycin induced stress. Scale bar = 2 µm.\n\nLower limits of explained differences of shape models caused by variation are taken into consideration if not lower than 0.8%. Our results suggest for all time-course acquisitions that mode 1 explains the majority of variation followed by width of the cells represented by mode 2 and 3. Considering the scale bar, the generalized models clearly show that puromycin is indeed affecting the cell length specifically thus cell division might be impaired. These findings correspond to analysis of cellular areas and curvatures.\n\nA) Boxplot comparison shows increased cell size distribution for all observed fusion proteins over time if stressed with puromycin (0 min: n = 412; 30 min: n = 455; 60 min: n = 338). Extreme value count increases over time for the pooled fusion protein samples. B) Probability density of larger cells increases over time for pooled fusion proteins. Results show decreasing number of cells with smaller area indicating that puromycin induced stress results in increase of larger cells for the whole sample. C) Cellular areas grouped according to respective strains containing different fusion proteins are differing: Ffh: n = 453; FtsY: n = 371; L1: n = 381. D) Probability density plot does not indicate a strong difference if compared between strains of different fusion proteins. E) Comparison of mean gray values (mgv) between groups of fusion proteins show slightly decreasing effects over time for Ffh (0 min: n = 131; 30 min: n = 184; 60 min: n = 138) and FtsY (0 min: n = 112; 30 min: n = 160; 60 min: n = 99). L1 (n = 169) appears to increase after 30 min (n = 111) of stress-induction followed by a strong decrease after 60 min (n = 101). Error bars refer to standard error (se). F) Integrated density (IntDen) comparison between monitored proteins over time show increasing tendencies over time for Ffh and FtsY. L1 increases after 30 min and decreases after 60 min. Thus IntDen is directly influenced by the area of the cells, it is plausible that IntDen show an overall increase over time compared to mgv, which is not influenced by the cellular area. Error bars refer to standard error (se).\n\nResults for cluster analysis show that intensity measurements are less powerful to uncover antibiotic stress response in our study compared to abnormal cell grow represented by increased cellular area (see Figure 6). For L1, 6 distinct clusters are identified to which the highest mgv is close beyond 2500 mgv (shown in green). No cell beyond a mgv of 2000 has a larger cellular area than 4 µm2 (see Figure 6 L1). This possibly indicates that higher mgv refers to a non-homogenously distributed population of cells with high L1 amount. It further supports the idea that abnormal cell shape (see Figure 3D and 4) and increased cellular area over time (see Figure 3A) are the relevant indicators for monitoring puromycin induced stress response. In contrast to L1, Ffh shows 10 clusters and FtsY 3 clusters. L1 (red), Ffh (red) and FtsY (green) show one central cluster. However, key finding of the cluster analysis is that cells of respective high protein amount have no enlarged cellular area beyond 4 µm2 for all investigated proteins. It confirms that stressed cells (indicated by enlarged cellular area) do not correspond to increased intensity measurements (compare to Figure 5E and F).\n\n5-Nearest Neighbors (NN) distance plots are used to define the appropriate epsilon values for dbscan and are adjusted manually according to knee of the curve (magenta). Resulting clusters are color coded for discrimination respectively (right).\n\n\nConclusions\n\nThe A.D.I.C.T. workflow is sensitive enough to monitor time-course drug-screening experiments in a reproducible manner. Binary images are very robust regarding their information content and useful for addressing complex questions involving cell shape modelling at nanoscale levels. However, binary images processed in this study are based on brightfield images and extended manual correction is necessary (see Figure 1). By using more powerful techniques like phase-contrast or specific membrane stains for instance, cell detection would be improved and the effort to manually correct binary images could be decreased further resulting in almost fully automated cell detection. Nevertheless, although we applied very basic image acquisition techniques, it is clearly demonstrated that cell division specific events can be monitored, processed and analyzed using the presented workflow. The advantage of the workflow is that every step can be redeployed and improved starting from the raw data processing to final statistical evaluation using high-level or low-level programming languages. Bias can be reduced by re-deployment and refinement of the database which enhances reproducible dissection and analysis of complex data sets in an automated fashion. The amount of useful information gathered from deploying the A.D.I.C.T. workflow in case of puromycin stress on our model organism is convincing but far away from being fully covered by this article. To sum up, our approach illustrates how powerful very basic imaging techniques can be, if applied with a robust, combined workflow and we hope that it empowers other researchers to take advantage from it for their own research tasks.\n\n\nData availability\n\nOpen Science Framework: Test data for A.D.I.C.T. workflow, https://doi.org/10.17605/OSF.IO/FNJ5G32\n\nThis project contains the following files:\n\nBinary images\n\nProjections\n\nROI\n\nmerged results tables (.csv)\n\nexample of brightfield raw images\n\nexample of time-lapse raw recordings\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nScripts from this study are available at Github: https://github.com/Image-processing-and-analysis-workflows/A.D.I.C.T.\n\nArchived scripts as at time of publication: http://doi.org/10.5281/zenodo.461606433\n\nLicense: GNU GPL 3.0",
"appendix": "Acknowledgements\n\nThis publication was supported by COST Action NEUBIAS (CA15124), funded by COST (European Cooperation in Science and Technology).\n\n\nReferences\n\nWalter P, Blobel G: Signal recognition particle: a ribonucleoprotein required for cotranslational translocation of proteins, isolation and properties. Methods Enzymol. 1983; 96: 682–91. PubMed Abstract | Publisher Full Text\n\nSeluanov A, Bibi E: Ftsy, the prokaryotic signal recognition particle receptor homologue, is essential for biogenesis of membrane proteins. J Biol Chem. 1997; 272(4): 2053–5. PubMed Abstract | Publisher Full Text\n\nPeschke M, Le Goff M, Koningstein GM, et al.: Srp, ftsy, dnak and yidc are required for the biogenesis of the e. coli tail-anchored membrane proteins djlc and flk. J Mol Biol. 2018; 430(3): 389–403. PubMed Abstract | Publisher Full Text\n\nLuirink J, High S, Wood H, et al.: Signal-sequence recognition by an escherichia coli ribonucleoprotein complex. Nature. 1992; 359(6397): 741–3. PubMed Abstract | Publisher Full Text\n\nHerskovits AA, Bibi E: Association of escherichia coli ribosomes with the inner membrane requires the signal recognition particle receptor but is independent of the signal recognition particle. Proc Natl Acad Sci U S A. 2000; 97(9): 4621–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDraycheva A, Bornemann T, Ryazanov S, et al.: The bacterial srp receptor, ftsy, is activated on binding to the translocon. Mol Microbiol. 2016; 102(1): 152–67. PubMed Abstract | Publisher Full Text\n\nJomaa A, Boehringer D, Leibundgut M, et al.: Structures of the e. coli translating ribosome with srp and its receptor and with the translocon. Nat Commun. 2016; 7: 10471. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDraycheva A, Lee S, Wintermeyer W: Cotranslational protein targeting to the membrane: Nascent-chain transfer in a quaternary complex formed at the translocon. Sci Rep. 2018; 8(1): 9922. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKuhn P, Draycheva A, Vogt A, et al.: Ribosome binding induces repositioning of the signal recognition particle receptor on the translocon. J Cell Biol. 2015; 211(1): 91–104. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFredrickson JK, Zachara JM, Kennedy DW, et al.: Biogenic iron mineralization accompanying the dissimilatory reduction of hydrous ferric oxide by a groundwater bacterium. Geochim Cosmochim Acta. 1998; 62(19–20): 3239–3257. Publisher Full Text\n\nYarmolinsky MB, Haba GL: Inhibition by puromycin of amino acid incorporation into protein. Proc Natl Acad Sci U S A. 1959; 45(12): 1721–1729. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDersch S, Mehl J, Stuckenschneider L, et al.: Super-resolution microscopy and single-molecule tracking reveal distinct adaptive dynamics of mreb and of cell wall-synthesis enzymes. Front Microbiol. 2020; 11: 1946. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchindelin J, Arganda-Carreras I, Frise E, et al.: Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012; 9(7): 676–82. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchindelin J, Rueden CT, Hiner MC, et al.: The imagej ecosystem: An open platform for biomedical image analysis. Mol Reprod Dev. 2015; 82(7–8): 518–29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRueden CT, Schindelin J, Hiner MC, et al.: Imagej2: Imagej for the next generation of scientific image data. BMC Bioinformatics. 2017; 18(1): 529. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPincus Z, Theriot JA: Comparison of quantitative methods for cell-shape analysis. J Microsc. 2007; 227(Pt 2): 140–156. PubMed Abstract | Publisher Full Text\n\nR Core Team: R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria, 2019. Reference Source\n\nRStudio Team: RStudio: Integrated Development Environment for R. RStudio, PBC., Boston, MA, 2020. Reference Source\n\nXie Y: knitr: A General-Purpose Package for Dynamic Report Generation in R. R package version 1.31. 2021. Reference Source\n\nWickham H, François R, Henry L, et al.: dplyr: A Grammar of Data Manipulation. R package version 1.0.4. 2021. Reference Source\n\nWickham H: ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York, 2016. Reference Source\n\nWickham H, Averick M, Bryan J, et al.: Welcome to the tidyverse. J Open Source Softw. 2019; 4(43): 1686. Publisher Full Text\n\nAhlmann-Eltze C: ggsignif: Significance Brackets for ’ggplot2’. R package version 0.6.0. 2019. Reference Source\n\nArnold JB: ggthemes: Extra Themes, Scales and Geoms for ’ggplot2’. R package version 4.2.4. 2021. Reference Source\n\nMorales M, with code developed by the R Development Core Team, with general advice from the R-help listserv community, et al.: sciplot: Scientific Graphing Functions for Factorial Designs. R package version 1.2-0. 2020. Reference Source\n\nAllaire JJ, Xie Y, McPherson J, et al.: rmarkdown: Dynamic Documents for R. R package version 2.6. 2020. Reference Source\n\nWilke CO: cowplot: Streamlined Plot Theme and Plot Annotations for ’ggplot2’. R package version 1.1.1. 2020. Reference Source\n\nWickham H, Hester J: readr: Read Rectangular Text Data. R package version 1.4.0. 2020. Reference Source\n\nHahsler M, Piekenbrock M, Doran D: dbscan: Fast density-based clustering with R. J Stat Softw. 2019; 91(1): 1–30. Publisher Full Text\n\nPeach KC, Bray WM, Winslow D, et al.: Mechanism of action-based classification of antibiotics using high-content bacterial image analysis. Mol Biosyst. 2013; 9(7): 1837–1848. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReuveni S, Ehrenberg M, Paulsson J: Ribosomes are optimized for autocatalytic production. Nature. 2017; 547(7663): 293–297. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMayer B, Schwan M, Thormann KM, et al.: Antibiotic drug screening and image characterization toolbox (a.d.i.c.t.): test data for workflow deployment and reproduction. 2021. http://www.doi.org/10.17605/OSF.IO/FNJ5G\n\nMayer B: Image-processing-and-analysis- workflows/a.d.i.c.t.: (version v1.0.0). zenodo. 2021. http://www.doi.org/10.5281/zenodo.4616064"
}
|
[
{
"id": "86409",
"date": "11 Jun 2021",
"name": "Massimiliano Lucidi",
"expertise": [
"Reviewer Expertise Image processing and bacterial imaging and microscopy"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors of the manuscript entitled “Antibiotic Drug screening and Image Characterization Toolbox (A.D.I.C.T.): a robust imaging workflow to monitor antibiotic stress response in bacterial cells in vivo” presented A.D.I.C.T, a workflow based on brightfield microscopy images that covers aspects of experimental setup deployment, data acquisition, image processing and statistical analysis of the Shewanella putrefaciens CN-32 cell morphological alterations upon exposure of puromycin-induced protein synthesis arrest.\nAlthough the paper is well structured and suitable for the broader readership of F1000Research, in my opinion there are few points that should be revised to increase the quality of this manuscript.\nMajor revisions\nThe authors employed the puromycin antibiotic to analyse bacterial cell morphology modifications. However, this antibiotic is poorly employed to induce morphological alteration in bacteria and has few applications in clinical settings for bacterial infection treatment. On the other hand, many antibiotics induce bacterial cell filamentation at sub-inhibitory concentration such as fluoroquinolones or beta-lactams (Nonejuie et al., 20131; Htoo et al., 20192). Why did the authors decide to use puromycin instead of other antibiotics? I suggest applying the CellTool-based method to evaluate bacterial morphological modifications induced by other antibiotics.\n\nWhat is the puromycin minimal inhibitory concentration (MIC) of Shewanella putrefaciens CN-32? How much below the MIC is the puromycin concentration used in this work (200 µg/ml)?\n\nThe most effective thresholding algorithms for bacterial image processing are Otsu or Bernsen (Nichele et al., 20203). Why did the authors employed ’Percentile’ thresholding algorithm? Please justify this choice in the manuscript.\nMinor revisions\nPlease substitute “druginduced” with “drug induced” in the Methods section (paragraph: “Biological model system”; line 10).\n\nPhotobleaching is a phenomenon produced by laser exposure in fluorescence microscopy and it is not a typology of fluorescence microscopy. Please eliminate “photobleaching” in the sentence “Images are acquired using brightfield and photobleaching fluorescence microscopy” from the Methods section (paragraph: “Image acquisition”; line 1) or justify the use of this word in the manuscript.\n\nPlease add the graph axis titles in Figures 3C and 3D.\n\nPlease substitute “Further more” with “Furthermore” in the Results section (paragraph: “Proof of concept; Cell shape analysis and modelling”; line 17).\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "7082",
"date": "09 Sep 2021",
"name": "Benjamin Mayer",
"role": "Author Response",
"response": "Dear Massimiliano Lucidi, Thank you for reviewing our work. We would like to answer questions and highlight improvements we made with this rebuttal letter. Major revisions 1. The authors employed the puromycin antibiotic to analyse bacterial cell morphology modifications. However, this antibiotic is poorly employed to induce morphological alteration in bacteria and has few applications in clinical settings for bacterial infection treatment. On the other hand, many antibiotics induce bacterial cell filamentation at sub-inhibitory concentration such as fluoroquinolones or beta-lactams (Nonejuie et al., 2013; Htoo et al., 2019). Why did the authors decide to use puromycin instead of other antibiotics? I suggest applying the CellTool-based method to evaluate bacterial morphological modifications induced by other antibiotics. Answer: Raw data used in the workflow was generated during a single molecule tracking study about the SRP-pathway (Mayer et al. 2021). There, our initial aim was to investigate SRP-ribosome dynamics but during the study, the appearance of abnormally altered cell morphology was observed and subsequently quantified using the A.D.I.C.T. workflow in order to systematically explore these changes. We applied puromycin, rifampicin and chloramphenicol (see figure 6 in the updated version) for inhibitory experiments studying protein-biosynthesis dynamics at single molecule levels. Puromycin is relatively affordable, available and not relevant for medical usage. Data based on puromycin stressed cells serves in this study as a control used for protein-biosynthesis inhibition because it is known to lead to premature peptide chain termination at the peptidyl-transferase site in the 50S ribosomal subunit (reviewed by Aviner in 2020). 2. What is the puromycin minimal inhibitory concentration (MIC) of Shewanella putrefaciens CN-32? How much below the MIC is the puromycin concentration used in this work (200 μg/ml)? Answer: With respect to the minimal inhibitory concentration, there is no information available for S. putrefaciens. According to general supplier informations, puromycin is weakly active against Gram-negative organisms and for E. coli, 100 µg/ml are recommended. In order to apply sufficient antibiotic stress, we used double of the recommended concentration and applied viability screenings simultaneously to each conducted experiment using serial dilutions to check if the cell response was sensitive enough towards puromycin exposure. Our results show that S. putrefaciens cells are susceptible towards puromycin at respective concentration on a sublethal basis (see fig 4B). To our knowledge, results show for the first time, how much puromycin could be used in order to induce sublethal cell-stress in Shewanella putrefaciens. However, further improvements of the workflow are also connected to more detailed experiments (e.g. different concentrations) and data-acquisition strategies. We therefore agree that different antibiotics with respective modes of action could be explored in more detail, but that would exceed the scope of this paper showing only a monitoring method focused on delivering useful information about the samples by using very basic and therefore broadly available imaging techniques. 3. The most effective thresholding algorithms for bacterial image processing are Otsu or Bernsen (Nichele et al., 2020). Why did the authors employed ’Percentile’ thresholding algorithm? Please justify this choice in the manuscript Answer: Regarding the usage of implemented thresholding algorithms, 'Percentile' was used because it is considered as the most robust tool for this specific purpose. 'Percentile' showed for this particular data set the best background detection without affecting cell areas on average. We added figure 2 to the Area outside cells is corrected manually thus regular brightfield images are used. The decision for this particular thresholding algorithm felt after comparing all thresholding algorithms using the 'Try all' function implemented in FIJI. As mentioned in the text, more advanced microscopy techniques (e.g. phase contrast) could give better images for thresholding and segmentation. Further more and not yet covered by this method paper, projections themselves can be used to detect and to compare drug stressed cell populations according to their shape. We however focused on the most simple imaging technique (brightfield) thus the aim of the study is to show how useful information gain can be established with the presented workflow. We agree with the idea that there are a lot more interesting experiments that could (and should) be conducted to address similar biological questions. We therefore hope that the presented workflow might empowers other investigators in establishing similar pipelines in order to increase reproducibility of their research and exploit their data as versatile and efficiently as possible. References: Aviner, Ranen. “The science of puromycin: From studies of ribosome function to applications in biotechnology.” Computational and structural biotechnology journal vol. 18 1074-1083. 24 Apr. 2020, doi:10.1016/j.csbj.2020.04.014 Mayer B, Schwan M, Oviedo-Bocanegra LM, Bange G, Thormann KM, Graumann PL. Dynamics of Bacterial Signal Recognition Particle at a Single Molecule Level. Front Microbiol. 2021 Apr 30;12:663747. doi: 10.3389/fmicb.2021.663747. PMID: 33995327; PMCID: PMC8120034."
}
]
}
] | 1
|
https://f1000research.com/articles/10-277
|
https://f1000research.com/articles/10-445/v1
|
04 Jun 21
|
{
"type": "Research Article",
"title": "Association between pesticide exposure and obesity: A cross-sectional study of 20,295 farmers in Thailand",
"authors": [
"Kajohnsak Noppakun",
"Chudchawal Juntarawijit",
"Kajohnsak Noppakun"
],
"abstract": "Background: Obesity is a serious condition because it is associated with other chronic diseases which affect the quality of life. In addition to diet and exercise, recent research has found that pesticide exposure might be another important risk factor.\n\nMethods: The objective of this large cross-sectional study was to determine the association between pesticide exposure and obesity among farmers in Nakhon Sawan and Phitsanulok province, Thailand. Data on pesticide use and obesity prevalence from 20,295 farmers aged 20 years and older was collected using an in-person interview questionnaire. The association was analysed using multivariable logistic regression, adjusted for its potential confounding factors. Results: Obesity was found to be associated with pesticide use in the past. The risk of obesity was significantly predicted by types of pesticides, including insecticides (OR = 2.27, 95% CI 1.09-4.74), herbicides (OR = 4.72, 95% CI 1.16-19.29), fungicides (OR = 2.17, 95% CI 1.37-3.44), rodenticides (OR = 2.52, 95% CI 1.59-3.99), and molluscicides (OR = 3.37, 95% CI 2.13-5.31). Among 35 surveyed individual pesticides, 24 were significantly associated with higher obesity prevalence (OR = 1.75, 95% CI 1.00-3.06 to OR = 8.37, 95% CI 3.97-17.64), including herbicide butachlor, 17 insecticides (three carbamate insecticides, five organochlorine insecticides, and nine organophosphate insecticides), and six fungicides. Conclusion: This study found obesity in farmers in Nakhon Sawan and Phitsanulok province, Thailand, to be associated with the long-term use of several types of pesticides. The issue should receive more public attention, and pesticide use should be strictly controlled.",
"keywords": [
"Pesticide exposure",
"obesity",
"farmer health",
"insecticide exposure",
"herbicide exposure",
"fungicide exposure"
],
"content": "Abbreviations\n\nBMI: body mass index\n\nCM: carbamate pesticide\n\nCVD: cardiovascular diseases\n\n2,5-DCP: 2,5-dichlorophenol\n\nDDT: dichlorodiphenyltrichloroethane\n\nEDC: endocrine-disrupting chemicals\n\nICD-10: International Classification of Diseases 10th\n\nOC: organochlorine pesticide\n\nOPs: organophosphate pesticide\n\nPCBs: polychlorinated biphenyl\n\np,p'-DDE: dichlorodiphenyldichloroethylene\n\nVHV: village health volunteers\n\n\nBackground\n\nObesity is a global public health problem. In 2016, the World Health Organization (WHO) reported that there were approximately two billion people aged 18 years and older who were overweight, of which 650 million were obese, with this number expected to rise.1 In Thailand, the latest national survey reported obesity prevalence among adults aged 18 years and older, to be 4.0% class I obesity (body mass index (BMI) 30.0-34.9 kg/m2), 0.8% class II obesity (BMI 35.0-39.9 kg/m2), and 0.1% class III obesity (BMI ≥40.0 kg/m2).2 Obesity is not just an image problem, it can also affect health and well-being. Obesity has been linked with various health problems, including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), cancer, and other health problems including liver and kidney disease, sleep apnea, and depression, which can eventually lead to mortality.3 Many factors can affect obesity, including age, genes, diet, a sedentary lifestyle, certain diseases, and medications, as well as other health conditions including sleeping habits, stress, and depression.4\n\nRecent studies have found that pesticide exposure may be associated with metabolic disorders such as obesity.5 Mice studies have reported that chlorpyrifos, an organophosphate pesticide, has interfered with mucus-bacterial interactions in the gut, leading to increased lipopolysaccharide entry into the body resulting in excess fat storage.6 A study in Korea found women with Methanobacteriales, a bacteria in the gut that is linked to obesity, have higher body weight and waist circumference.7 This finding was consistent with a study in the United States of America (U.S.A) that with the use of the National Health and Nutrition Examination Survey (NHANES), found that obesity in adults was associated with the fumigant insecticide paradichlorobenzene,8 and 2,5-dichlorophenol (2,5-DCP) exposure.9 In a cohort study, dichlorodiphenyldichloroethylene (p,p'-DDE), and polychlorinated biphenyl (PCBs) were associated with higher BMI, high triglyceride levels, and insulin resistance.10 A recent study also linked a simultaneous exposure to bisphenol A (BPA), bisphenol S (BPS), and mono (carboxyoctyl) phthalate (MCOP), to an elevated risk of obesity.11\n\nAs far as we know, to date, this issue has not been investigated in Thailand. This cross-sectional study aimed to determine the association between pesticide exposure and obesity among farmers in Nakhon Sawan and Phitsanulok province, Thailand. Identification of individual pesticides to predict the risk of obesity was the main interest. The results will be useful for verification of previous results and prevention of obesity.\n\n\nMethods\n\nData in this cross-sectional study was collected from farmers in Nakhon Sawan and Phitsanulok province, Thailand. Nakhon Sawan province is located about 250 km north of Bangkok, Thailand, with a population of 1,066,455 people and 401,432 households, from 15 districts (data for the year 2016). The majority of people are farmers, and the main crops are rice, sugarcane, and cassava. In 2017, the province had a gross domestic product (GDP) of 21,852 THB (716 USD).12 In 2019, Phitsanulok province, located 377 km north of Bangkok, had a population of 865,368 people from nine districts and 342,787 households. Agriculture is the biggest sector of the economy, generating about 28% of GDP with an employment rate of 41.9%. The major crops in the province are rice, sugar cane, cassava, and vegetables13 (Thailand Information Centre, n.d.).\n\nStudy participants were farmers aged 20 years and older, who had worked as farmers for at least five years. Participants were selected using multistage sampling. Firstly, three districts from each province were randomly selected. In each district, three sub-districts were further randomly selected. In each sub-district, we selected 2,100-4,500 farmer families, accounting for about 30-100% of all farmer families in each sub-district. Using data from the local authority and personal contact, village health volunteers (VHV) identified farmer families, who were contacted for data collection. In each family, one adult who met the inclusion criteria was interviewed.\n\nAll local hospitals inside the selected subdistrict were contacted and public health staff and its membership VHV were invited to participate in the study. VHV who had mobile phone and internet access to the online questionnaires were recruited. These volunteers also had to attend a one-day training session to be informed about the project and to be trained on interviewing the participants, along with the correct use of online questionnaires. Most of the interviews took place in the participant’s home, however sometimes in other places, e.g. local temple or hospital. Data was collected between October 2020 and February 2021. Data from all 20,295 participants were included in the data analysis.\n\nThe minimum sample size was calculated to be 18,772, based on the following assumptions: significance level = 95%; power of detection = 80%; ratio of unexposed/exposed = 1; percent of unexposed with outcome = 5%; odds ratio = 1.2.\n\nData was collected using an in-person interview questionnaire and an online version. The questionnaire had three major parts (provided as Extended data15). Part I, contained demographic information, including gender, age, marital status and education. Information on cigarette smoking and alcohol consumption were also collected.\n\nIn part II, there were questions regarding the long-term use of pesticides. This question was modified from the questionnaire used in our previous study.16 Data on both types and individual pesticides were collected. Pesticides were categorized into insecticides, herbicides, fungicides, rodenticides, and molluscicides. Insecticides were further subdivided into four classes: organochlorine, organophosphate, carbamate, and pyrethroid. For individual pesticides, we collected data on 35 pesticides that were commonly used in Thailand and have been reported in previous literatures to affect obesity.16 Study participants were asked whether they have ever used the pesticides, using a ‘yes’ or ‘no’ question. Pesticide use was defined as a mixture or spray pesticides for agriculture purposes. Household pest control was excluded in this study.\n\nIn part III, participants were asked whether they had been medically diagnosed with obesity by using a “yes” or “no” question. This information was later confirmed by the disease record ICD-10 of the local hospitals. The confirmed cases were included in the data analysis, while the missing data was excluded. In Thailand, the Ministry of Public Health follows the International Diabetes Federation’s definition (2005), which defines obesity as a waist circumference of no more than 90 cm for men and 80 cm for women, plus two out of the following four criteria:17\n\n1. Triglyceride level ≥150 mg/dL\n\n2. HDL less than 40 mg/dL for men, or 50 mg/dL for women\n\n3. Blood pressure ≥130/85 mmHg, or taking medication for hypertension\n\n4. Fasting blood glucose ≥100 mg/dL, or taking medication for hyperglycemia\n\nDemographic data were analysed using descriptive statistics (frequency, percentage, mean, and standard deviation). An association between pesticides and obesity was determined using multivariable logistic regression, adjusted for gender (male, female), age (20-30, 31-40, 41-50, 51-60, 60>), smoking (non-smoker, ex-smoker, smoker) and alcohol consumption (non-drinker (or abstainer), ex-drinker, regular drinker), presented in odds ratio (OR), 95% confidence intervals.\n\nP-values <0.05 were statistically significant. All data analysis was performed using IBM SPSS Statistics (version 26) and OpenEpi online version 3.5.1.\n\n\nEthical considerations\n\nThe study was approved by the Ethical Committee of Naresuan University (COA No. 657/2019). Before the interviews, all the study participants gave informed consent to participate in the study, and they had the right to stop the interview at any time.\n\n\nResults\n\nOut of the 20,295 participants, most were women (45%), aged 40 years and older, with an average age of 55 (± 12 years). Current smokers were 11%, while 15% drank alcohol. Demographic data of the participants is shown in Table 1 and the Underlying Data.18\n\n* Statistically significant difference with p-value <0.05.\n\n** Chi-square test\n\nA total of 90 participants were diagnosed with obesity. Among these individuals, 12 were not confirmed by the ICD-10 record, thus only 78 were included in the data analysis. The prevalence of obesity among participants was 0.4% (Table 2). Besides obesity, many of the patients also had other diseases, e.g., hypertension, T2DM, dyslipidemia.\n\nIt was found that all types of pesticides, including insecticides, herbicides, fungicides, rodenticides, and molluscicides, were significantly associated with obesity prevalence (Table 3). The associations were also found in many of the surveyed individual pesticides (Table 4). Those pesticides were from various types of pesticide, including herbicides butachlor, 18 insecticides (three carbamate (CM) insecticide, five organochlorine pesticides (OC) insecticide, and nine organophosphate pesticides (OP) insecticide), and six fungicides.\n\n* Adjusted variables: Gender (male, female), age (20-30, 31-40, 41-50, 51-60, 60+), smoking (never, ex-smoker, current smoker), alcohol consumption (never, used to drink, currently drink).\n\n** Significant OR were indicated in bold numbers.\n\n* Adjusted variables: Gender (male, female), age (20-30, 31-40, 41-50, 51-60, 60+), smoking (never, ex-smoker, current smoker), alcohol consumption (never, used to drink, currently drink).\n\n** Significant OR were indicated in bold numbers.\n\n\nDiscussion\n\nIn this study, the prevalence of obesity was very low (0.4%). This might be due to the fact that the patients had underlying medical conditions, as stated in the ICD-10 records. This group of patients represent those with severe obesity or other health problems that needed medical attention. This was consistent with the data from a national survey in Thailand which found that the prevalence of obesity among adults aged 18 years and older to be 4.0% class I obesity (BMI 30.0-34.9 kg/m2), 0.8% class II obesity (BMI 35.0-39.9 kg/m2), and 0.1% class III obesity (BMI ≥40.0 kg/m2).2 In further analysis, this study also found that many of the obesity cases have other health problems (hypertension (55%), T2DM (30%)) (Table 2).\n\nThis results of this study also found that many pesticides are strongly associated with the prevalence of obesity. The risk of obesity was significantly predicted by various types of pesticides, including insecticides (OR = 2.27, 95% CI 1.09-4.74), herbicides (OR = 4.72, 95% CI 1.16-19.29), fungicides (OR = 2.17, 95% CI 1.37-3.44), rodenticides (OR = 2.52, 95% CI 1.59-3.99), and molluscicides (OR = 3.37, 95% CI 2.13-5.31) (Table 3). Among 35 surveyed individual pesticides 24 were significantly associated with obesity (OR = 1.75, 95% CI 1.00-3.06 to OR = 8.37, 95% CI 3.97-17.64), including herbicide butachlor, 17 insecticides (three CMs- carbaryl, methomyl, carbosulfan, five organochlorine insecticides- endosulfan, dieldrin, aldrin, DDT, chlordane, and nine organophosphate insecticides- abamectin, chlorpyrifos, folidol (parathion), methamidophos, monocrotophos, mevinphos, dicrotophos, dichlorvos, profenofos), and six fungicides- metalaxyl, propineb, carbendazim, thiophanate, benomyl, bordeaux mixture (Table 4). Turnbaugh et al,19 found pesticides affect the gut microbiome that controls the energy harvest, which may lead to obesity. This finding was supported by a recent study that found long-term exposure to chlorpyrifos affects gut microbiota homeostasis and induces inflammation, resulting in excess fat accumulation in the body.6 Additionally, a Korean study reported on the Methanobacteriales in the gut being associated with increased waist circumference, and bodyweight.7\n\nSome pesticides are endocrine-disrupting chemicals (EDC). These are exogenous chemicals that interfere with the action of hormones, and/or obesogens, that inappropriately regulate lipid metabolism and adipogenesis to promote obesity.20 At present, there are 105 pesticides listed as EDC, insecticides (46%) e.g. OCs DDT, 2,4-D, aldrin, endosulfan, chlorpyrifos, herbicide (21%) e.g. alachlor, diuron, glyphosate, and fungicides (31%) e.g., benomyl, carbendazim. A study found EDCs affect weight gain by altering lipid metabolism, fat cell size and number, and hormones involved in appetite, food preference, and energy metabolism.21\n\nEpidemiological studies on the association between pesticide exposure and obesity are rare. U.S.A National Health and Nutrition Examination Survey (NHANES) from 2005-2008, indicated that obesity of the general population was associated with environmental exposure to some pesticides, e.g. 2,4-dichlorophenol (2,4-DCP), and 2,5-dichlorophenol (2,5-DCP).8 Among non-diabetic individuals, a study found that exposure to OC pesticides, especially p,p'-DDE, increased the risk of higher BMI, triglycerides, and decreased HDL cholesterol.10 Another study using NHANES survey from 2003-2006, also found exposure to environmental pesticides increased obesity in children aged 6-19 years.22 In this study, a dose-dependency was observed between the quartile of exposure to 2,5-DCP and the prevalence of obesity. These results were supported by a follow-up study which found 2,5-DCP exposure to be significantly associated with obesity (OR = 1.09, 95% CI 1.1-1.19) among children and adolescents aged 6-18 years.9 A follow-up cohort study has found that middle-aged obese women were associated with mothers that used DDT, while pregnant with these women. (OR = 1.26, 95% CI 6-49 to OR = 1.31, 95% CI 6-62).23\n\nThough a large sample size was used, the number of obese participants was still small. This limited the power of detection and control of confounding factors. Data on other risk factors, such as diet, exercise, or genetics were not collected. These confounding factors might have a different impact on the results. Another concern was that the obesity cases from ICD-10 records may not have been valid or represent the prevalence of the disease in the study. Currently, data on the validity of ICD-10 diagnosis coding for overweight/obesity in Thailand is not available. However, studies in Europe e.g., Sweden and Denmark, reported that the data is accurate and suitable to be used in epidemiological research.24\n\nThe strength of this study was in its large sample size, and the ability to identify several groups and individual pesticides that were associated with obesity. This finding supported the literature and the hypothesis that pesticide exposure can increase obesity risk.\n\n\nConclusion\n\nIn Nakhon Sawan and Phitsanulok province of Thailand, obesity in farmers was associated with the long-term use of several types of pesticides, including insecticides, herbicides, fungicides, rodenticides, and molluscicides. The study additionally found 24 individual pesticides that increased the risk of obesity. This finding was consistent with the literature and studies done in other countries. The information should be publicized, and pesticide use should be controlled. Further studies should be done to confirm the results, and to determine a safe limit of pesticide exposure for obesity risk.\n\n\nData availability\n\nFigshare: Dataset for study on pesticide exposure and obesity, among farmers in Nakhon Sawan and Phitsanulok province, Thailand.\n\nhttps://doi.org/10.6084/m9.figshare.14524983.v1.18\n\nThis project contains the following underlying data:\n\n• Dataset Pesticide and obesity (SAV and CSV). (All underlying data gathered in this study)\n\n• Data Dictionary (DOCX).\n\nFigshare: Dataset for study on pesticide exposure and obesity, among farmers in Nakhon Sawan and Phitsanulok province, Thailand.\n\nhttps://doi.org/10.6084/m9.figshare.14524980.v1.15\n\nThis project contains the following extended data:\n\n• Questionnaire-pesticide and obesity-English (DOCX). (Study questionnaire in English)\n\n• Questionnaire-pesticide and obesity-Thai (DOCX). (Study questionnaire in Thai)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgments\n\nThe author is grateful to all the study participants who took the time to participate in this study and provided valuable information. Thank you very much to local hospital staff from Nakhon Sawan, and Phitsanulok province, and the village health volunteers for collecting data. Thank you also to Mr. Kevin Mark Roebl of Naresuan University’s Writing Clinic (DIALD) for editing assistance.\n\n\nReferences\n\nWorld Health Organization: Obesity and Overweight. WHO. Publisher Full Text\n\nJitnarin N, Kosulwat V, Rojroongwasinkul N, et al.: Prevalence of overweight and obesity in Thai population: Results of the National Thai Food Consumption Survey. Eat Weight Disord. 2011; 16(4): e242. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPi-Sunyer X: The medical risks of obesity. Postgrad Med. 2009; 121(6): 21–33. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEndalifer ML, Diress G: Epidemiology, Predisposing Factors, Biomarkers, and Prevention Mechanism of Obesity: A Systematic Review. J Obes. 2020; 2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCzajka M, Matysiak-Kucharek M, Jodłowska-Jędrych B, et al.: Organophosphorus pesticides can influence the development of obesity and type 2 diabetes with concomitant metabolic changes. Environ Res. 2019; 178: 108685. PubMed Abstract | Publisher Full Text\n\nLiang Y, Zhan J, Liu D, et al.: Organophosphorus pesticide chlorpyrifos intake promotes obesity and insulin resistance through impacting gut and gut microbiota. Microbiome. 2019; 7(1): 19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLee HS, Lee JC, Lee IK, et al.: Associations among organochlorine pesticides, methanobacteriales, and obesity in Korean women. Luque RM, ed. PLoS One. 2011; 6(11): e27773. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWei Y, Zhu J, Nguyen A: Urinary concentrations of dichlorophenol pesticides and obesity among adult participants in the U.S. National Health and Nutrition Examination Survey (NHANES) 2005-2008. Int J Hyg Environ Health. 2014; 217(2-3): 294–299. PubMed Abstract | Publisher Full Text\n\nParastar S, Ebrahimpour K, Hashemi M, et al.: Association of urinary concentrations of four chlorophenol pesticides with cardiometabolic risk factors and obesity in children and adolescents. Environ Sci Pollut Res. 2018; 25(5): 4516–4523. PubMed Abstract | Publisher Full Text\n\nLee DH, Steffes MW, Sjödin A, et al.: Low dose organochlorine pesticides and polychlorinated biphenyls predict obesity, dyslipidemia, and insulin resistance among people free of diabetes. Pan X, ed. PLoS One. 2011; 6(1): e15977. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang Y, Dong T, Hu W, et al.: Association between exposure to a mixture of phenols, pesticides, and phthalates and obesity: Comparison of three statistical models. Environ Int. 2019; 123: 325–336. PubMed Abstract | Publisher Full Text\n\nNakhon Sawan Provincial Office: Nakhon Sawan Province.2021. Reference Source\n\nPhitsanulok Provincial Agriculture and Cooperatives Office: Basic Agricultural Data, Phitsanulok (In Thai). 2021. Reference Source\n\nThailand Information Center: Phitsanulok province. Accessed February 22, 2021. Reference Source\n\nJuntarawijit C: Questionnaire-pesticide and rhinitis-Thailand. Figshare. Dataset. . 2021. Publisher Full Text\n\nJuntarawijit C, Juntarawijit Y: Association between diabetes and pesticides: A case-control study among Thai farmers. Environ Health Prev Med. 2018; 23(1). PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhamchata L, Dumrongpakapakom P, Theeranut A: Metabolic Sydrome: Dangerous signs required management. Srinagarind Med J. 2018; 33(4): 386–395.\n\nJuntarawijit C: Pesticide and obesity. Figshare. Dataset. Published . 2021; Publisher Full Text\n\nTurnbaugh PJ, Ley RE, Mahowald MA, et al.: An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444(7122): 1027–1031. PubMed Abstract | Publisher Full Text\n\nHatch EE, Nelson JW, Stahlhut RW, et al.: Association of endocrine disruptors and obesity: Perspectives from epidemiological studies. Int J Androl. Blackwell Publishing Ltd; 2010; 33: 324–332. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGupta R, Kumar P, Fahmi N, et al.: Endocrine disruption and obesity: A current review on environmental obesogens. Curr Res Green Sustain Chem. 2020; 3: 100009. Publisher Full Text\n\nTwum C, Wei Y: The association between urinary concentrations of dichlorophenol pesticides and obesity in children. Rev Environ Health. 2011; 26(3): 215–219. PubMed Abstract | Publisher Full Text\n\nLa Merrill MA, Krigbaum NY, Cirillo PM, et al.: Association between maternal exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and risk of obesity in middle age. Int J Obes. 2020; 44(8): 1723–1732. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGribsholt SB, Pedersen L, Richelsen B, et al.: Validity of ICD-10 diagnoses of overweight and obesity in danish hospitals. Clin Epidemiol. 2019; 11: 845–854. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "94404",
"date": "01 Oct 2021",
"name": "Yankai Xia",
"expertise": [
"Reviewer Expertise Exposure to pesticides and health effects"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study used questionnaire-based pesticide exposure data of 20,295 farmers to determine the association between pesticide use and obesity in Thailand. With the large-scale cross-sectional epidemiological data, the study determined that regional obesity in farmers could be associated with pesticide use. The study displayed novelty and value in public health on Thailand regional health. However, I thought there were several questions in this manuscript. Therefore, I thought major revision was necessary. The detailed review points were listed below.\nIn the abstract, the authors declared that they collected the long-term pesticide exposure data. However, I thought the term ‘long-term’ should be considered carefully as the questionnaire did not collect the frequencies of pesticides use (only yes or no). Also, the nature of the cross-sectional study (without follow-up) could poorly support the conclusion.\n\nIn the farmer population, pesticide-attributed obesity may be associated with the living conditions or geographical location of these individuals. Therefore, I thought it would be helpful if the authors provided the related data of these individuals.\n\nMethods: Since there is a great difference between genders on obesity diagnosis, I recommended the authors perform stratified analysis to determine the gender-specific associations.\n\nResults: The authors checked the relations between pesticide exposure and obesity. Is there any interaction between the different pesticides?\n\nResults: The authors should clarify the demographic characteristics in detail.\n\nResults: It will be helpful to display the C-index of each model to validate the reliability.\n\nDiscussion: I noticed that the OR for pesticides is from 1.75 to 8.37, while the OR over 3 may be overestimated and lead to unnecessary panic for public health. I thought the authors should discuss their results more carefully.\n\nDiscussion: I thought the authors should declare the nature of the cross-sectional study and tell the readers that the study was limited in explaining the causality.\n\nDiscussion: The strengthen part only replicates the conclusion.\n\nOne of the most limited parts of this study was the lack of dose or level data of pesticides use, which may cause serious bias. The authors should make a discussion about this.\n\nThe authors should explain the reliability and validity of their questionnaire as there may be information bias that exists with the questionnaire method.\n\nI recommended the authors list the data on body measure index or waist circumstances in Table 1.\n\nWaist circumferences and baseline diseases should be adjusted as covariates.\n\nAccording to the previous literature, there is a great difference between populations in different age groups. Therefore, I thought age-specific associations between pesticides use and obesity should be considered.\n\nAs the authors declared, the limited data on dietary patterns, physical activities, and genetic variants may lead to potential bias. However, I thought the authors should be concerned about whether their adjusted models could explain the variance.\n\nCould the authors list the blood pressure, glucose, triglyceride, and HDL value in the tables? Also, I think adjusting them in the model should be considered.\n\nThe effects of pesticides exposure may have co-exposure patterns, the authors should notice that.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7491",
"date": "02 Feb 2022",
"name": "Chudchawal Juntarawijit",
"role": "Author Response",
"response": "Comment This study used questionnaire-based pesticide exposure data of 20,295 farmers to determine the association between pesticide use and obesity in Thailand. With the large-scale cross-sectional epidemiological data, the study determined that regional obesity in farmers could be associated with pesticide use. The study displayed novelty and value in public health on Thailand regional health. However, I thought there were several questions in this manuscript. Therefore, I thought major revision was necessary. The detailed review points were listed below. Response Thank you very much for your time and effort to review this manuscript and for providing valuable suggestions. Comment 1. In the abstract, the authors declared that they collected the long-term pesticide exposure data. However, I thought the term ‘long-term’ should be considered carefully as the questionnaire did not collect the frequencies of pesticides use (only yes or no). Also, the nature of the cross-sectional study (without follow-up) could poorly support the conclusion. Response The term ‘long-term use’ has been replaced with ‘historical use’. In this study, actually, we also collected data on the frequency and duration of pesticides use and calculated cumulative days of exposure. Unfortunately, there was only a small number of cases with obesity, therefore the association between quartile days of exposure and obesity could not be performed. Comment 2. In the farmer population, pesticide-attributed obesity may be associated with the living conditions or geographical location of these individuals. Therefore, I thought it would be helpful if the authors provided the related data of these individuals. Response In this survey, we collected data from respondents who are farmers living in a rural area of six districts but found obesity cases in five districts (Table 1). For socioeconomic data, only the district location of participants, and their education, and monthly income were collected. However, these factors were not included in the model because of several reasons. For district location, most of the participants were farmers from rural areas. Moreover, the district was closely related to pesticide use and will cause multicollinearity problems, if included in the model (Bhandari, 2020). For income, there was no relationship with obesity in middle-income countries, e.g. Thailand (Ameye and Swinnen, 2019). For education, previous research found a higher risk of obesity to be inversely associated with education (Anyanwu, 2010). However, in this study more obesity was found among those with higher education (Table 1). In addition, when these two variables were included in the model, not many effects on OR were found. For example, for molluscicide, the OR was changed from 2.28 (1.48-3.64) to 2.37 (1.48-3.79) when added education and to 2.39 (1.49-3.83) when added income (Table 2-1). For baseline diseases, most of them should be considered as the so-called ‘downstream outcome’ closely related to obesity and thus, should not be included in the model (DVL, 2020). More demographic information has been added to Table 1. Comment 3. Methods: Since there is a great difference between genders on obesity diagnosis, I recommended the authors perform stratified analysis to determine the gender-specific associations. Response Thank you for bringing up a good point. Though, there is a great difference between genders on obesity diagnosis, the prevalence of obesity between gender was not different (p=0.173) (Table 1). In addition, we already added gender as a covariate in the analysis of the adjusted odds ratio as shown in Table 2 and Table 3. Moreover, the number of subjects with obesity diagnosed was too small to do stratification. Comment 4. Results: The authors checked the relations between pesticide exposure and obesity. Is there any interaction between the different pesticides? Response That is a good point. Yes, we also believed that there might be some interaction between the different pesticides. However, due to limitations on small cases, the problem could not be further investigated. The issue has been added to the discussion section. Comment 5. Results: The authors should clarify the demographic characteristics in detail. Response The results and Table 1 have been revised. Comment 6. Results: It will be helpful to display the C-index of each model to validate the reliability. Response According to Austin and Steyerberg (2012), there are three primary reasons to develop a logistic regression model. The first one is to determine the independent predictors of a binary outcome. The second one is to define the association between a predictive variable and the outcome after adjusting for confounding factors. The third reason is to predict the probability of the occurrence of a binary outcome given a specific vector of covariates. The third reason often occurs in biomedical research, where researchers are interested in predicting the prognosis of individual patients. And the C-statistic is an indicator of assessing the prediction of the logistic regression model. However, the main objective was to find the association between obesity and pesticide exposure. Comment 7. Discussion: I noticed that the OR for pesticides is from 1.75 to 8.37, while the OR over 3 may be overestimated and lead to unnecessary panic for public health. I thought the authors should discuss their results more carefully. Response Yes, we agree with you and the statement ‘Some results were with high OR and wide confidence intervals, and thus should be interpreted with caution.’ has been added to the study limitation section. Comment 8. Discussion: I thought the authors should declare the nature of the cross-sectional study and tell the readers that the study was limited in explaining the causality. Response Thank you for your suggestion. The following statements have been added to the study limitation: ‘There were several limitations to the study that need to be mentioned. By using a cross-sectional design, the study was limited in explaining the causality since both disease and exposure data were examined at the same time.’ Comment 9. Discussion: The strengthen part only replicates the conclusion. Response The statement has been deleted. Comment 10. One of the most limited parts of this study was the lack of dose or level data of pesticides use, which may cause serious bias. The authors should make a discussion about this. Response Pesticide dose is a good marker for short-term pesticide exposure. However, it was costly and may not be suitable for a large survey study. The questionnaire method is probably the best alternative to collect data on long-term pesticide exposure. The method is commonly used in epidemiological studies e.g., Agricultural Health Study in the United State. For studies using a large group of participants, the method has been proved to be useful without any serious bias (Coble et al., 2011) (Hoppin et al., 2002). The limitation on the issue was further discussed as suggested. Comment 11. The authors should explain the reliability and validity of their questionnaire as there may be information bias that exists with the questionnaire method. Response The limitation of questionnaire use was further discussed. As mentioned before, the questionnaire method might be the only option for the study of long-term exposure to pesticides among a large population. Since the technique was used in both case and control groups, information bias if occur might be non-differential. Comment 12. I recommended the authors list the data on body measure index or waist circumstances in Table 1. Response In this study, data on BMI and WC were not collected as most previous studies did. The study was designed to be a descriptive cross-sectional study to explore the prevalence of medical-diagnosed obesity using ICD-10 records and to identify its associated risk factors. The usefulness and limitation of the ICD-10 data were already discussed in the manuscript. Comment 13. Waist circumferences and baseline diseases should be adjusted as covariates. Response As mentioned before, we did not have waist circumference data since the study used a medical diagnosis of obesity (ICD-10), which is also based on BMI and waist circumferences data. For baseline diseases, they should be considered as a so-called ‘downstream outcome’ variable. According to Dan VanLunen (2020), this type of variable should not be used as a covariate. Comment 14. According to the previous literature, there is a great difference between populations in different age groups. Therefore, I thought age-specific associations between pesticides use and obesity should be considered. Response We agree that age-specific association could improve study quality. This study uses a different study design from those in the literature. In this study, we use a descriptive cross-sectional design, whereas, most of the literature uses analytical cross-sectional with a control group. The analytical study might be better in control of confounding variables but not suitable for a large-scale study. In this study, the age-specific association was also not possible because the number of cases with obesity was small. Comment 15. As the authors declared, the limited data on dietary patterns, physical activities, and genetic variants may lead to potential bias. However, I thought the authors should be concerned about whether their adjusted models could explain the variance. Response Yes, we agree. More information has been added to the study limitation as follows: 'Data on other risk factors, such as diet, exercise, or genetics were not collected. These confounding factors might have a different impact on the results. However, the problem may not have much effect on the study results since the case and control groups were from the same community and had the same occupation.' Comment 16. Could the authors list the blood pressure, glucose, triglyceride, and HDL value in the tables? Also, I think adjusting them in the model should be considered. Response As mentioned before, the study was designed as a simple descriptive cross-sectional survey to try to find a prevalence of obesity using ICD-10 data. Among the two types of a cross-sectional study, descriptive and analytical, each one has its own strength and limitations. The descriptive studies, which could be conducted in a large-scale study, are often used for prevalence studies. For the analytical study, a study with a control group, often found in a medical study, and has better control for confounding. Comment 17. The effects of pesticides exposure may have co-exposure patterns, the authors should notice that. Response Thank you for raising this good point. Yes, co-exposure was an interesting issue. However, with the study design and the small number of cases, this study could not evaluate the problem. The issue has been added in the discussion as a study limitation. References Anyanwu, G. E., Ekezie, J., Danborno, B., & Ugochukwu, A. I. (2010). Impact of education on obesity and blood pressure in developing countries: A study on the Ibos of Nigeria. North American journal of medical sciences, 2(7), 320–324. https://doi.org/10.4297/najms.2010.2320 Austin, P.C., and Steyerberg, E.W. (2012). Interpreting the concordance statistic of a logistic regression model: relation to the variance and odds ratio of a continuous explanatory variable. BMC Med Res Methodol 12 (82). https://doi.org/10.1186/1471-2288-12-82 Bhandari A. (2020). What is multicollinearity? Here’s everything you need to know. Analytics Vidhya. Available: Multicollinearity | Detecting Multicollinearity with VIF (analyticsvidhya.com) Coble et al., (2011). An updated algorithm for estimation of pesticide exposure intensity in the agricultural health study, Int. J. Environ. Res. Public Health; 8(12), 4608–4622. doi: 10.3390/ijerph8124608. Dan VanLunen (DVL). (2020). Get a Grip! When to Add Covariates in a Linear Regression. A Guide to Accurately and Precisely Measuring Effects! Available: https://towardsdatascience.com/get-a-grip-when-to-add-covariates-in-a-linear-regression-f6a5a47930e5 Hannah Ameye and Johan Swinnen, (2019). Obesity, income and gender: The changing global relationship, Global Food Security, 23, 267-281. https://doi.org/10.1016/j.gfs.2019.09.003. Hoppin, F. Yucel, M. Dosemeci, and D. P. Sandler, (2002). Accuracy of self-reported pesticide use duration information from licensed pesticide applicators in the Agricultural Health Study, J. Expo. Anal. Environ. Epidemiol.; 12(5), 313–318. doi: 10.1038/sj.jea.7500232."
},
{
"c_id": "7493",
"date": "02 Feb 2022",
"name": "Chudchawal Juntarawijit",
"role": "Author Response",
"response": "Table 2-2 OR after adding more variables to the model. Pesticide: Molluscicide OR (as shown in Table2) 3.36 (2.13-5.31) OR (after add baseline diseases) 3.30 (2.08-5.22) OR (add district location) 2.28 (1.43-3.64) OR (add education) 2.37 (1.48-3.79) OR (add income) 2.39 (1.49-3.83)"
}
]
},
{
"id": "95935",
"date": "15 Oct 2021",
"name": "Yuki Ito",
"expertise": [
"Reviewer Expertise Exposure assessment of pesticides and their association with health effects."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have investigated the relationships of pesticides used by farmers and obesity following the Thailand Ministry of Public Health definitions. They found a positive association between pesticide use and obesity. However, there are major points to be concerned as mentioned below. Also, the paper may benefit from an English language edit.\nAbstract:\nBackground in the Abstract should be specified by demonstrating the relationships between pesticides exposure and obesity.\n\nThe authors should write the objective in the background section, not in the method section.\nBackground:\nThe background should address the rationale of the study.\n\nIn the last line of the first paragraph of the background section, the authors have stated lots of factors associated with obesity. Unfortunately, they cited only one article. More corresponding references should be added in this section.\n\nIn the second paragraph, the authors described the association of PCBs, bisphenols, and one phthalate with obesity. Instead of these descriptions, the authors should cite other epidemiological studies examining the relationship between pesticide exposure and obesity.\n\nAuthors stated that “identifications of individual pesticides to predict the risk of obesity was the main interest”. However, they did not assess the risk of pesticide exposure. They only investigated the observational relationships between the groups of pesticide use and obesity. The last line has no basis to write in this section.\nMethods:\nThe authors should remove the duplicate statement such as, “the major crops in the province are rice, sugar cane, casava and vegetables” from the study settings and design section.\n\nPlease clarify the last two lines of “study participants and sampling procedure”. Define the term exposed and unexposed.\n\nA major concern is the definition of obesity. The authors investigated the relationship between pesticide use and obesity following the definition of the Thailand Ministry of Public Health. However, the definition of obesity is not clear. Based on the author’s statement, it seems like the definition of a metabolic syndrome but not obesity (see the article by Engin, 20171). The authors should clarify it. They can consider BMI, WC, and/or other anthropometric indices of overweight and obesity if data is available.\nResults:\nOut of 20,295, only 78 study participants were obese. The overall prevalence of obesity was very low, although the authors did not calculate prevalence both in males and females.\n\nTables 1 and 2 were not prepared carefully. These two tables should merge and put data in each column and row carefully.\n\nIf possible, please provide all the demographic data (collected by questionnaires), including socio-economic status, education, ethnicity, etc.\n\nFor investigating the OR, they have adjusted the results only by gender, age, smoking, and alcohol consumption. They have no data about diet, physical activity, socioeconomic status or income that may affect the results.\nDiscussion:\nThis section should be written based on results deeply and sharply. They should explain their findings, e.g. why and how by comparing other studies.\n\nAdditionally, this study is only based on questionnaire data and did not monitor the individual exposure levels of pesticides. This is another major limitation of this study.\n\nConclusion:\nThe conclusion should be short and specific based on the results.\n\nThe authors should not use “increased the risk of obesity”.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7492",
"date": "02 Feb 2022",
"name": "Chudchawal Juntarawijit",
"role": "Author Response",
"response": "Comment The authors have investigated the relationships of pesticides used by farmers and obesity following the Thailand Ministry of Public Health definitions. They found a positive association between pesticide use and obesity. However, there are major points to be concerned as mentioned below. Also, the paper may benefit from an English language edit. Response Thank you, we really appreciate your time and effort to review the manuscript. We admitted that this study may be far from perfect. By using a descriptive cross-sectional study, this study has several limitations. As compared to an analytical cross-sectional study, a better study design with a control group is often found in medical studies. With the descriptive design, this study had some limitations and could not be compared with the analytical one. This study lacks data on some confounding variables and relies only on the questionnaire method for pesticide exposure data. However, the results supported the usefulness of ICD-10 data for studying obesity. We hope that the result could be useful as a small piece of information to the relatively rare literature on the association of pesticides and obesity. The English language was edited by Mr. Kevin. Abstract: Comment Background in the Abstract should be specified by demonstrating the relationships between pesticides exposure and obesity. Response Currently, there was not enough evidence demonstrating the relationship between pesticides exposure and obesity. With 250 words as the maximum word count limited by F1000Research, the issue, therefore, was only briefly described here. Comment The authors should write the objective in the background section, not in the method section. Response We agree and the objective has been revised and moved to the background section, as follows: Background: ...The objective of this study was to determine the association between pesticide exposure and obesity among farmers in Nakhon Sawan and Phitsanulok province, Thailand. Methods: This study was a population-based cross-sectional study. Background: Comment The background should address the rationale of the study. Response The main reason why this study is needed was that obesity is an important public health problem and exposure to pesticides might be one of its causes. However, currently, there was only limited evidence. This study was among a few studies trying to investigate the association between obesity and pesticide exposure using a large cross-sectional study design. Comment In the last line of the first paragraph of the background section, the authors have stated lots of factors associated with obesity. Unfortunately, they cited only one article. More corresponding references should be added in this section. Response The reference was a systematic review that mentioned various factors associated with obesity. Comment In the second paragraph, the authors described the association of PCBs, bisphenols, and one phthalate with obesity. Instead of these descriptions, the authors should cite other epidemiological studies examining the relationship between pesticide exposure and obesity. Response In this section, we try to present information on pesticides and obesity. To our knowledge, all of the epidemiological studies on pesticides and obesity were already included. In the last statement, we just want to mention that not only pesticides but also some other compounds, e.g., PCBs, bisphenols, and one phthalate might also cause obesity. To make it clear, the statement has been revised. Comment Authors stated that “identifications of individual pesticides to predict the risk of obesity was the main interest”. However, they did not assess the risk of pesticide exposure. They only investigated the observational relationships between the groups of pesticide use and obesity. The last line has no basis to write in this section. Response To be more precise, the statement “identifications of individual pesticides to predict the risk of obesity was the main interest” has been revised as follows: \"The main interest was to associate obesity to pesticides, either by group or individual chemical.” Methods: Comment The authors should remove the duplicate statement such as, “the major crops in the province are rice, sugar cane, cassava and vegetables” from the study settings and design section. Response Actually, that statement was not duplicated but they described major crops of the two different provinces, Nakhon Sawan and Phitsanulok. Comment Please clarify the last two lines of “study participants and sampling procedure”. Define the term exposed and unexposed. Response Exposed refers to the exposure group or those who used pesticides. Unexposed refers to the unexposed group or those who do not use pesticides. This information has been added to the paper. Comment A major concern is the definition of obesity. The authors investigated the relationship between pesticide use and obesity following the definition of the Thailand Ministry of Public Health. However, the definition of obesity is not clear. Based on the author’s statement, it seems like the definition of a metabolic syndrome but not obesity (see the article by Engin, 20171). The authors should clarify it. They can consider BMI, WC, and/or other anthropometric indices of overweight and obesity if data is available. Response We thank you the reviewer for making a very important point and agreeing to revise our manuscript as we picked up the case with obesity using a diagnosis in ICD-10. We have deleted the statement “In Thailand, the Ministry of Public Health follows the International Diabetes Federation’s definition (2005), which defines obesity as a waist circumference of no more than 90 cm for men and 80 cm for women, plus two out of the following four criteria:..” and replaced with the following, “In Thailand, the Ministry of Public Health follows The World Health Organization obesity criteria for Asia Pacific Region in which body mass index over 25.0 kg/m2 was identified as obesity.\". Results: Comment Out of 20,295, only 78 study participants were obese. The overall prevalence of obesity was very low, although the authors did not calculate prevalence both in males and females. Response Prevalence of obesity was very low since the study use data from ICD-10 records, instead of survey data on BMI or waist circumstance. The issue was already discussed in the manuscript. Comment Tables 1 and 2 were not prepared carefully. These two tables should merge and put data in each column and row carefully. Response The two tables have been merged. An error in the table head has been corrected. Comment If possible, please provide all the demographic data (collected by questionnaires), including socioeconomic status, education, ethnicity, etc. Response In this survey, we collected data from respondents who are farmers living in a rural area of six districts but found obesity cases in five districts (Table 1). For socioeconomic data, only the district location of participants, and their education, and monthly income were collected. However, these factors were not included in the model because of several reasons. For district location, most of the participants were farmers from rural areas, thus there was no reason to believe district location to associate with obesity. Moreover, the district was closely related to pesticide use and will cause multicollinearity problems, if included in the model (Bhandari, 2020). For income, there was no relationship with obesity in middle-income countries, e.g. Thailand (Ameye and Swinnen, 2019). For education, previous research found a higher risk of obesity to be inversely associated with education (Anyanwu, 2010). However, in this study more obesity was found among those with higher education (Table 1). In addition, when these two variables were included in the model, not much effects on OR were found. For example, for molluscicide the OR was changed from 2.28 (1.48-3.64) to 2.37 (1.48-3.79) when added education and to 2.39 (1.49-3.83) when added income (Table 2-1). For baseline diseases, most of them should be considered as the so-called ‘downstream outcome’ closely related to obesity and thus, should not be included in the model (DVL, 2020). More demographic information has been added to Table 1. For ethnicity, in Thailand, we did not have ethnic groups. Comment For investigating the OR, they have adjusted the results only by gender, age, smoking, and alcohol consumption. They have no data about diet, physical activity, socioeconomic status or income that may affect the results. Response Yes, we agree that that information on diet and physical activity would be useful and should be used for the adjustment. It is a study limitation and the issue was already discussed in the study limitation. The problem should not seriously affect study results since all of the participants were farmers from rural areas. For data on socioeconomic, actually, we also collected data on district location, education, and monthly income. However, these factors were not included in the model because of several reasons. For district location, most of the participants were farmers from rural areas, thus there was no reason to believe district location to associate with obesity. However, the district was closely related to pesticide use and caused a multicollinearity problem, therefore, it was not be included in the model (Bhandari, 2020). For education and income, previous research found a higher risk of obesity to inversely associate with education (Anyanwu, 2010). For income, there was no relationship with obesity in middle-income countries, e.g. Thailand (Ameye and Swinnen, 2019). When the model included these two variables, the OR was not much changed. For example, for Molluscicide the OR was changed from 2.28 (1.48-3.64) to 2.37 (1.48-3.79) when added education and to 2.39 (1.49-3.83) when added income (Table 2-1). For baseline diseases, most of them should be considered as the so called ‘downstream outcome’ closely related to obesity but not confounding and thus, should not be included in the model as well (DVL, 2020). Discussion: Comment This section should be written based on results deeply and sharply. They should explain their findings, e.g. why and how by comparing other studies. Response Thank you for the suggestion. We agree and try to comply with your suggestion as much as we can. Comment Additionally, this study is only based on questionnaire data and did not monitor the individual exposure levels of pesticides. This is another major limitation of this study. Response For a large study of long-term effects of pesticides, a questionnaire might be the only option. Since pesticide dose is a good marker for short-term pesticide exposure. However, it was costly and may not be suitable for a large survey study. The questionnaire method is probably the best alternative to collect data on long-term pesticide exposure. The method is commonly used in epidemiological studies e.g., Agricultural Health Study in the United State. For studies using a large group of participants, the method has been proved to be useful without any serious bias (Coble et al., 2011) (Hoppin et al., 2002). The limitation was further discussed as suggested. Conclusion: Comment The conclusion should be short and specific based on the results. Response Thank you for the suggestion. We agree and try to comply with your suggestion as much as we can. Comment The authors should not use “increased the risk of obesity”. Response The statement has been changed to “The study additionally found exposure to 24 individual pesticides was significantly associated with obesity.\" References Anyanwu, G. E., Ekezie, J., Danborno, B., & Ugochukwu, A. I. (2010). Impact of education on obesity and blood pressure in developing countries: A study on the Ibos of Nigeria. North American Journal of Medical Sciences, 2(7), 320–324. https://doi.org/10.4297/najms.2010.2320 Bhandari A. (2020). What is multicollinearity? Here’s everything you need to know. Analytics Vidhya. Available: Multicollinearity | Detecting Multicollinearity with VIF (analyticsvidhya.com) Coble et al., (2011). An updated algorithm for estimation of pesticide exposure intensity in the agricultural health study, Int. J. Environ. Res. Public Health; 8(12), 4608–4622. doi: 10.3390/ijerph8124608. Hannah Ameye and Johan Swinnen, (2019). Obesity, income and gender: The changing global relationship, Global Food Security, 23, 267-281. https://doi.org/10.1016/j.gfs.2019.09.003. Hoppin, F. Yucel, M. Dosemeci, and D. P. Sandler, (2002). Accuracy of self-reported pesticide use duration information from licensed pesticide applicators in the Agricultural Health Study, J. Expo. Anal. Environ. Epidemiol.; 12(5), 313–318. doi: 10.1038/sj.jea.7500232. Table 2-1 Odds ratio when more variables were added to the model. Pesticide: Molluscicide OR (in the table 2) 3.36 (2.13-5.31) OR (when add baseline disease) 3.30 (2.08-5.22) OR (add district location) 2.28 (1.43-3.64) OR (add education) 2.37 (1.48-3.79) OR (add income) 2.39 (1.49-3.83)"
}
]
}
] | 1
|
https://f1000research.com/articles/10-445
|
https://f1000research.com/articles/11-533/v1
|
17 May 22
|
{
"type": "Research Article",
"title": "Title-comparison of coronally advanced flap with chorion membrane vs coronally advanced flap with connective tissue graft in the treatment of multiple gingival recessions: a split-mouth randomised controlled study",
"authors": [
"Sweta Pradhan",
"Neetha Shetty",
"Deepa Kamath",
"Sweta Pradhan",
"Deepa Kamath"
],
"abstract": "Background: The importance of esthetics has escalated over the years. The purpose of any perioplastic surgery is to address gingival recession while ensuring predictable root coverage and a pleasing appearance. An array of surgical procedures have been recommended for the management of recession defects. The present study compares the clinical and patient related outcome measures of coronally advanced flap with chorion membrane and connective tissue graft in the management of multiple adjacent gingival recessions. Methods: The study was a prospective randomized controlled trial which included eight systemically healthy patients with an age range of 30-44 years with 36 labial/buccal, multiple adjacent, Cairo’s RT1 gingival recession defects, bilaterally. CAF+CM was performed on one side whereas CAF+CTG was performed on the other side. The two groups were compared clinically at three and six months postoperatively. Results: There was statistically significant decrease in recession depth, recession width, probing depth and clinical attachment level in both the groups from baseline to three and six months. However, intergroup comparisons revealed no statistically significant difference. At six months, both groups showed statistically significant improvements in keratinized tissue width and gingival thickness. The gingival thickness of the CAF+CM group increased significantly at three and six months. In terms of root coverage aesthetic score (RES), there was no significant difference observed between the two groups. In terms of patient reported outcome measures (PROMS), patients preferred the CAF+CM technique. Conclusion: Within the limits of the current study, the use of chorion membrane resulted in considerable root coverage and increased gingival thickness. Periodontal regeneration can be facilitated by the distinctive features of the chorion membrane. Coronally advanced flap plus chorion membrane is a novel approach for root coverage procedures.",
"keywords": [
"Chorion Membrane",
"Coronally advanced flap",
"Esthetics",
"Gingival recession",
"Perio-plastic surgery."
],
"content": "Introduction\n\nAn attractive smile contributes significantly to esthetics as well as self-confidence and health. An ideal smile should be determined by the anatomical relationship between the teeth, the periodontium, and the surrounding oral tissues. When any of these components are out of harmony, the result is a smile that is perceived as unattractive.1 Periodontal disease alters the relationship between teeth and gingiva. Treatment for periodontal disease for centuries has been focused more on preserving and restoring periodontal health than achieving aesthetically pleasing result.2\n\nGingival recession describes the migration of the marginal gingiva beyond cementoenamel junction.3,4 Aesthetic considerations, dentinal hypersensitivity, root caries prevention, and cervical abrasions are the primary indications for root coverage procedures.5 This condition often negatively impacts aesthetics when it occurs in the anterior regions. Therefore, many patients seek cosmetic correction in order to meet their aesthetic and functional demands, which remains a major therapeutic challenge.6,7 The coronally advanced flap, double papilla rotating flap, laterally moved flap, subepithelial connective tissue graft, free gingival graft and their variants were proposed for the management of recession in the last 60 years.7,8 Some authors have coupled allografts such as acellular dermal matrix,9 collagen matrix,10 and platelet concentrates such as Platelet rich fibrin and plasma11 with some of the above stated procedures, particularly the coronally advanced flap approach. Every technique has its own indications, contraindications, advantages, and disadvantages. The management of recession defects has been the subject of numerous systematic reviews and meta-analyses. Coronally advanced flap with connective tissue grafts have been proved to be the gold standard for addressing multiple gingival recession defects in many studies.12,13 But this approach is associated with several major drawbacks such as: the addition of another surgical site to obtain an autologous soft tissue graft, presence of vertical incisions, which can create discomfort and delayed healing for patients.\n\nRecent literature documents the use of newer materials like the Placental Membranes such as the chorion membrane.14 Chorion membranes are placental allografts that emerge as a versatile and novel material. These allografts hold antimicrobial and antibacterial properties and are immunomodulatory. They have special biological features that aid wound healing and regeneration.15,16 According to studies, fresh chorion has a higher load of growth factors and cytokines.15 Since decades, placental membranes have been used for various medical purposes. Currently, these membranes are used in root coverage procedures.\n\nThe reticular layer, basement membrane, and trophoblast layer are the three layers of the chorion membrane. Collagen fibres, fibronectin, proteoglycans, and laminin make up the extracellular matrix of the chorion membrane. Collagen Types I, III, IV,V, VI are present and are well tolerated with inherent haemostatic properties, as well as being bioabsorbable, allowing epithelial cells and surrounding autogenous connective tissue to migrate.17,18 Fibronectin is vital for tissue repair, blood coagulation, cell migration, and adhesion.19 Cell proliferation, cell-to-cell adhesion, cell expansion, and cell differentiation is promoted by laminin.20\n\nIn light of these biologic properties, we hypothesized that coronally advanced flap with Chorion membrane would be effective in management of multiple gingival recession defects.\n\nThe aim of the study is to compare and evaluate the clinical and patient related outcomes of coronally advanced flap plus chorion membrane and coronally advanced flap plus connective tissue graft in the management of multiple gingival recession defects.\n\n\nMethods\n\nThe clinical and patient-related outcome measures of coronally advanced flap utilising chorion membrane (CAF+CM) as the test site and coronally advanced flap using connective tissue graft as the control site (CAF+CTG) are compared in this prospective, randomised, comparative split mouth study. Over the course of six months, this clinical trial was conducted. This study protocol was approved by the Research Ethics Committee of MCODS, Mangalore (Ref no-19088) and registered with the Clinical Trial Registry of India (CTRI No- 039332). Before enrolment, all participants signed written informed consent forms. All procedures were conducted in compliance with the Helsinki Declaration 1975.\n\nStudy subjects\n\nEight study participants were chosen from the outpatient department of Periodontics at Manipal College of Dental Sciences Mangalore, MAHE University, Karnataka, India.\n\nSample size calculation\n\nUsing the above formula, the sample size was calculated.\n\nWhere Z (1-α/2) = Z score for the α error chosen.\n\nZ (1-β) = Z score for the power chosen.\n\nσ = average standard deviation. d = the minimum difference between in the values with which make clinically relevant impact.\n\nBased on the study by Lafzi et al,21 the study contained an eight-patient sample size with 80 percent power and a clinically significant difference of 0.9 units.\n\nRandomization\n\nThe investigator (DK) was in charge of enrolling participants and allocating surgical procedures. The coin toss approach was used for randomization. The lead investigator (SP) performed all surgical operations. A masked investigator (NS) assessed the patients during the recall period and was blinded to all the surgical treatments that had been assigned.\n\n\n\n1. Patients who had signed the informed consent and were willing to be a part of the study.\n\n2. Patients with age range of 20-50 years.\n\n3. Patients fulfilling Cairo classification22 of Recession Type 1 (RT1) involving any two teeth on either side of the midline extending from central incisors to the premolars in either maxilla or mandible.\n\n4. Full mouth Plaque score less than one\n\n5. Full mouth Mombelli’s sulcular bleeding score less than 20%\n\n6. Cervical abrasion with or without restorations.\n\n\n\n1. Compromised systemic illness\n\n2. Pregnancy\n\n3. History of root coverage\n\n4. Need for antibiotic prophylaxis\n\n5. Patients with habit of smoking.\n\n6. Teeth with buccal and lingual inclinations.\n\n7. Patients with fixed orthodontic appliances.\n\nEight patients had been assessed for eligibility and allocated to interventions. As it is a split mouth study, both the interventions were done on the same patient. On one side, CAF+CHORION MEMBRANE (Test Group) was done whereas CAF+CTG (control group) was done on the other side. After 4 weeks of the first intervention on one side, patient was recalled for the second intervention on the other side.\n\nClinical measurements were taken at baseline, three and six months after surgery. The measurements were\n\n\n\n1. Plaque Index by Sillness and Loe (1964)23\n\n2. Modified sulcular bleeding index by Mombelli et al (1987)24\n\n3. Recession Depth (RD)\n\n4. Recession Width (RW)\n\n5. Probing Depth (PD)\n\n6. Clinical attachment level (CAL)\n\n7. Width of the Keratinized Tissue (WKT)\n\n8. Gingival Thickness (GT)\n\n9. Root coverage esthetics score (RES)\n\nMean and complete root coverage percentages were determined after six months.\n\n10. Patient Reported Outcome Measures (PROMS)\n\nThe baseline pre-operative Clinical measurements were shown in Figures 1A, 1B and 2A, 2B.\n\nFor all the patients, a complete medical and dental history, periodontal assessment using clinical parameters, radiographs, and clinical pictures were taken. Initial treatment included instructions for oral hygiene maintenance and full mouth prophylaxis. Buccal prominences, as well as trauma from occlusion, were treated with coronoplasty. To curtail tooth brushing trauma, patients with recession type defects were advised to use a modified Stillman Brushing technique. All research participants were advised to rinse for one minute with 0.2 percent Chlorhexidine gluconate, prior to the surgery. The surgical procedure was done under complete asepsis and infection control protocols. The baseline clinical pictures are presented in Figures 1 (A, B) and 2 (A, B).\n\nSurgical preparation\n\nThe surgical technique adopted in this study was the envelope coronally advanced flap put forward by Zucchelli and De Sanctis (2000).25\n\nLocal Anaesthesia (2% lidocaine with 1:80000 epinephrine) was administered. The exposed root surfaces were planned with curettes. This was done to eliminate any debris, calculus, soft tooth structures or undercuts. The root surfaces were irrigated with saline solution after instrumentation to remove any detached fragments from the defect site and operative field. Horizontal incisions at the level of the cementoenamel junction (CEJ) were made, followed by sulcular incisions in the buccal aspect of the affected teeth with a No 15 BP blade. The split-full-split flap technique was performed. The papilla was deepithelialized in the interdental area. The flap was reflected in full thickness apical to the gingival margin to allow the periosteum to cover the avascular root surfaces. To assist the coronal repositioning of the flap, it was elevated partially beyond the mucogingival junction (Figures 1C, 2C).\n\nTest group (CAF+CM)\n\nApproximately five to ten minutes prior to surgery, the chorion membrane was removed from the cryo-box container according to the manufacturer’s protocol. The cryopreserved chorion membrane was cut according to the recipient site size before being transplanted as shown is Figure 1 (D, E).\n\nControl group (CAF+CTG)\n\nHarvesting of the connective tissue graft26\n\nPalatal infiltration was administered with 2% lidocaine with 1:80000 epinephrine. In the palate, a horizontal partial thickness incision 3-5mm apical to gingival margin was performed. Vertical releasing incisions were made mesiodistally, roughly corresponding to the length and width of the required graft. An initial partial thickness flap was raised parallel to the palatal gingiva in the centre of the palate. The connective tissue graft underneath was visible. The blade contacted the bone during the secondary incision. The connective tissue graft was reflected with a tiny periosteal elevator or Kirkland knife. After harvesting the connective tissue graft, interrupted sutures were used to approximate the flap (Figure 2D, E).\n\nPlacement of CTG\n\nA no.15 BP blade was used to trim CTG according to the required size. In the recipient site, after reflecting the split-full-split flap, CTG was placed at the defect area and stabilised as shown in Figure 2F.\n\nThe reflected flap was advanced coronally and sutured over the papilla that had been de-epithelialized. Sling sutures with 5-0 non-resorbable sutures were used to stabilise the flap without causing any tension as presented in Figure 1F and Figure 2I. At the defect site, a periodontal pack was applied.\n\nTo avoid post-surgical infections, all patients were given Cap Amoxicillin 500 mg thrice daily and Tab Lyser-D twice daily for 5 days. For two weeks, all the patients were told to use 10 mL Chlorhexidine Mouth Rinse (0.2%) twice a day. All the patients were instructed to maintain good oral hygiene and abstained from brushing their teeth in the operative field for a period of 14 days. Two weeks following surgery, the sutures and periodontal pack were removed. All the patients were recalled after 7, 14, 25, and then once a month for the next six months. De-plaquing was carried out for all the patients at follow up visits.\n\nThe post-operative clinical pictures of = were presented in Figures 1 (G, H, I) and 2 (J, K, L).\n\nStatistical analysis was implemented on the data gathered at baseline, three and six months. Recession depth (RD), Recession width (RW), and Clinical Attachment Level (CAL) were the primary outcome variables, while the rest were secondary. SPSS Version 20.0, a commercially accessible programme, was used to conduct the statistical analysis. For each parameter, the mean+SD for the clinical variables was determined. For intragroup comparisons, the paired t-test was utilised. Independent t-test was applied for intergroup comparisons.\n\n\nResults\n\nEight systemically healthy patients with labial/buccal, multiple adjacent, maxillary, or mandibular Cairo’s RT1 gingival recession defects, bilaterally, with a mean age of 35.88 year (mean age range: 30-44 years) were assessed and randomly assigned as shown in Table 1. There were 36 recession defects addressed in total, with 18 defects each in both test and control group. No statistically significant differences were observed between the CAF+CM group and CAF+CTG group in presurgical/baseline parameters.\n\nThere were no dropouts in the study. No adverse effects were observed for the duration of the study. All patients experienced uneventful healing.\n\nAt baseline, three and six months, the patient’s mean PI were 0.86±0.05, 0.75±0.12, 0.83±0.05 respectively. The patient’s mean mBI were 19.3±0.75, 18.65±0.97 and 18.85±0.88 at baseline, three months, and six months respectively. As indicated in Table 2, plaque and bleeding scores decreased from baseline to three months and six months.\n\nThe baseline RD in the CAF+CM group was 2.72±0.67. At three months, the recession depth reduced to 0.72±0.73 and at six months, it was 0.78±0.73. In the other group i.e., CAF+CTG, the mean values at baseline, three and six months were 2.67±0.84, 0.44±0.62 and 0.5±0.62 respectively. The RW at baseline, three and six months in the CAF+CM group were 3.11±0.76, 1.39±1.24 and 1.44±1.25 respectively. In CAF+CTG group, the RW at baseline was 3.17±0.51. The RW reduced to 0.61±0.923 at three months and 0.72±0.96 at six months. The Probing depth at baseline was 2.72±0.46 in CAF+CM group. At three months and six months, it reduced to 2.25±0.49 and 2.33±0.49 respectively. In the CAF+CTG group, the baseline PD was 2.67±0.49 and at three and six months was 2.33±0.49. The CAF+CM group showed mean CAL of 5±0 at baseline, 3.03±0.87 and 3.11±0.83 at three and six months. CAF+CTG group exhibited CAL of 5.33±1.08 at baseline and at three and six months, 2.78±0.94 and 2.72±0.89 respectively. The mean WKT in the chorion membrane group at baseline was 3.18± 0.64 and at three and six months, the mean WKT increased to 4.35±0.49. In the connective tissue graft group, the WKT was 3.17±0.86 at baseline and at three and six months, the WKT was 4.17±0.86. The Gingival thickness (GT) was 1.56±0.57 at baseline in the CAF+CM group. There was significant increase of 1.56 at six months while in CAF+CTG, the baseline GT was 1.53±0.44. At three months, it was 2.5±0.51. There was increase of 0.006 ±0.16 at six months. The root coverage percentage achieved at the end of six months in the chorion membrane plus CAF group was 73.7% and, in CAF + CTG group was 84.1%. The root coverage esthetics score at six months for the chorion membrane group plus CAF was 8.5±1.6 and for CTG group was 9.25±1.39. Tables 3, 4 and 5 indicate the mean changes in the study variables at all the three time points.\n\n* p=0.05.\n\n* p=0.05.\n\n\nDiscussion\n\nThis is the only study that we are aware of that compares both clinical and patient-related outcome measures of coronally advanced flap with connective tissue graft and chorion membrane. In the present study, we used the Zucchelli’s (2000) technique of CAF,25 i.e., without vertical incisions to get good aesthetical outcomes. Hofmanner et al27 published a systematic evaluation on predictability of root coverage procedures. The root coverage acquired with CAF without vertical releasing incisions was found to be steady over a five-year period, according to the systematic review’s findings. Graziani et al.28 published a comprehensive review and meta- analysis, stated that there is no “one perfect surgical method” for treating multiple gingival recession defects. The evidence states that usage of a graft or modification of flap design, may improve the clinical results of root coverage. Therefore, a plethora of regenerative procedures were combined with coronally positioned flap techniques to enhance the predictability.\n\nAccording to the recent literature, the gold standard technique is coronally advanced flap with subepithelial connective tissue graft.12 The drawback with this is the procurement of CTG which requires an additional surgical site and many a times, there is limited availability of the graft which hinders the treatment. To bypass the need of another surgical site and ensure sufficient graft availability and increase patient acceptance, a wide array of graft biomaterials such as chorion membranes have been described in the literature, as a suitable alternative to CTG. There are very few studies that have assessed the efficacy of chorion membrane for root coverage. The direct comparison between Zucchelli’s technique25 of coronally positioned flap using chorion membrane or connective tissue graft have been subjected to limited investigation. There are inconsistent data available based on the esthetic and the patient related outcome measure, therefore further investigations comparing these two techniques are needed.\n\nThus, the split mouth randomized clinical study consisting of eight systemically healthy patients was attempted to compare and evaluate the clinical and patient related outcome measures of coronally advanced flap without vertical releasing incisions (CAF) by using CTG and/or CM in the management of Cairo’s RT1 multiple gingival recessions. The present study was accomplished in six months. There were no significant difference observed in terms of the clinical parameters at baseline between the two groups. The results revealed that both biomaterials were extremely effective at obtaining root coverage.\n\nThe mean Plaque Index (PI)23 and Mombelli’s Sulcular Bleeding Index (BI)24 scores were < 1 and <20% respectively throughout the study period. This is because the patient maintained their oral hygiene throughout the study period along with periodic recall for professional oral prophylaxis at one, three and six months. From baseline to three and six months, there was a decrease in the Plaque and Bleeding Index. These findings can be substantiated by the fact that since the patients included in this study had a good degree of oral hygiene but with gingival recession, implying that these patients used to employ incorrect brushing techniques. This is in agreement with the findings of Tezel29 and Oliveira et al30 who stated that faulty tooth brushing with medium bristle toothbrush leads to periodontal attachment loss and eventually leads to gingival recession.\n\nThere were insignificant differences among the two groups when comparing the mean values of recession depth at all the three time points. When the disparities between both the groups are compared from baseline to three months and three-six months, the control group’s mean value is higher by 0.22, although the difference is statistically insignificant (p value=0.227). In a study by Lafzi et al,21 which is similar to the current investigation, the values from baseline to three months revealed substantial results. However, in our trial, the baseline RD was lower compared to the previous study. According to Huang et al31 variations in recession depth following a coronally positioned flap procedure are linked to the baseline depth of recession defect. At baseline, the mean recession width in the CAF+CM group was 3.11±0.76 with mean recession widths of 1.39±1.24 and 1.44±1.25 at three and six months respectively. These findings are consistent with Sharma et al32 study, in which the author analysed for six, 12, and 36 months and found a significant difference. Other studies previously mentioned such as in Chakraborty et al study33 reported similar findings. The differences among the groups in terms of probing depth at baseline, three and six months were found to be statistically insignificant. The current study’s findings were similar to those of Gupta et al study.14 In both the groups, the clinical attachment level increased approximately by two mm. No significant variations in CAL were identified between both the groups at three and six months. The gain in CAL can be interpreted as some form of root surface attachment. On comparing the mean width of the keratinised tissue (WKT) at three and six months, the mean WKT of the CAF+CM was higher with a difference of 0.22 but was statistically insignificant. The difference in keratinized tissue width observed by histochemical and visual methods at 3 and 6 months, according to Lafzi et al21 study were also found to be insignificant. When the mean gingival thickness (GT) of both the groups were compared at three and six months, the CAF+CM group’s mean GT was greater, with a difference of 0.61 and 0.55 respectively and the findings were significant statistically when compared with the baseline values. These findings are supported by several studies and case studies. Ghahroudi et al. (2013)34 in a study and Aravind S (2015)35 in a case report have observed increase in width of the keratinized tissue and thickness with amniotic membrane when compared to CTG. It might be because of the presence of keratinocyte growth factor which is released from the amnion-chorion membrane and that helps the mucogingival junction retain its position by promoting keratinization of the epithelial cells.34 The percentage of root coverage attained at six months was 73.7% and 84.1% in CAF+CM and CAF+CTG groups respectively. The connective tissue group revealed slightly more percentage of root coverage than the chorion membrane group, but the difference was statistically not significant. The Root coverage esthetic score (RES) in the present study for CAF+CM group was 8.5±1.6 and for CAF+CTG group was 9.25±1.39. No significant differences on mean RES were observed on comparing both the groups (Pvalue-0.17). The high esthetic scores in both the groups can be attributed to several factors. First, there were no releasing incisions given, which preserves the blood supply of the flap. The preservation of papillary integrity aids in more aesthetically pleasing wound healing. Second, using chorion membrane and connective tissue grafts allows for better colour and texture matching with the surrounding area. Third, using microsurgical instruments allows for precise manipulation of soft tissue and suturing, which improves primary wound closure and stability.\n\nPatient reported outcome measures (PROMS) were evaluated in this study using a questionnaire and visual analogue scale to evaluate dentinal hypersensitivity, esthetic outcomes, and other comorbidities such as post-operative pain, bleeding etc. PROMs were included as one of the defining parameters in our study, which is in line with the recent consensus and systematic review published by American Academy of Periodontology and Cairo.36,37 The results obtained reveal considerable difference between the two treatment modalities, with coronally advanced flap plus chorion membrane being the favoured surgical procedure among the patients. This is mostly owing to the creation of another surgical site in the connective tissue group, which in some cases resulted in post-operative pain. There were no adverse reactions during the study. The chorion membrane’s self-adhesiveness is a bonus feature. This biologic membrane binds to the tissues when it comes into contact with them, eliminating the need for additional suturing and simplifying the treatment procedure. In our study, with the use of Chorion membrane with CAF elevated the patient satisfaction with a good color match, soft tissue texture and root coverage.\n\nThe present study has a few limitations. The sample size taken was small and the follow-up period was also short. Short-term analyses, such as the one used in this study, cannot determine the stability of root coverage. However, more studies on histological evaluation of chorion membrane should be focussed to assess regeneration of the periodontal tissues.\n\n\nConclusions\n\nThe following conclusions were drawn from analysis of the results and limitations of the present study:\n\n• In this study, both treatment groups demonstrated significant improvements in root coverage. When comparing the gold standard method CTG and Chorion membrane with coronally advanced flap, no significant differences were observed. Hence, supporting the use of Chorion membrane for the management of multiple adjacent recession defects.\n\n• When compared to CAF+CTG group, the CAF + Chorion membrane demonstrated a substantial increase in gingival thickness. This is mostly due to the chorion membrane’s distinctive characteristics and its delayed resorption rate. It can hold its physical form up to 4 weeks. This ensures that the chorion membrane leads to periodontal regeneration if they can retain their form till 4 weeks.\n\n\n\n• Further studies should be done in future to explore the effectiveness of Chorion membrane in root coverage procedures with the help of surgical microscope. This may result in complete root coverage due to enhanced precision and manipulation of the tissues under magnification.\n\n• Computerized image analysis should also be explored to better understand the clinical outcomes of root coverage.\n\n\nData availability\n\nFigshare: Underlying data for “Comparison of coronally advanced flap with chorion membrane vs coronally advanced flap with connective tissue graft in the treatment of multiple gingival recessions: A split mouth study”. DOI: https://doi.org/10.6084/m9.figshare.19401410.v538\n\nThis project contains the underlying following data:\n\n• Data file 1: Master Chart for both the group.xlsx (Table containing the raw data of the study)\n\n• Data file 2: Master chart for Plaque and Bleeding Index.xlsx\n\n• Data file 3: Demographic data.xlsx\n\n• Data file 4: Percentage of root coverage calculation.xlsx\n\n• Data file 5: Sample size calculation formula\n\n• Data file 6: Statistical analysis\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nFigshare: Extended data for “Comparison of coronally advanced flap with chorion membrane vs coronally advanced flap with connective tissue graft in the treatment of multiple gingival recessions: A split mouth study”. DOI: https://doi.org/10.6084/m9.figshare.19402178.v339\n\n• This project contains the following data\n\n• Case Performa\n\n• Questionnaire\n\n• Informed consent form in three languages (English, Kannada and Malayalam)\n\n• Ethical Committee Approval letter\n\n• Clinical Trial Protocol\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReporting guidelines\n\nFigshare: CONSORT check list and flow chart for “Comparison of coronally advanced flap with chorion membrane vs coronally advanced flap with connective tissue graft in the treatment of multiple gingival recessions: A split mouth study”. DOI: https://doi.org/10.6084/m9.figshare.19401587.v340\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAuthors’ contribution\n\nAll the authors have equal contribution to this research in manuscript preparation, data collection and interpretation.\n\n\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThe author(s) declared that no grants were involved in supporting this work.",
"appendix": "Acknowledgements\n\nThe authors would like to express their gratitude to the Manipal College of Dental Sciences, Mangalore for all the help and support.\n\n\nReferences\n\nCairo F, Graziani F, Franchi L, et al.: Periodontal plastic surgery to improve aesthetics in patients with altered passive eruption/gummy smile: A case series study. Int. J. Dent. 2012; 2012: 1–6. PubMed Abstract | Publisher Full Text\n\nSawai ML, Kohad RM, Bherwani C, et al.: An evaluation of a periodontal plastic surgical procedure for the reconstruction of interdental papillae in maxillary anterior region: A clinical study. J. Indian Soc. Periodontol. 2012; 16(4): 533–538. PubMed Abstract | Publisher Full Text\n\nWennström JL: Mucogingival Therapy. Mucogingival Therapy. 1996; 1(1): 671–701. Publisher Full Text\n\nCohen RE: Glossary of periodontal terms. The American Academy of. Periodontology. 2001.\n\nKassab MM, Cohen RE: The etiology and prevalence of gingival recession. J. Am. Dent. Assoc. 2003; 134: 220–225. Publisher Full Text\n\nRavipudi S, Appukuttan D, Prakash PSG, et al.: Gingival Recession: Short Literature Review on Etiology. Classifications and Various Treatment Options. 2017; 9(2): 215–220.\n\nNelson SW: The Subpedicle Connective Tissue Graft Coverage of Denuded A Bilaminar Reconstructive Procedure for the.1986; (April): 95–102.\n\nShkreta M, Atanasovska-stojanovska A, Dollaku B, Belazelkoska Z: Exploring the Gingival Recession Surgical Treatment Modalities: A Literature Review.2018; 6(4): 698–708.\n\nWoodyard JG, Greenwell H, Hill M, et al.: The clinical effect of acellular dermal matrix on gingival thickness and root coverage compared to coronally positioned flap alone. J. Periodontol. 2004 Jan; 75(1): 44–56. PubMed Abstract | Publisher Full Text\n\nRoccuzzo M, Lungo M, Corrente G, et al.: Comparative Study of a Bioresorbable and a Non-Resorbable Membrane in the Treatment of Human Buccal Gingival Recessions. J. Periodontol. 1996; 67: 7–14. PubMed Abstract | Publisher Full Text\n\nBashutski JDWH: Role of platelet-rich plasma in soft tissue root-coverage procedures: a review. Quintessence Int. 2008 Jun; 39(6): 473–483. PubMed Abstract\n\nChambrone L, Chambrone D, Pustiglioni FE, et al.: Can subepithelial connective tissue grafts be considered the gold standard procedure in the treatment of Miller Class I and II recession-type defects?. J. Dent. 2008; 36(9): 659–671. PubMed Abstract | Publisher Full Text\n\nChambrone L, Tatakis DN: Periodontal Soft Tissue Root Coverage Procedures: A Systematic Review From the AAP Regeneration Workshop.2015; 5(2).\n\nGupta A, Kedige SD, Jain K: Amnion and Chorion Membranes: Potential Stem Cell Reservoir with Wide Applications in Periodontics. Int. J. Biomater. 2015; 2015: 1–9. PubMed Abstract | Publisher Full Text\n\nGeorge AK, Dalvi YB, Balram B, et al.: Amnion and Chorion Membranes for Root Coverage Procedures: An in vitro Evaluation of its Physical Characteristics. Periodontics Prosthodont. 2018; 04(02): 12–16. Publisher Full Text\n\nChen EHE, Tofe AJA: A Literature Review of the Safety and Biocompatibility of Amnion Tissue. J. Implant. Adv. Clin. Dent. 2010.\n\nNiknejad H, Peirovi H, Jorjani M, et al.: Properties of the amniotic membrane for potential use in tissue engineering. Eur. Cell. Mater. 2008 Apr; 15: 88–99. PubMed Abstract | Publisher Full Text\n\nSteinberg AD, LeBreton G, Willey R, et al.: Extravascular Clot Formation and Platelet Activation on Variously Treated Root Surfaces. J. Periodontol. 1986 Aug 1; 57(8): 516–522. PubMed Abstract | Publisher Full Text\n\nRuoslahti E: Fibronectin And Its Receptors. Annu. Rev. Biochem. 1988; 57: 375–413. Publisher Full Text\n\nAumailley M, Smyth N: The role of laminins in basement membrane function. J. Anat. 1998; 193: 1–21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLafzi A, Abolfazli N, Faramarzi M, et al.: Clinical comparison of coronally-advanced flap plus amniotic membrane or subepithelial connective tissue in the treatment of Miller’s class I and II gingival recessions: A split-mouth study. J. Dent. Res. Dent. Clin. Dent. Prospects. 2016; 10(3): 162–168. PubMed Abstract | Publisher Full Text\n\nCairo F, Nieri M, Cincinelli S, Mervelt J, The PU: The interproximal clinical attachment level to classify gingival recessions and predict root coverage outcomes: an explorative and reliability study.2011; 661–6.\n\nLöe H: The gingival index, the plaque index and the retention index systems. J. Periodontol. 1967 Nov-Dec; 38(38): 610–616. Publisher Full Text\n\nMombelli A, van Oosten MA , Schurch E Jr, et al.: The microbiota associated with successful or failing osseointegrated titanium implants. Oral Microbiol. Immunol. 1987; 2(2): 145–151. Publisher Full Text\n\nZucchelli GDSM: Treatment of multiple recession-type defects in patients with esthetic demands. J. Periodontol. 2000 sep; 71(9): 1506–1514. PubMed Abstract | Publisher Full Text\n\nEdel A: Clinical evaluation of free connective tissue grafts used to increase the width of keratinised gingiva. J. Clin. Periodontol. 1974; 1: 185–196. PubMed Abstract | Publisher Full Text\n\nHofmänner P, Alessandri R, Laugisch O, et al.: Predictability of surgical techniques used for coverage of multiple adjacent gingival recessions-A systematic review. Quintessence Int. 2012 Jul-Aug; 43: 545–554. PubMed Abstract\n\nGraziani F, Gennai S, Roldán S, et al.: Efficacy of periodontal plastic procedures in the treatment of multiple gingival recessions. J. Clin. Periodontol. 2014; 41: S63–S76. PubMed Abstract | Publisher Full Text\n\nTezel A, Canakçi V, Ciçek YDT: Evaluation of gingival recession in left- and right-handed adults. Int. J. Neurosci. 2001; 110(3–4): 135–146. PubMed Abstract | Publisher Full Text\n\nDouglas de Oliveira DW, Oliveira-Ferreira F, Flecha OD, et al.: Is Surgical Root Coverage Effective for the Treatment of Cervical Dentin Hypersensitivity? A Systematic Review. J. Periodontol. 2013; 84: 295–306. PubMed Abstract | Publisher Full Text\n\nCheng GL, Fu E, Tu YK, et al.: Root coverage by coronally advanced flap with connective tissue graft and/or enamel matrix derivative: A meta-analysis. J. Periodontal Res. 2015; 50(2): 220–230. Publisher Full Text\n\nReport CC: Long-term Clinical Evaluation of Coronally Advanced Flap with Chorion Membrane for the Treatment of Multiple Adjacent Gingival Recession Defects.2020.\n\nChakraborthy S, Sambashivaiah S, Kulal R, et al.: Amnion and chorion allografts in combination with coronally advanced flap in the treatment of gingival recession: A clinical study. J. Clin. Diagnostic Res. 2015; 9(9): 98–101. Publisher Full Text\n\nGhahroudi AA, Khorsand A, Rokn AR, et al.: Comparison of amnion allograft with connective tissue graft for root coverage procedures: a double-blind, randomized, controlled clinical trial. J. Int. Acad. Periodontol. 2013 Oct; 15(4): 101–112. PubMed Abstract\n\nKumar A, Chandra RV, Reddy AA, et al.: Evaluation of clinical, antiinflammatory and antiinfective properties of amniotic membrane used for guided tissue regeneration: A randomized controlled trial. Dent. Res. J. 2015; 12(2): 127–135.\n\nRichardson CR, Allen EP, Chambrone L, et al.: Periodontal Soft Tissue Root Coverage Procedures: Practical Applications From the AAP Regeneration Workshop. Clin Adv. Periodontics. 2015 Feb; 5(1): 2–10. PubMed Abstract | Publisher Full Text\n\nCairo F, Barootchi S, Tavelli L, et al.: Aesthetic-And patient-related outcomes following root coverage procedures: A systematic review and network meta-analysis. J. Clin. Periodontol. 2020 Nov; 47(11): 1403–1415. PubMed Abstract | Publisher Full Text\n\nPradhan S, Shetty N, Kamath DG: Master Chart containing raw data of both the groups and sample size calculation and statistical anlysis. figshare. Dataset. 2022. Publisher Full Text\n\nPradhan S, Shetty N, Kamath DG: extended data. figshare. Dataset. 2022. Publisher Full Text\n\nPradhan S, Shetty N, Kamath DG: Repository data. figshare. Dataset. 2022. Publisher Full Text"
}
|
[
{
"id": "138132",
"date": "24 May 2022",
"name": "Dr. Preetha Jayasheela Shetty",
"expertise": [
"Reviewer Expertise Cancer Genetics and Molecular Medicine."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe title of the article, “comparison of coronally advanced flap with chorion membrane vs coronally advanced flap with connective tissue graft in the treatment of multiple gingival recessions: a split mouth study”, accurately, succinctly, and appropriately expresses the theme and contents of the study.\nThe introduction gives a comprehensive overview of the management of gingival recession defects, identifies the drawbacks associated, and summarises the current scenario. Chorion membrane is a very novel material that has been used in the medical front for many years. It is very recently that this versatile membrane has been used in dentistry. The authors have done justice in citing the novelty of the membrane and the superiority of the material in the field of periodontics. The authors have clearly mentioned the purpose of the study, which was to compare the two materials, namely Chorion membrane and connective tissue graft, in the management of gingival recession defects. The research question thus proposed has been substantiated with proper evidence.\nThe author has succeeded in clearly describing the necessary armamentarium required for the research and has also chalked down a step wise methodology, which would be of great help to even other fellow researchers, who wish to carry out future research on this novel technique. A randomised clinical trial is evaluated by how comprehensibly the randomisation process has been described and followed. The authors have done justice to this aspect by outlining the randomisation process in a very systematic manner. The split mouth design of the study has also been justified. Thus, the selection of the study design is justified and the work showcases academic merit.\nStudent’s t test was done for the intra and inter group comparisons which appropriately provides statistical support to the data. The statistical analysis and its interpretation look appropriate.\nThe results and interpretations are sound and supported by relevant and current evidence. The authors have stated the findings, highlighting key aspects in tables and figures. The results with significant and non-significant values also have been cited well in the study. All the source data, underlying the results, are available to ensure a high level of reproducibility.\nThe study provides initial evidence towards the advantage of the chorion membrane substantiated by marked increase in the gingival thickness in the chorion membrane group. The percentage of root coverage, however, was insignificantly more in the control group but the results of the test group at all the three intervals have been very promising.\nThe discussion has been written in a very appropriate manner justifying all the significant values that have been addressed in the above tables. The discussion of the findings is suitable, gives answers to the research objectives, and incorporates adequate literature support. The inconsistencies and surprising results are explained in light of previous studies. The distinction between results and inferences is apparent, and the speculations are well supported by the current literature. The statements of various metanalysis and systematic reviews are well incorporated and compared with this study.\nOne of the major drawbacks of the study is small sample size which has also been mentioned by the authors. Along with that few other limitations such as the use of microscopes have also been mentioned.\nThe conclusions are sound, justified and logically explained, and supported by the results. The authors have emphasized the significance of the findings and placed them in the context of past research as well as the work's application.\nThe authors have also managed to throw some light on the future prospects.\nThis article can be accepted for indexing in its current form. No revisions are required.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "138134",
"date": "06 Jun 2022",
"name": "Neelesh Singh",
"expertise": [
"Reviewer Expertise Periodontologist"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nTitle of the study is well going with the work and self explanatory.\n\nThe study is an excellent attempt towards research on the management of Gingival Recession. It is a comparison of Chorion membrane vs CTG using a similar flap “Coronally Advanced Flap”. It's an attempt to achieve success with a material that is readily available so that patient’s treatment can be achieved and even preventing the secondary trauma to the palate for the graft (CTG) procurement.\n\nIts is an interesting study and the authors have collected a unique dataset using cutting edge methodology. The paper as a whole is generally well written, structured and concluded.\n\nThe Introduction provides an overview of the history of the two techniques in question and the need of present study followed by a robust explanation of the materials and methods including stats.\n\nAll the cases present depict the results clearly. The power of study is good and the advantageous thing is that it is a split mouth pattern. Furthermore, the pictures taken are clear. The results are well jotted and easy to understand for the reader.\n\nThe main part 'Discussion' is extremely well structured with emphasis on the deficiencies and comparison to the previous classic research on the related techniques. The authors have even explained the short coming, which is appreciable.\n\nThe paper as a whole marks a good step in periodontal research and can be Approved for indexing.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-533
|
https://f1000research.com/articles/11-532/v1
|
17 May 22
|
{
"type": "Study Protocol",
"title": "Mathematical models on COVID-19 in India: A systematic review protocol",
"authors": [
"Sezal Panchal",
"Denny John",
"Geetha R. Menon",
"Narassima M.S.",
"Tushar Shaw",
"Sezal Panchal",
"Geetha R. Menon",
"Narassima M.S.",
"Tushar Shaw"
],
"abstract": "Background: More than 278 million cases and more than 5.4 million deaths due to coronavirus disease (COVID-19) were reported worldwide by the end of 2021. More than 34 million cases and more than 478,000 deaths have been reported in India. Epidemiologists, physicians and virologists are working on a number of conceptual, theoretical or mathematical modelling techniques in the battle against COVID-19.\n\nProtocol: This systematic review aims to provide a comprehensive review of published mathematical models on COVID-19 in India and the concepts behind the development of mathematical models on COVID-19, including assumptions, modelling techniques, and data inputs. Initially, related keywords and their synonyms will be searched in the Global Literature on Coronavirus Disease database managed by World Health Organisation (WHO). The database includes searches of bibliographic databases (MEDLINE, Scopus, Web of Science, EMBASE etc.,), preprints (MEDRXIV), manual searching, and the addition of other expert-referred scientific articles. This database is updated daily (Monday through Friday). Two independent reviewers will be involved in screening the titles and abstracts at the first stage and full-texts at the second stage, and they will select studies as per the inclusion and exclusion criteria. The studies will be selected for their quality, transparency, and ethical aspects, using the Overview, Design concepts, Details (ODD) protocol and International Society for Pharmacoeconomics and Outcomes Research-Society for Medical Decision Making (ISPOR-SMDM) guidelines. Data will be extracted using standardized data extraction tools and will be synthesized for analysis. Disagreements will be resolved through discussion, or with a third reviewer.\nConclusions: This systematic review will be performed to critically examine relevant literature of existing mathematical models of COVID-19 in India. The findings will help to understand the concepts behind the development of mathematical models on COVID-19 conducted in India in terms of their assumptions, modelling techniques, and data inputs.",
"keywords": [
"COVID-19",
"mathematical model",
"transparency",
"ethics"
],
"content": "Introduction\n\nThe sudden outbreak of a new pathogen called the coronavirus disease (COVID-19) in Wuhan province has threatened the world population within a short period of its occurrence. The COVID-19 pandemic has been exhausting the health care resources not only in poor or developing countries but in developed countries as well. By December 2021 more than 278 million cases including 5.4 million deaths were reported by World Health Organisation.1 The paucity of health resources in terms of financing and availability, and large population in India has put forth more challenges compared to high-income countries. Initial non-pharmaceutical preventive measures, such as lockdowns, social distancing and sanitation measures were successful in managing the spread of disease but in later stages, COVID-19 caused depletion of medical supply, shortage of health care workers, hospital beds, intensive care units (ICUs), diagnostic safety kits and oxygen cylinders.2–5 Cumulatively with the existing living and health conditions like lack of nutrition, limited access to clean water and sanitation, communicable and non-communicable diseases, it has consecutively created a helpless situation for the government. Moreover, factors such as mass migration of workers, unemployment, the education system, and management of critical non-COVID patients have become a concern amidst the pandemic.\n\nMathematical models are potential tools in providing a better understanding of disease spread dynamics and transmission. These mathematical models can help us to understand the epidemic, the size and duration of the pandemic wave, and the extent of illness in co-morbid conditions in countries that are struggling with health resources. A prerequisite for a model is that it should provide predictions corresponding to reality.6 During the past year and a half, several mathematical models have been published for COVID-19 in low-and-middle income countries (LMICs).7,8 China has published a few models for quantitative prediction of infection.9–12 Other models were developed to predict the effect of non-pharmaceutical measures on epidemic dynamics.13–15 In India, a number of mathematical models on COVID-19 were proposed and published in peer-reviewed journals and as grey literature during this period of time.16–19\n\nThis systematic review aims to provide a comprehensive review of existing mathematical models on COVID-19 in India that are published from January 2020 to January 2022. The identified studies from the systematic review would be helpful in filling this research gap. The review additionally helps to understand the concept behind the development of mathematical models on COVID-19 conducted in India in terms of their assumptions, modelling techniques, and data inputs. The review will also aim to identify, where feasible, the reliability of the various mathematical models in predicting the COVID-19 pandemic in India. These insights might help to develop a methodology and the potential use of these models in predicting epidemic outbreaks in a limited resourced setting for future pandemics. A preliminary search on the Cochrane database of systematic review, PROSPERO, MEDLINE, and Implementation reports was conducted, and no systematic reviews on the topic were identified.\n\n\nProtocol\n\nThe study design is a systematic review of mathematical models on COVID-19 in India. The method has been developed and reported in compliance with Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocol (PRISMA-P).20 Please see Reporting guidelines41 for the completed checklist. The search for the final review will be documented and reported as per PRISMA-S.21\n\n\n\n1) To perform a comprehensive review of existing mathematical models on COVID-19 and to assess the reported number of cases of infections, the peak of infections, mortalities, and spread of the epidemic in India.\n\n2) To identify the concept behind the development of the mathematical models on COVID-19, for example, assumptions, modelling techniques and data inputs.\n\n3) If possible, to check the reliability of mathematical models (i.e., the closeness of the predictions with the actual data) in predicting the real epidemic situation in a limited resource country.\n\nWhat are the concepts behind the development of the mathematical models on COVID-19?\n\nWhat are the assumptions, modelling techniques, and data inputs and the qualities, transparency and ethical considerations of mathematical modelling on COVID-19 in India?\n\nInclusion criteria\n\nResearch articles adopting infectious disease modelling, mathematical modelling, autoregressive integrated moving average (ARIMA) modelling,22,23 regression modelling,24 agent-based25 network,26 or simulation models27 on COVID-19 published in peer-reviewed journals and preprint servers focusing on the population of India will be assessed for inclusion in the review. A study will be selected if it presents a mathematical or statistical model of COVID-19 and reports the following parameters - an incubation period, basic reproduction number (Rο) infectious period, fatality, peak time, peak size, total infection number, or elimination time.\n\nExclusion criteria\n\nThis review will be limited to English language studies. and studies with the following criteria will be excluded from the review:\n\n1. Articles on mathematical modelling of COVID-19 in countries other than India.\n\n2. Articles on non-COVID outcomes.\n\n3. Articles where the abstract or full text is not available.\n\n4. Articles not conducting and reporting mathematical models will be excluded.\n\n5. Articles will be excluded if they only present on evaluating intervention strategies without offering parameter estimates or trajectory projection\n\n6. Review papers, empirical studies, emergency response articles, microbiological studies, disease surveillance studies focused on treatment or vaccination in the host, studies that are not disease-specific, studies not involving population-wide spread, studies on computer viruses, social media modelling, internet modelling, or phone modelling.\n\n7. Reviews and non-original papers.\n\nThe comprehensive search strategy has been developed in consultation with an information specialist. The developed search strings will be used to search in the database, i.e. WHO (Global literature on coronavirus disease) and will be supplemented by a manual search at Semantic Scholar for relevant English language articles published from 1 January 2020 to January 2022. Additionally, cross-referencing of included studies focussed on India from previously published systematic reviews on the topic, and forward and backward citations of included studies will be conducted to identify more studies. The global literature on coronavirus disease database includes searches of bibliographic databases (MEDLINE, Scopus, Web of Science, Europe PMC, EMBASE), pre-prints (MEDRXIV), clinical trial registry (ICTRP), manual searching, and the addition of other expert-referred scientific articles, and this database is updated daily (Monday through Friday).28\n\nSearch terms related to COVID-19, methodology, and population were identified and used concurrently as: “SARS-CoV-2,” “Coronavirus Disease 2019,” “COVID-19,” “2019-nCoV,” “coronavirus,” OR “pneumonia” AND “model,” “modelling,” “modelling,” “dynamic,” “estimation,” “prediction,” OR “transmission” AND “India,” OR “Republic of India,” OR “India,” “Indian”. A study will be selected if it presents a mathematical or statistical model of COVID-19 and reports the following parameters - an incubation period, basic reproduction number (Rο) infectious period, fatality, peak time, peak size, total infection number, or elimination time. Reference lists will be manually searched and onward citation searching will be conducted using WHO for all included studies.\n\nThe search strategy will be internally reviewed using CADTH PRESS 2015 guidelines.29\n\nStudies identified through search strategy across identified databases and grey literature will be imported to Covidence (version 2.0) software (Rayyan is an example of a free alternative that can be used to replicate the study) and will be first screened at the title and abstract level by two authors (SP and DJ). After both the reviewers screen the articles, the following criteria will be used for categorizing: (1) both authors agree on inclusion; (2) one author recommends inclusion; (3) both authors are unsure; (4) one author recommends exclusion and the other is unsure or (5) both authors agree on exclusion. Full-text articles for abstracts classified as 1 or 2 will be retrieved. Those classified as 3 or 4 will be discussed with the third reviewer for inclusion in the full-text review. Records classified as 5 will be excluded.\n\nThe full texts will be reviewed by the reviewers (SP and DJ) as per the inclusion/exclusion criteria. Reasons for exclusion at the full-text stage will be reviewed and recorded. The screening decisions will be reported using PRISMA-2020 guidelines.30\n\nFor quality assessment for selected studies, a modified critical appraisal checklist prepared by Fone et al.31 will be used. The checklist is provided in Extended data.41 For epidemiological models32 a modified risk of bias tool will be used to assess the risk of bias of individual studies. This bias tool is also provided in Extended data.41 Assessment for risk of bias for components such as; model setting and population, appropriateness of modelling methodology and structure, fitting methodology, and reporting the conflicts of interest, which are essential for assessing the reproducibility of the model, alignment of the model and research question, will be performed. The Professional Society for Health Economics and Outcomes Research- Society for Medical Decision Making (ISPOR-SMDM)33 for good practices guidelines will be referred to for the task.\n\nIdentification of ethical risks associated with the development of mathematical models and their implementation is important. An ethical framework will be considered for the accountability of scientists for the communication and translation of mathematical models to policymakers for a better understanding of the strengths and weaknesses of scientific evidence. Moreover, ethical framework for mathematical models helps to understand the ethical and socioeconomic impact of biased and unpredictable events. A biomedical ethics-based evaluation will be conducted using parameters mentioned in Appendix 4 in Extended data.41\n\nData will be extracted from included articles into a piloted, standardized Excel database by two independent reviewers. Reference lists will be manually searched and further online citations of all included studies will be searched using the Web of Science. The following data will be extracted from each article; the date of publication, location/setting and study population (urban or rural) and duration, age, gender, the density of population, number of people in every household and locality, study duration and sample size. The source of data for population, risk of exposure at workplace and work-from-home capabilities if industry-specific constraints are to be included, as well as the source of data for population, source of data for epidemiology and travel. Detailed demography about the population is also being extracted.\n\nWe will also extract data about on following parameters: percentage of pre-symptomatic transmissions, pre-symptomatic transmission period, percentage of asymptomatic patients, serial interval, incubation period, the onset of symptoms/ illness onset to diagnosis, onset of symptoms/ illness onset to hospital admission, hospital stay length, time from hospital admission to death/discharge, the onset of symptoms/ illness onset to death, the onset of symptoms/ illness onset to discharge/recovery, the proportion of patients who require ventilator support, duration of ventilator support, percentage of deaths, percentage of discharged, the percentage in hospital, percentage of patients requiring oxygen support percentage of ICU admissions, the onset of symptoms/illness onset to ICU admission, ICU stay length, percentage of deaths from ICU, percentage of discharged from ICU, the percentage in hospital from ICU, and percentage transferred from ICU to general hospital wards. Other outcomes, namely magnitude of infection, confirmed cases, peak time, mortality due to infection, further consequences of disease, validation and performance of each model will be assessed. The secondary outcomes and implementation of the models in preparedness for epidemic will also be studied.\n\nIn the case where we encounter a model that has been considering vaccination and acquired immunity from the previous infection, we will consider parameters such as the proportion of people who are immune to infections for the following reasons: (a) already infected and recovered, (b) vaccinated (single double/double dose).\n\nThe assumption involved in the development of models and the outcome(s) is to be predicted. Other extracted data will include sample size, mean, standard deviation (SD), confidence interval, median, interquartile range (IQR) and fitted distribution used in estimation, missing data, model fitting and calibration approaches. The method or strategies used for checking model performance and evaluation will also be studied. If any uncertainty of missing data is found, the corresponding author will be contacted for additional information or missing data.\n\nWe will record how the sensitivity analysis was performed, as well as the data bias considerations and finally the results and interpretation and discussion for the model.\n\nA narrative summary of included literature will be produced with the qualitative synthesis of extracted data. The selected studies will be evaluated for case data sources (epidemiological, population and travel), modelling approaches, compartments used, population mixing assumptions, model fitting and calibration approaches, sensitivity analysis used and data bias considerations. We will use the Bio-surveillance Analytics Resource Directory (BARD)34 framework to systematically characterize the models. Additionally, the final included studies will be subjected to an ethical framework for mathematical models for policymaking.35 The certainty of the evidence will be assessed for four primary outcomes: incidence, onward transmission, mortality, and resource use. Covidence systematic review software will be used for conducting the systematic review. The systematic review will be documented as a publication and policy brief for decision-makers. We will classify the models based on their theoretical types, epidemiological and population data types, and validation data types. A summary of the evidence table from all the included articles will be prepared.\n\nSince mathematical models of COVID-19 use different methods there would be variations in data inputs and assumptions and hence we do not envisage conducting estimations of summary effect measures. However, if we find two or more studies that can be pooled we will use pooled estimates using random-effects meta-analysis of a number of infections, number of confirmed cases, and mortality. In the absence of meta-analysis, we aim to use synthesis without meta-analysis (SWiM) approaches for grouping of studies into intervention analysis (social distancing, testing, travel ban, personal hygiene & sanitation, and therapeutic interventions/treatments, epidemiological data classification, population data classification, travel data classification, and validation data classification). We will also focus on the modelling methods used, estimates of epidemiological impact, and reporting standards. We will also identify the limitations and gaps in each of the models as per SWiM guidelines.\n\nSince COVID-19 does not seem to affect children and teens in the same way as adults, any obtained data on paediatric patients will be analysed separately.36,37\n\nIf possible, for various parameters identified from the included studies, we will conduct meta-analysis using the statistical software R version 3.6.2 (meta, metaphor and dmter packages). For parameters reporting mean and standard deviation (SD), or median and interquartile range (IQR), a meta-analysis of single means will be conducted, and where mean and SD are not reported, they will be estimated from median and IQR.36,38 For those parameters presented as percentages, a meta-analysis of proportions will be used. To take into account the variability between and within studies, the random-effects model will be fitted with the Restricted Maximum Likelihood Method (REML). In order to meet the normality assumption underlying the meta-analysis, the natural logarithm transformation will be applied. The null hypothesis of no variance among studies will be tested using the Q-statistic, and the degree of heterogeneity will be quantified using the I2 index. Outliers and influencers diagnoses will also be performed.\n\nMeta-analysis results will be presented as pooled mean or percentage and its associated 95% confidence interval (CI) provided by the meta-analysis for parameters for two or more studies. For each parameter, forest plots will be developed and presented to visualize all the included studies.\n\nThe publication bias will be assessed through generation of a funnel plot if at least 10 studies are included in meta-analysis. The symmetry of funnel plot will be tested by Egger test; Meta-analysis: publication bias.39\n\nWe will use the GRADE approach to rate the quality of evidence for the primary outcomes, where effectiveness of interventions has been estimated using mathematical modeling.40\n\nEthical approval is not required for this study. The completed systematic review will be submitted for publication in a peer-reviewed journal.\n\nA protocol of the systematic review has been registered on PROSPERO (registration number: CRD42022299112). Relevant searches have been completed in academic and non-academic databases, and study screening is currently ongoing.\n\n\nConclusions\n\nThis systematic review will be performed to identify, and critically review published mathematical models on COVID-19 in India. Understanding of the concept behind the development of COVID-19 mathematical models in India in terms of their assumptions, modelling techniques and data inputs could help the policymaker, scientist and physicians to promote best practices in mathematical modelling. If possible the review will aim to rule out the reliability of mathematical models to predict the real epidemic situation.\n\n\nData availability\n\nNo underlying data are associated with this article.\n\nFigshare: Mathematical models on COVID-19 in India: A Systematic review and meta-analysis protocol. https://doi.org/10.6084/m9.figshare.19204695.v1.41\n\nThis project contains the following extended data:\n\n• Annexure-1 Critical Appraisal Sheet.docx.\n\n• Appendix-2 Risk of Bias.docx (tool for assessment of epidemiological modelling studies).\n\n• Data Extraction sheet.xlsx (data extraction tool for epidemiological burden studies).\n\n• Appendix 4. docx (list of parameters for biomedical ethics-based evaluation).\n\n• PRISMA-S.docx (template for PRISMA-S checklist that will be completed after the final review).\n\n• Final Search strategy_Mathematical models on Covid-19 in India.docx.\n\n\nReporting guidelines\n\nFigshare: PRISMA-P checklist for ‘Mathematical models on COVID-19 in India: A systematic review protocol’. https://doi.org/10.6084/m9.figshare.19204695.v1.41\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nThe authors wish to thank Ms Vasumathi Sriganesh, Founder & CEO, QMed Foundation, Mumbai, for providing inputs for the development of the search strategy.\n\n\nReferences\n\nWHO Coronavirus Disease (COVID-19) Dashboard: [cited 2021 Sep 8]. Reference Source\n\nWHO: Shortage of personal protective equipment endangering health workers worldwide. World Health Organization; 2020 [cited 2022 Feb 20]. Reference Source\n\nUnited Nations Children’s Fund (UNICEF) and United Nations Educational, Scientific, and Cultural Organization (UNESCO): India Case Study: Situation analysis of the effects of and responses to COVID-19 on the education sector in Asia. Nepal, Thailand: UNICEF Thailand: UNESCO; 2021.\n\nMigration Data Portal: Migration data relevant for the COVID-19 pandemic.[cited 2021 Sep 8]. Reference Source\n\nSharma A, Gupta P, Jha R: COVID-19: Impact on Health Supply Chain and Lessons to Be Learnt. J. Health Manag. 2020 Aug 11 [cited 2022 Feb 20]; 22(2): 248–261. Publisher Full Text\n\nHuppert A, Katriel G: Mathematical modelling and prediction in infectious disease epidemiology. Clinical Microbiology and Infection. Blackwell Publishing Ltd; 2013; Vol. 19. : p. 999–1005.\n\nWaqas M, Farooq M, Ahmad R, Ahmad A: Analysis and Prediction of COVID-19 Pandemic in Pakistan using Time-dependent SIR Model.2020.\n\nCOVID-19: Legal Impact in Mexico; measures issued by various authorities|White & Case LLP: [cited 2021 Sep 9]. Reference Source\n\nBacker J, Klinkenberg D, Wallinga J: The incubation period of 2019-nCoV infections among travellers from Wuhan, China. Eurosurveillance. Euro Surveill. 2020. 2020; 25(5): pii=2000062. PubMed Abstract | Publisher Full Text\n\nNg K, Poon BH, Kiat Puar TH, et al.: COVID-19 and the Risk to Health Care Workers: A Case Report. Ann. Intern. Med. 2020 Mar 16 [cited 2021 Sep 9]; 172: 766–767. PubMed Abstract | Publisher Full Text Reference Source\n\nZhang Y, Jiang B, Yuan J, et al.: The impact of social distancing and epicentre lockdown on the COVID-19 epidemic in mainland China: A data-driven SEIQR model study. medRxiv. 2020 [cited 2021, Sep 9]. Publisher Full Text\n\nJia Z, Lu Z: Modelling COVID-19 transmission: from data to intervention. Lancet Infect. Dis. 2020 Apr; 20: 757–758. PubMed Abstract | Publisher Full Text\n\nMandal S, Bhatnagar T, Arinaminpathy N, et al.: Prudent public health intervention strategies to control the coronavirus disease 2019 transmission in India: A mathematical model-based approach. Indian J. Med. Res. 2021 Sep 9; 151: 190. Publisher Full Text Reference Source\n\nHu Z, Ge Q, Li S, et al.: Evaluating the effect of public health intervention on the global-wide spread trajectory of Covid-19. medRxiv. 2020 [cited 2021 Sep 8]; 2020.03.11.20033639. Publisher Full Text\n\nFong MW, Gao H, Wong JY, et al.: Nonpharmaceutical Measures for Pandemic Influenza in Nonhealthcare Settings-Social Distancing Measures. Emerg. Infect. Dis. 2020; 26(5): 976–984. PubMed Abstract | Publisher Full Text\n\nNarassima MS, Anbuudayasankar SP, Jammy GR, et al.: An agent based model for assessing transmission dynamics and health systems burden for COVID-19. Indones J. Electr. Eng. Comput Sci. 2021; 24(3): 1735–1743. Publisher Full Text\n\nMegiddo I, Nandi A, Prabhakaran D, Laxminarayan R: IndiaSim: An Agent-based Model for Estimating the Health and Economic Benefits of Secondary Prevention of Coronary Heart Diseases in India 1.2014.\n\nMahajan A, Sivadas NA, Solanki R: An epidemic model SIPHERD and its application for prediction of the spread of COVID-19 infection in India. Chaos Soliton Fract. 2020; 140(1): 110156. PubMed Abstract | Publisher Full Text\n\nKapoor G, Sriram A, Joshi J, et al.: COVID-19 in India: State-Wise Estimates of Current Hospital Beds, ICU Beds, and Ventilators. CDDEP and Princeton University; 2020. Reference Source\n\nMoher D, Shamseer L, Clarke M, et al.: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 2015; 4: 1. PubMed Abstract | Publisher Full Text\n\nRethlefsen ML, Kirtley S, Waffenschmidt S, et al.: PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst. Rev. 2021; 10: 39. PubMed Abstract | Publisher Full Text\n\nDixit A, Vishnoi S, Paul SB: Adding Structure to Statistics: A Study on COVID-19 Dynamics in India. medRxiv 2020.05.26.20113522. Publisher Full Text\n\nGupta R, Pal SK: Trend Analysis and Forecasting of COVID-19 outbreak in India.[cited 2021 Sep 10]. Publisher Full Text\n\nChauhan P, Kumar A, Jamdagni P: Regression Analysis of COVID-19 Spread in India and its Different States.[cited 2021 Sep 9]. Publisher Full Text\n\nNarassima MS, Rajesh Jammy G, Pant R, et al.: An Agent Based Model methodology for assessing spread and health systems burden for Covid-19 using a synthetic population from India.[cited 2021 Sep 9]. Publisher Full Text\n\nKumar A: Modelling geographical spread of COVID-19 in India using network-based approach. medRxiv. [cited 2021 Sep 9]; 2020.04.23.20076489. Reference Source\n\nWelling A, Patel A, Kulkarni P, et al.; Multilevel Integrated Model with a Novel Systems Approach (MIMANSA) for Simulating the Spread of COVID-19.[cited 2021 Sep 10]. Publisher Full Text\n\nWHO Global research on coronavirus disease (COVID-19): [cited 2021 Sep 8]. Reference Source\n\nMcGowan J, Sampson M, Salzwedel DM, et al.: PRESS – Peer Review of Electronic Search Strategies: 2015 Guideline Explanation and Elaboration (PRESS E&E).2016.\n\nPage MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 372: n71–n2021. PubMed Abstract | Publisher Full Text\n\nFone D, Hollinghurst S, Temple M, et al.: Systematic review of the use and value of computer simulation modelling in population health and health care delivery. J. Public Health Med. 2003; 25(4): 325–335. PubMed Abstract | Publisher Full Text\n\nHarris RC, Sumner T, Knight GM, et al.: Systematic review of mathematical models exploring the epidemiological impact of future TB vaccines. Vol. 12, Human Vaccines and Immunotherapeutic. Taylor and Francis Inc.; 2016 [cited 2021 Sep 10]; 2813–2832. Publisher Full Text\n\nCaro JJ, Briggs AH, Siebert U, Kuntz KM: Modelling Good Research Practices-Overview: A Report of the ISPOR-SMDM Modelling Good Research Practices Task Force-1.2012 [cited 2021 Sep 10]. Reference Source\n\nMargevicius KJ, Generous N, Abeyta E, et al.: The Bio surveillance Analytics Resource Directory (BARD): Facilitating the Use of Epidemiological Models for Infectious Disease Surveillance. PLoS One. 2016 [cited 2021 May 9]; 11: e0146600. PubMed Abstract | Publisher Full Text Reference Source\n\nRoberts M, Russell LB, Paltiel AD, et al.: Conceptualizing a model: A report of the ISPOR-SMDM modelling good research practices task force-2. Value Heal. 2012 Sep 1; 15(6): 804–811. PubMed Abstract | Publisher Full Text\n\nLuo D, Wan X, Liu J, et al.: Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat. Methods Med. Res. 2018 Jun; 27(6): 1785–1805. PubMed Abstract | Publisher Full Text\n\nDu W, Yu J, Wang H, et al.: Clinical characteristics of COVID-19 in children compared with adults in Shandong Province, China. Infection. 2020 Jun; 48(3): 445–452. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWan X, Wang W, Liu J, et al.: Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. 2014 Dec 19; 14: 135. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeeks JJ, Higgins JPT, Altman DG, et al.: Chapter 10: Analysing data and undertaking meta-analysis. Cochrane Hand book for Systematic Reviews of Interventions version 6.3 (updated February 2022). Higgins JPT, Thomas J, Chandler J, et al., editors. Reference Source\n\nGuyatt G, Oxman AD, Akl EA, et al.: GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J. Clin. Epidemiol. 2011 Apr; 64(4): 383–394. PubMed Abstract | Publisher Full Text\n\nPanchal S, John D, Menon GR, et al.: Mathematical models on COVID-19 in India: A Systematic review and meta-analysis protocol. figshare. Dataset. 2022. Publisher Full Text"
}
|
[
{
"id": "145464",
"date": "12 Aug 2022",
"name": "Konstantin B. Blyuss",
"expertise": [
"Reviewer Expertise Mathematical biology and epidemiology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe aim of the protocol is unclear. I might be wrong, but I have always thought that systematic reviews are aimed at addressing specific scientific questions, or approaches to the treatment of specific medical conditions. Here, on the other hand, the scope appears to be so broad. More specifically, it is unclear whether the emphasis is on a survey of mathematical models and techniques developed in them, most of which are theoretical, or on the extraction of parameter values from epidemiological and observational studies. Mathematical modelling studies used for short- or long-term forecasting have relied on earlier obtained data and in that sense do not contribute to extracting parameters from the data. In contrast, observational/epidemiological studies may contain useful data on various disease parameters, but there is still a myriad of models that can be developed using these same data depending on the specific modelling methodology, and the questions being studied.\nSince COVID-19 is a disease affecting the entire world population, there are/should be no particular parameter values characterising fundamental properties of the virus, such as incubation and infectious periods, percentage of asymptomatic patients, etc., that would be unique to India as opposed to any other country, hence it is unclear why would one consider focusing on extracting these and similar parameters from Indian data only, and what would make them different from those used to study in other countries.\nIn terms of actual data used for the systematic review, the authors mention medRxiv, but for some reason do not mention arXiv, where also a number of mathematical models of COVID-19 transmission in India have been posted (I have checked). Also, I think restricting the check of reference lists against the Web of Science database would be quite restrictive for two reasons: a number of journals are not indexed there, and any study that may have had a huge impact but has not yet been published (even if already accepted for publication and available online) would not feature on this database.\nIn summary, this might be an interesting protocol, but the authors should more clearly formulate the specific questions they are trying to address, and better motivate the need for studying them in light of thousands of studies looking at various modelling approaches for COVID-19, not to mention huge amounts of available data.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "180751",
"date": "17 Aug 2023",
"name": "Samrat Chatterjee",
"expertise": [
"Reviewer Expertise Mathematical Biology",
"Mathematical Modelling",
"Systems Biology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article aims to comprehensively review existing mathematical models on COVID-19. However, the literature could be more extensive and more active on the mathematical techniques used to build models. So, I needed to understand the motivation behind the current article. They aim to focus on developing Mathematical models for COVID-19, but the article limits itself to the collection of database for estimation of parameters. There are various forms of Mathematical models addressing different questions related to disease dynamics. The present review is very limited in this perspective. Parameter estimation is applied after a model is developed with different differential equation forms to make it more realistic. So, discussing the formation of a model is necessary for the readers to understand the application. The article also limits itself to discussing the model analysis, which is vital in making hypotheses on disease dynamics. With the same model and data, the different depths of analysis could produce different predictions. These two vital points are necessary for the present article to clear the reader's doubts.\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-532
|
https://f1000research.com/articles/10-979/v1
|
28 Sep 21
|
{
"type": "Software Tool Article",
"title": "Doublet identification in single-cell sequencing data using scDblFinder",
"authors": [
"Pierre-Luc Germain",
"Aaron Lun",
"Will Macnair",
"Mark D. Robinson",
"Aaron Lun",
"Will Macnair"
],
"abstract": "Doublets are prevalent in single-cell sequencing data and can lead to artifactual findings. A number of strategies have therefore been proposed to detect them. Building on the strengths of existing approaches, we developed scDblFinder, a fast, flexible and accurate Bioconductor-based doublet detection method. Here we present the method, justify its design choices, demonstrate its performance on both single-cell RNA and accessibility sequencing data, and provide some observations on doublet formation, detection, and enrichment analysis. Even in complex datasets, scDblFinder can accurately identify most heterotypic doublets, and was already found by an independent benchmark to outcompete alternatives.",
"keywords": [
"single-cell sequencing",
"doublets",
"multiplets",
"filtering"
],
"content": "Introduction\n\nHigh-throughput single-cell sequencing, in particular single-cell/nucleus RNA-sequencing (scRNAseq), has provided an unprecedented resolution on biological phenomena. A particularly popular approach uses oil droplets or wells to isolate single cells along with barcoded beads. Depending on the cell density loaded, a proportion of reaction volumes (i.e. droplets or wells) will capture more than one cell, forming ‘doublets’ (or ‘multiplets’), i.e. two or more cells captured by a single reaction volume and thus sequenced as a single-cell artifact. The proportion of doublets has been shown to be proportional to the number of cells captured (Bloom 2018; Kang et al. 2018). It is therefore at present common in single-cell experiments to have 10-20% doublets, making accurate doublet detection critical.\n\n‘Homotypic’ doublets, which are formed by cells of the same type (i.e. similar transcriptional state), are very difficult to identify on the basis of their transcriptome alone (McGinnis, Murrow, and Gartner 2019). They are also, however, relatively innocuous for most purposes, as they appear highly similar to singlets. ‘Heterotypic’ doublets (formed by cells of distinct transcriptional states), instead, can appear as an artifactual novel cell type and disrupt downstream analyses (Germain, Sonrel, and Robinson 2020).\n\nExperimental methods have been devised for detecting doublets in multiplexed samples, using barcodes (Stoeckius et al. 2018) or genotypes (e.g. single-nucleotide polymorphisms) to identify droplets containing material from more than one sample (Kang et al. 2018). While evidently useful, these identify only a fraction of the doublets, and fail to detect doublets formed by cells from the same sample, including heterotypic doublets.\n\nA number of computational approaches have therefore been developed to identify doublets on the basis of their transcriptional profile (McGinnis, Murrow, and Gartner 2019; DePasquale et al. 2019; Wolock, Lopez, and Klein 2019; Bais and Kostka 2020; Bernstein et al. 2020). Most of these approaches rely on the generation of artificial doublets by summing or averaging real cells, and score the similarity between them and the real cells. For example, DoubletFinder generates a k-nearest neighbor (kNN) graph on the union of real cells and artificial doublets, and estimates the density of artificial doublets in the neighborhood of each cell (McGinnis, Murrow, and Gartner 2019). In a similar fashion, one of the methods proposed by Bais and Kostka (2020), bcds, generates artificial doublets and trains a classifier to distinguish them from real cells. Real cells that are classified with artificial doublets are then called as doublets. Finally, another strategy proposed by Bais and Kostka (2020) is a coexpression score, cxds, which flags cells that co-express a number of genes that otherwise tend to be mutually exclusive across cells.\n\nXi and Li (2021a) recently reported a benchmark of computational doublet detection methods, using both simulations and real datasets with genotype-based true doublets. Interestingly, despite several new publications, the benchmark identified the oldest method, DoubletFinder (McGinnis, Murrow, and Gartner 2019), as the most accurate. However, another important observation from the benchmark was that no single method was systematically the best across all datasets, highlighting the necessity to test and benchmark methods across a variety of datasets, and suggesting that some strategies might have advantages and disadvantages across situations.\n\nHere, we present the scDblFinder package, building on the extensive single-cell Bioconductor methods and infrastructures (Amezquita et al. 2019) and implementing a number of doublet detection approaches. In particular, the scDblFinder method integrates insights from previous approaches and novel improvements to generate fast, flexible and robust doublet prediction. scDblFinder was independently tested by Xi and Li in the protocol extension to their initial benchmark and was found to have the best overall performance (Xi and Li 2021b).\n\n\nMethods\n\nFigure 1 gives an overview of the scDblFinder method.\n\nAs a first step, the dataset is reduced to its top most expressed features (1000 by default); if the cluster-based approach is used, the top features per cluster are instead selected.\n\nIf using the cluster-based approach (and not manually specifying the clusters), a fast clustering is performed (see Fast clustering). Artificial doublets are then created by combining cells of different clusters, proportional to the cluster sizes. In explicitly concentrating on inter-cluster doublets, we do not attempt to identify homotypic doublets, which are virtually unidentifiable and relatively innocuous anyway. In doing so, we reduce the necessary number of artificial doublets (since no artificial doublet is ‘lost’ modeling homotypic doublets), and prevent the classifier from being trained to recognize cells that are indistinguishable from singlets (and would therefore call singlets as doublets). An alternative strategy, also available through scDblFinder, is to generate fully random artificial doublets, and use the iterative procedure (see below) to exclude unidentifiable artificial doublets from the training. In practice, the two approaches have comparable performances (see below), and they can also be combined.\n\nDimension reduction is then performed on the union of real cells and artificial doublets, and a nearest neighbor network is generated. The network is then used to estimate a number of characteristics for each cell, in particular the proportion of artificial doublets among the nearest neighbors. Rather than selecting a specific neighborhood size, the ratio is calculated at different values of k, creating multiple predictors that will be used by the classifier. A distance-weighted ratio is also included. Further cell-level predictors are added, including: projections on principal components; library size; and co-expression scores (based on a variation of Bais and Kostka 2020). scDblFinder then trains gradient boosted trees to distinguish, based on these features, artificial doublets from real cells. Finally, a thresholding procedure decides the score at which to call a cell by simultaneously minimizing the misclassification rate and the expected doublet rate (see Thresholding).\n\nA key problem with classifier-based approaches is that some of the real cells are mislabeled, in the sense that they are in fact doublets labeled as singlets. These can mislead the classifier. For this reason, classification and thresholding are performed in an iterative fashion: at each round, the real cells identified as doublets are removed from the training data for the next round.\n\nUsing the benchmark datasets from Xi and Li (2021a), we next optimized a number of parameters in the procedure, notably regarding features to include and hyperparameters, so as to provide robust default parameters (see Germain 2021b, Figures 1-6). Some features, such as the distance to the nearest doublet or whether the nearest neighbor is an artificial doublet, had a negative impact on performance (see Germain 2021b, Figure 1), presumably because it led to over-fitting. Indeed, because artificial doublet creation can only approximate real doublets, a risk of classifier-based approaches is that the exact classification problem on which they are trained, namely distinguishing artificial doublets from real cells, slightly differs from the real problem on which they are expected to function (distinguishing real doublets from real singlets). To test the hypothesis that this can lead to overfitting, we used scDblFinder without the dimensional reduction and kNN steps, which arguably involve a loss of information, and trained the classifier directly on the expression of the selected genes. This resulted in a reduction in area under the precision and recall curve (AUPRC) in real datasets (see Germain 2021b, Figure 2; see also Figure 4). Finally, in line with a discrepancy between the trained and real problems, we observed that the variable importance calculated during training (see Germain 2021b, Figure 3) did not necessarily match that of the variable drop experiments (see Germain 2021b, Figure 1).\n\nPlotted are the false negative rate (FNR; the rate of misclassified artificial doublets), the false positive rate (FPR; the proportion of real cells classified as doublets), the squared proportion deviation from the expected doublet rate (denoted ‘dev’), and the integrated cost function to be minimized (mean of the previous). The dashed line indicates the threshold called.\n\nA: Observed median (and +/- one median absolute deviation in) library sizes per cell type against additive expectation for single cell and doublet types in a real dataset. The dashed line indicates the diagonal. B: Relative contribution of composing cell types in real doublets (each point represents a doublet) plotted against the expected relative contributions (based on the ratio between the median library sizes of the composing cell types). Values indicate the relative contribution of one of the two cell types to the doublet’s transcriptome. The dashed line indicates the diagonal, and the thick line indicates the weighted mean per doublet type.\n\nWe finally optimized hyperparameters (see Germain 2021b, Figure 4) as well as the number of iterations (see Germain 2021b, Figure 5), finding that a relatively low number of iterations (2-3) was sufficient.\n\nAccuracy (area under the precision and recall curve) of doublet identification using alternative methods across 16 benchmark datasets. The size of the dots indicate the relative ranking for the dataset, and the numbers indicate the actual area under the (PR) curve. For each dataset, the top method is circled in black. Methods in bold are available through the scDblFinder package.\n\nA: Schematic (toy data) representing the different types of doublets. Within-genotype heterotypic doublets will wrongly be labeled as false positives, and inter-genotype homotypic will be labeled as false negatives. B: Adjusted PR curve for an example sample (GSM2560248). The two shaded areas represent the expected proportion of within-genotype heterotypic doublets (i.e. wrongly labeled as singlets in the truth) and inter-genotype homotypic doublets, respectively.\n\nFast clustering\n\nIrlba-based singular value decomposition is first run using the scater package, and a kNN network is generated using the Annoy approximation implemented in BiocSingular. Louvain clustering is then used on the graph. If the dataset is sufficiently large (>1000 cells), a first rapid k-means clustering (using the mbkmeans package) is used to generate a large number of meta-cells, which are then clustered using the graph-based approach, propagating clusters back to the cells themselves.\n\nThresholding\n\nUnless manually given, the expected number of doublets (e) is specified by e=n2/10−5 (where n is the number of cells captured). This is then restricted to heterotypic doublets using random expectation from cluster sizes or, if not using the cluster-based approach, using the proportion of artificial doublets misidentified. The doublet rate is accompanied by an uncertainty interval (dbr.sd parameter), and the deviation from the expected doublet number for threshold t is then calculated as\n\nwhere ot represents the number of real cells classified as doublets at threshold t, and elow and ehigh represent, respectively, the lower and higher bounds of the expected number of heterotypic doublets in the dataset (based on the given or estimated doublet rate the dbr.sd parameter). The cost function being minimized is then simply given by costt=FNRt+FPRt+deviationt2, where the false negative rate (FNRt) represents the proportion of artificial doublets misclassified as singlets at threshold t, and the false positive rate (FPRt) represents the proportion of real cells classified as doublets. This is illustrated in Figure 2.\n\nSince this is performed in an iterative fashion, the FPR is calculated ignoring cells which were called as doublets in the previous round.\n\nCluster stickiness\n\nCluster ‘stickiness’ can be evaluated by fitting a single generalized linear model on the observed abundance of doublets of each origin, in the following way:\n\nwhere observedi and ei represent the numbers of doublets formed by specific combination i of clusters which are respectively observed or expected from random combinations, and ai, bi and ci (etc) indicate whether or not (0/1) the doublet involves each cluster.\n\nBecause some doublets are easier to identify than others, some deviation from their expected abundance is typically observed. For this reason, a difficultyi term is optionally included, indicating the difficulty in identifying doublets of origin i, estimated from the misclassification of scDblFinder’s artificial doublets of that origin (by default, the term is included if at least seven clusters). A βa significantly different from zero, then, indicates that cluster a forms more or less doublets than expected – if positive, it indicates cluster ‘stickiness.’\n\nFor the (quasi-)binomial distributions, logit was used instead of log transformation, and the mean of observed and expected counts was used as observational weights.\n\nEnrichment for specific combinations\n\nTo account for the different identification difficulty across doublet types, we first fit the following global negative binomial model:\n\nThe fitted values are then considered the expected abundance, and the probability of each double type count given this expectation is calculated using either underlying distributions (for the negative binomial, the global over-dispersion parameter calculated in the first step is used).\n\nThe direct classification approach is implemented in the directDblClassification function of the package. It uses the same doublet generation, thresholding and iterative learning procedures as scDblFinder, but trains directly on the normalized expression matrix of real and artificial cells instead of kNN-based features. The hyperparameters were the same except for the maximum tree depth, which was increased to six to account for the increased complexity of the predictors.\n\nFor feature aggregation, scDblFinder first normalizes the counts using the Term Frequency - Inverse Document Frequency (TF-IDF) normalization, as implemented in Stuart et al. (2019). Principal component analysis (PCA) is then performed and the features are clustered into the desired number of meta-features using mini-batch k-means (Hicks et al. 2021) or, if not available, simple k-means. The counts are then summed per meta-feature.\n\nscDblFinder is provided as a bioconductor package. The input data for scDblFinder (denoted x below) can be either i) a count matrix (full or sparse), with genes/features as rows and cells/droplets as columns; or ii) an object of class SingleCellExperiment. In either case, the object should not contain empty drops, but should not otherwise have undergone very stringent filtering (which would bias the estimate of the doublet rate). The doublet detection can then be launched with:\n\nlibrary (scDblFinder)\n\nsce <- scDblFinder(x)\n\nThe output is a SingleCellExperiment object including all of the input data, as well as a number of columns to the colData slot, the most important of which are:\n\n• sce$scDblFinder.score: the final doublet score (the higher the more likely that the cell is a doublet)\n\n• sce$scDblFinder.class: the binary classification (doublet or singlet)\n\nscDblFinder can run on any system running R >= 4.0 and Bioconductor >= 3.12.\n\nFor more details, see the package’s vignettes.\n\n\nResults\n\nAs most approaches rely on some comparison of real cells to artificial doublets, it is crucial to appropriately simulate doublets. To this end, we first characterized real doublets using a dataset of genetically distinct cell lines (Tian et al. 2018). Because each cell line represents a distinct and more or less homogeneous transcriptional state, it is possible to identify the ‘cell types’ composing each doublet (Figure 3). Although often larger, the median library sizes of doublets were systematically smaller than the sum of the median library sizes of composing cell types (Figure 3A). We next investigated the relative contributions of the composing cell types using non-negative least square regression, expecting the larger cell types to contribute more to the doublet’s transcriptome.\n\nAlthough differences in median library size across cell types were small (less than two-fold) compared to other datasets, we observed a weak association of the relative contributions with the relative sizes of the composing cell types (Figure 3B, p = 2e-10). This effect was however considerably smaller than the variation within doublet type. This suggests that there are i) large variations in real cell size within a given cell type, and/or ii) large variations in the mRNA sampling efficiency that are independent for the two composing cells. In light of these ambiguities, we opted for a mixed strategy in the generation of artificial doublets: a proportion is generated by summing the libraries of individual cells, another by performing a poisson resampling of the obtained counts, and a third by re-weighting the contributions of cells depending on the relative median sizes of the composing cell types.\n\nA previous version of scDblFinder was already compared, and shown to be superior to existing alternatives in an independent benchmark by Xi and Li (2021a). Here we reproduced this benchmark using the most recent versions of the packages, and including variant methods from the scDblFinder package (among which the updated version of scran’s original method, and now available in the scDblFinder package as computeDoubletDensity). Figure 4 compares the performance of scDblFinder to alternatives across the real benchmark datasets. scDblFinder has the highest mean area under the precision-recall (PR) curve (see Germain 2021b, Figure 7), ranking first in a majority of datasets, and otherwise typically very close to the top. In addition, scDblFinder runs at a fraction of the time required by the next best methods (Figure 4, left).\n\nSeveral of the benchmark datasets have true doublets flagged by their mixing of single-nucleotide polymorphisms from multiple individuals (Kang et al. 2018). In most of these cases, however, the doublets include also inter-individual homotypic doublets (in the sense of being a combination of cells of the same type from different individuals), which are difficult to detect from gene expression (Figure 5A). In addition, they miss heterotypic doublets that are the result of the combination of different cell types from the same individual. Indeed, datasets where there is a full correspondence between cell type and individual (such as the human-mouse mixtures, e.g. hm-6k and hm-12k) typically have a much higher area under the Receiver-operator characteristic (ROC) and precision-recall (PR) curves (Figure 4). It is therefore likely that the accuracy reported in the benchmark is below the actual one in detecting heterotypic doublets. Based on the frequency of the different individuals and cell types in a dataset, it is possible to infer the expected rate of inter-individual homotypic doublets and within-individual heterotypic doublets. This, in turns, allows us to adjust the measured true positive rate (TPR) and false discovery rate and get a better picture of our ability to detect heterotypic doublets. Figure 5B shows such an analysis for a complex dataset from Kang et al. (2018) . The inflection point of the PR curve roughly coincides with the expected proportion of heterotypic doublets among those flagged as true doublets.\n\nAdjusting for both types of error in the truth, the area under the PR curve is considerably better (0.82 instead of 0.64), and at the automatic threshold we estimate that 87% of heterotypic doublets can be identified with a real FDR of 32% (a similar analysis for a different sample is shown in Germain 2021b, Figure 9).\n\nMost doublet detection methods provide a ‘doublet score’ that is higher in doublets than in singlets, and users are left to decide on a threshold above which cells will be excluded as doublets. Because scDblFinder’s scores come from a classifier, they can directly be interpreted as a probability. Nevertheless, a threshold needs to be set, and it should ideally be placed at the inflection point (assuming there is one) of the ROC or PR curve, so that most doublets and not too many singlets are excluded. While these curves are typically not available in practice, we found that in most cases the scDblFinder scores are rapidly changing from high to low very close to the inflection point (Figure 6). One possibility is therefore to use directly a fixed probability threshold to call doublets. In some cases, however, there is a more gradual change in score (e.g. nuc-MULTI dataset), making it more difficult to establish a threshold in a non-arbitrary fashion. Building on the fairly tight relationship (especially in 10x-based datasets) between the number of cells captured and the rate of doublets generated (Kang et al. 2018), another approach consists in setting the threshold based on the number of doublets (or heterotypic doublets) one expects to find in the data. scDblFinder includes a thresholding method that combines both rationales, and attempts to minimize both the proportion of artificial doublets being misclassified and the deviation from the expected doublet rate (see Thresholding).\n\nReceiver-operator characteristic (ROC) curves (with square-root transformation on the x axis) of the different benchmark datasets. In B-C, the colors indicate the scDblFinder doublet scores, and the crosses indicate the thresholds established through the thresholding method (B) or by taking the expected number of heterotypic doublets (C).\n\nThe identified thresholds are shown in Figure 6A-B, and compared to thresholds based on the expected doublet rate in Figure 6C. In general, scDblFinder thresholds are closer to the inflection point.\n\nMultiple samples are often profiled and analyzed together, with the very common risk of batch effects (either technical or biological) across samples (Lütge et al. 2021). Therefore, while the cells from all samples might in principle provide more information for doublet detection than a single sample can afford on its own, this must be weighted against the risk of bias due to technical differences. To investigate this, we implemented different multi-sample approaches and tested them on two real multi-sample datasets with demuxlet-based true doublets, as well as a sub-sampling of them (Figure 7).\n\nB1 and B2 the two batches from dataset GSE96583, and contain 3 and 2 captures, respectively. The datasets with the suffix ‘s’ are versions downsampled to 30%. Using doublet detection on each capture separately (full split) was generally comparable to treating the captures as one (and adjusting the doublet rate).\n\nThe different multi-sample strategies had only a minor impact on the accuracy of the identification. Based on these results, the best overall strategy appears to be to process all samples as if they were one, however in our experience this can lead to biases against some samples when there are very large variations (e.g. in number of cells or coverage) across samples (not shown). This approach also greatly increases running time. In contrast, running the samples fully separately is computationally highly efficient, and is often equally accurate.\n\nWe next investigated whether scDblFinder could be applied to other types of single-cell data prone to doublets, such as single-cell Assay for Transposase-Accessible Chromatin sequencing (ATACseq). To evaluate this, we used the mixture of 10 cell lines from Granja et al. (2021). With default parameters, scDblFinder performed very poorly (Figure 8). This is chiefly because scDblFinder follows the common scRNAseq strategy of selecting an informative subset of the features, while ATACseq reads are typically sparsely distributed across the genome. However, working with all features (i.e. peaks) is computationally very expensive. An alternative to both approaches is to begin by reducing the size of the dataset by aggregating correlated features into a relatively small set, thereby using information from all. These aggregated features can then directly be used as the space in which to calculate distances. This method yielded equal or better performance than specialized single-cell ATACseq software (Figure 8).\n\nPerformance of scDblFinder with default (.raw) parameters or on aggregated features (.aggregation) versus ArchR (GSE162690 dataset).\n\nWhen artificial doublets are generated between clusters, we can keep track of the clusters composing them, and we reasoned that this information could be used to infer the clusters composing real doublets (hence after referred to as ‘doublet origin’). Using a simulation as well as the aforementioned real dataset with doublets of known origins (mixture of five cell lines from Tian et al. (2018)), we assessed the accuracy of doublet origin prediction based on the nearest artificial doublets in the kNN. These proved inaccurate, both in real and simulated data (see Germain 2021b, Figure 9A-B). Even training a classifier directly on this problem failed (see Germain 2021b, Figure 9C-D). The problem appears to be that, due to the very large variations in library sizes (and related variations in relative contributions of the composing cells – see Figure 3B), doublets often contain a large fraction of reads from one cell type, and conversely a small fraction from the other cell type. As a consequence, we can typically call at least one of the two originating cell types, but seldom both. In the real dataset, at least one of the two originating cell type is correctly identified in 73% of doublets (random expectation: 36%), but both are correct in only 20% of cases.\n\nA, B: Doublet enrichment in a toy example. A: Proportion of different doublet types from random expectations based on the cell type abundances. B: The fold-enrichment over this expectation in two different doublet enrichment scenarios. C, D: Performance of the cluster stickiness tests (C) and tests for enrichment of specific combinations (D) using different underlying distributions.\n\nWhile the identification of doublet origins remains a challenge, for the sake of completeness we nevertheless developed strategies to investigate whether certain doublet types were found more often than expected. Such enrichment could, for instance, indicate cell-to-cell interactions. We defined two forms of doublet enrichment (Figure 9A-B), and specified models to test each possibility: i) enrichment in doublets formed by a specific combination of celltypes, or ii) enrichment in doublets involving a given cell type, denoted ‘sticky.’\n\nThe `stickiness’ of each cluster (as proxy for cell types) can be evaluated by fitting a single generalized linear model on the observed abundance of doublets of each origin (see Methods). We tested the performance of this test under different underlying distributions using simulated doublet counts. The number of doublets of each type is generated from random expectation with or without added stickiness (as factors of 1 to 3 on the probability) using negative binomial distributions with different over-dispersion parameters (Figure 9C and Germain 2021b, Figure 10). The quasi-binomial showed the best performance, followed by the negative binomial, but in all cases the p-values were not well calibrated and many false positives were reported at a nominal FDR<0.05. This was robust across different over-dispersion values (see Germain 2021b, Figure 10).\n\nWe next sought to establish a test for the enrichment of specific combinations. Here, we simply computed the probability of the observed counts for each combination using different models (see Methods). We again tested this approach relying on different underlying distributions, on simulations with varying over-dispersion. The negative binomial performed best, however all variants suffered a high false discovery rate (Figure 9C).\n\n\nConclusions\n\nThe characterization of real doublets suggests a multi-layered variation in mRNA capture efficiency, and calls for a varied approach to artificial doublet generation. The scDblFinder package includes a set of efficient methods for doublet detection. In particular, the main scDblFinder approach uses mixed doublet generation approaches and integrates insights from previous approaches into a comprehensive doublet detection method that provides robustly accurate detection across a number of benchmark datasets, at a considerably greater speed and scalability than the best alternatives. Even in complex datasets, most heterotypic doublets can be accurately identified. Although the doublet scores given by scDblFinder can be directly interpreted as probabilities, simplifying their interpretation, the method also includes a trade-off thresholding procedure incorporating doublet rate expectations with classification optimization, thereby facilitating its usage. Finally, we further demonstrate that, with slight changes in parameters, the approach is also amenable to other data types such as single-nucleus ATAC-seq.\n\nscDblFinder additionally provides utilities for identifying the origins of doublets (in terms of composing cell types) and testing for different forms of doublet enrichment. At present, however, the value of such tests is limited by the difficulty of accurately identifying doublet origins. Further research will be needed to assess to what extent this can be improved.\n\nIn conclusion, we believe that scDblFinder, with its flexibility, accuracy and scalability, represents a key resource for doublet detection in high-throughput single-cell sequencing data.\n\n\nSoftware availability\n\nscDblFinder is available from Bioconductor: http://www.bioconductor.org/packages/release/bioc/html/scDblFinder.html.\n\nThe source code is available from: https://github.com/plger/scDblFinder.\n\nArchived source code at time of publication: https://doi.org/10.6084/m9.figshare.16543518.v1 (Germain, 2021a).\n\nThe software is released under the GNU Public License (GPL-3).\n\n\nData availability\n\nfigshare: scDblFinder. https://doi.org/10.6084/m9.figshare.16543518.v1 (Germain, 2021a).\n\nThis repository contains the following underlying data:\n\n• scDblFinder 1.7.4 (archived software version used in the paper).\n\n• scDblFinder_paper (code to reproduce the analyses and figures).\n\nThe code to reproduce the analyses and figures is additionally available at https://github.com/plger/scDblFinder_paper.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nfigshare: Supplementary Figures for the scDblFinder paper. https://doi.org/10.6084/m9.figshare.16617571.v1 (Germain, 2021b)\n\nThis repository contains the following extended data:\n\n• Supplementary Figures 1-10\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nWe thank Nan Miles Xi and Jingyi Jessica Li for help with their benchmark datasets; Jeffrey Granja for support with ArchR and its attached dataset; and the Robinson group and users for feedback. MDR acknowledges support from the University Research Priority Program Evolution in Action at the University of Zurich.\n\n\nReferences\n\nAmezquita RA, Lun ATL, Becht E, et al.: Orchestrating Single-Cell Analysis with Bioconductor. Nat. Methods. December, 1–9 2019; 17: 137–145. Publisher Full Text\n\nBais AS, Kostka D: Scds: Computational Annotation of Doublets in Single-Cell RNA Sequencing Data. Bioinformatics. 2020; 36(4): 1150–58. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBernstein NJ, Fong NL, Lam I, et al.: Solo: Doublet Identification in Single-Cell RNA-Seq via Semi-Supervised Deep Learning. Cell Systems. 2020 June; 11: 95–101.e5. PubMed Abstract | Publisher Full Text\n\nBloom JD: Estimating the Frequency of Multiplets in Single-Cell RNA Sequencing from Cell-Mixing Experiments. PeerJ. 2018; 6(September): e5578. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDePasquale EAK, Schnell DJ, Van Camp P-J, et al.: DoubletDecon: Deconvoluting Doublets from Single-Cell RNA-Sequencing Data. Cell Rep. 2019; 29(6): 1718–1727.e8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGermain, Pierre-Luc: scDblFinder. figshare. Software. 2021a. Publisher Full Text\n\nGermain, Pierre-Luc: Supplementary Figures for the scDblFinder paper. figshare. Figure. 2021b. Reference Source\n\nGermain P-L, Sonrel A, Robinson MD: pipeComp, a General Framework for the Evaluation of Computational Pipelines, Reveals Performant Single Cell RNA-Seq Preprocessing Tools. Genome Biol. 2020; 21(1): 227. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGranja JM, Ryan Corces M, Pierce SE, et al.: ArchR Is a Scalable Software Package for Integrative Single-Cell Chromatin Accessibility Analysis. Nat. Genet. 2021 February, 1–9; 53: 403–411. Publisher Full Text\n\nHicks SC, Liu R, Ni Y, et al.: Mbkmeans: Fast Clustering for Single Cell Data Using Mini-Batch k-Means. PLoS Comput. Biol. 2021; 17(1): e1008625. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKang HM, Subramaniam M, Targ S, et al.: Multiplexed Droplet Single-Cell RNA-Sequencing Using Natural Genetic Variation. Nat. Biotechnol. 2018; 36(1): 89–94. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLütge A, Zyprych-Walczak J, Kunzmann UB, et al.: CellMixS: Quantifying and Visualizing Batch Effects in Single-Cell RNA-Seq Data. Life Sci. Alliance. 2021; 4(6): e202001004. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcGinnis CS, Murrow LM, Gartner ZJ: DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors. Cell Systems. 2019; 8(4): 329–337.e4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStoeckius M, Zheng S, Houck-Loomis B, et al.: Cell Hashing with Barcoded Antibodies Enables Multiplexing and Doublet Detection for Single Cell Genomics. Genome Biol. 2018; 19(1): 224. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStuart T, Butler A, Hoffman P, et al.: Comprehensive Integration of Single-Cell Data. Cell. 2019; 177(7): 1888–1902.e21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTian L, Dong X, Freytag S, et al.: scRNA-Seq Mixology: Towards Better Benchmarking of Single Cell RNA-Seq Protocols and Analysis Methods. bioRxiv. 2018 October. Publisher Full Text\n\nWolock SL, Lopez R, Klein AM: Scrublet: Computational Identification of Cell Doublets in Single-Cell Transcriptomic Data. Cell Systems. 2019; 8(4): 281–291.e9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXi NM, Li JJ: Benchmarking Computational Doublet-Detection Methods for Single-Cell RNA Sequencing Data. Cell Systems. 2021a; 12(2): 176–194.e6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXi NM, Li JJ: Protocol for Executing and Benchmarking Eight Computational Doublet-Detection Methods in Single-Cell RNA Sequencing Data Analysis. arXiv:2101.08860 [q-Bio]. 2021b June. Reference Source"
}
|
[
{
"id": "95679",
"date": "19 Oct 2021",
"name": "Zev J. Gartner",
"expertise": [
"Reviewer Expertise Tissue engineering and single cell analysis method development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary\nThe authors describe scDblFinder — a doublet detection algorithm that uses gradient boosted trees to classify doublets as cells with elevated proportions of artificial nearest neighbors, library sizes, and co-expression scores. The authors describe parameter selection and hyperparameter optimization workflows before benchmark their method against the Xi & Li datasets. These efforts effectively demonstrate that scDblFinder performs very strongly relative to other doublet detection methods. Moreover, building on the existing doublet detection literature, the authors also make the following improvements/alterations to existing workflows and reaffirmations of previous observations:\n\nAuthors simulate doublets using a ‘mixed strategy’ including summing counts, Poisson resampling of counts, and weighted-averaging of counts based on cell-type-specific library sizes. This approach is distinct from current methods which simulate doublets by summing/averaging counts or averaging PC coordinates — Perhaps an improvement but needs more analysis (Major comment #1).\n\nAuthors demonstrate that scDblFinder is predominantly sensitive to heterotypic doublets and that removing homotypic doublets from ground-truth data improves doublet prediction performance metrics — Affirming previous observations in the DoubletFinder and other manuscripts.\n\nAuthors threshold doublet classification probability distributions (i.e., likelihood scores generated from gradient boosting) using a combination of two known approaches: (i) Threshold based on artificial doublet misclassification rate (from Scrublet) or (ii) Threshold based on expected number of doublets inferred from droplet microfluidics Poisson loading statistics (from DoubletFinder) — Perhaps an improvement (Major comment #2).\n\nAuthors show that scDblFinder (and other classifiers) should be run on individual scRNA-seq samples in instances when those samples are not multiplexed using Cell Hashing, MULTI-seq, etc. — This is an ‘unwritten’ rule for doublet detection workflows but hadn’t been definitively demonstrated.\n\nAuthors show that scDblFinder performs as well as ArchR for predicting doublets in snATAC-seq data after aggregating features — This is good to know, but authors need to include the current gold-standard for snATAC-seq doublet detection in their analysis, AMULET, such that readers are correctly informed about their analytical options for snATAC-seq doublet detection (Major Comment #3).\n\nAuthors present a strategy for inferring doublet origins which could be useful for identifying instances of biological doublets formed due to cell-cell interactions or ‘stickiness’ — Could be useful theoretically, but the approach is not sufficiently developed to be useful (although we commend the authors for including this analysis)\n\nOn balance, we believe that scDblFinder is a great method (likely the new gold standard for the field) and strongly recommend its indexing, assuming that our Major Comments are addressed.\n\nMajor Comments\n\nThe authors do a good job at justifying the theoretical utility of the proposed ‘mixing strategy’ for doublet simulation in Figure 3. However, while the authors compare scDblFinder performance before/after dimensionality reduction and kNN and using cluster-limited vs random doublet simulation, they do not do analogous analyses for comparing the ‘mixing strategy’ to more standard methods (e.g., summing, averaging, etc.). As such, it is unclear whether the proposed strategy improves performance.\n\nIn Figure 6, the authors plot ROC curves annotated by the thresholds defined by their proposed cost-minimization framework (Fig. 6B) or by the expected number of doublets (Fig. 6C). Since the cost-minimization framework also aims to minimize artificial doublet misclassification rate (as implemented by Scrublet), we would also like to see the same ROC plots with thresholds defined by this strategy (i.e., instead of just the expected doublet strategy implemented by DoubletFinder). We would also like the authors to provide summary statistics for the comparisons (see Minor Comment #1) Without this, it is unclear whether the cost-minimization framework is actually an improvement over existing approaches.\n\nThe application of scDblFinder to snATAC-seq data is not satisfactory as it only involves benchmarking against ArchR, which was recently shown in the AMULET paper (Thibodeau, Eroglu, et al. Genome Biology, 2021) to perform sub-optimally on snATAC-seq data. The authors need to include reference to AMULET in this section and benchmark the performance of AMULET, ArchR, and scDblFinder.\n\nWe believe that the manuscript in its current form suffers from poor readability – we really had to parse every sentence in the Methods section to understand what the authors were intending to convey. For one tangible example, when discussing the overfitting hypothesis on page 4 (which itself was conveyed quite clearly), the authors could include a clear rationale for why comparing scDblFinder performance before and after dimensionality reduction and kNN addresses the hypothesis. Notably, we believe that this manuscript was very well-executed and that scDblFinder is a great method. We also recognize that the authors write very accessibly in the Results section. However, many in the single-cell genomics community who may want to use scDblFinder are not machine learning experts will likely have a hard time appreciating the quality of this work, especially in its current structure (i.e., Methods section before Results). As such, we strongly recommend that the authors add more ‘plain English’ explanations to the Methods section (or put the Results before the Methods section, if the journal will allow that) to improve readability for a broader audience.\n\nMinor Comments\nShould provide quantitative analysis of distance of scDblFinder vs heterotypic doublet thresholding strategies to the real inflection point (related to Figure 6).\n\nAuthors should cite papers related to the benchmarking datasets used in Xi & Li.1\n\nAuthors should cite Chord from Xiong and colleagues, which also uses boosting to improve doublet detection.2\n\nOn page 3, the authors state that multiplexing approaches “identify only a fraction of the doublets” — this is technically true, but a bit misleading. The fraction of doublets detected in multiplexing experiments scales with the number of multiplexed samples. In instances where only a handful of samples are multiplexed, it is fair to say that ‘only a fraction' are identified. However, any modestly large experiment will result in the vast majority of doublets being detected. And even in the lowly multiplexed contexts, it is straightforward to remove heterotypic at the cluster-level by identifying clusters enriched for empirically-defined doublets. Authors should clarify (or remove) this statement as it suggests that scDblFinder is a ‘competitor’ with multiplexing approaches for doublet detection performance. Computational prediction will very rarely out-compete empirical measurements — instead, scDblFinder has the key advantage of being applicable to any past or future scRNA-seq data, which is not the case for Cell Hashing, MULTI-seq, etc.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "8148",
"date": "16 May 2022",
"name": "Pierre-Luc Germain",
"role": "Author Response",
"response": "We thank the reviewers for their thorough reading and useful comments, and have tried to address all of them in the revised version. A detailed point-by-point version will be made available along with the new version, but here are the main points of response: Artificial doublet generation: The reviewers are right that we simply assumed, because the doublets showed lower library size than expected from summation, that the mixed strategy would be superior. We now tested this, along with averaging. While averaging expectedly resulted in poorer performance, we in fact did not see a clear overall improvement of the mixed strategy. We now discuss this explicitly. Thresholding: Following the reviewers' suggestions, we also rewrote much of this section in a more open fashion, reflecting the choices that ultimately enter any thresholding decision (i.e. the lack of an objective optimal threshold), and changed the figure to provide clearer readouts that compare more alternative procedures. scATACseq: Thanks for the suggestions, at the time of submission we were not aware of the AMULET method. We now included it in the comparison, along with the dataset with ground truth with which it was published. We also reimplemented the method in our package, for the convenience of R users. Text structure and clarity: With permission from f1000, we now moved the Methods section to the end (as it was originally conceived), tried to offer a simpler overview of the method in the Results section, and to clarify the methods. Finally we also addressed the minor comments."
}
]
},
{
"id": "95560",
"date": "08 Nov 2021",
"name": "Dennis Kostka",
"expertise": [
"Reviewer Expertise computational genomics",
"evolutionary genomics",
"statistical phylogenetics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary\nThe authors describe scDblFinder, a computational tool for doublet/multiplet annotation in single-cell RNA sequencing and single-cell ATAC sequencing data. They explain and motivate method design and parameter choices, reproduce a benchmark on scRNA-seq data (originally performed by Xi and Li 2021) and demonstrate scDblFinder’s performance; this includes inferring cell-types of origin for doublets, deriving binarized doublet calls, and annotating doublets scATAC-seq data.\nGeneral Comments\nThe reviewers note that they have not considered other reviews for the same manuscript prior to or during the writing of this report.\nscDblFinder is probably the most competitive method for computational doublet annotation, so this manuscript, describing the method in detail, is an important contribution and valuable for the community. We have the following general comments:\nPositive points of the manuscript that stand out are the authors’ discussion of their results on annotating cell-types of origin for doublets (and the conclusion that it remains a challenge), scDblFinder’s good performance on scATAC-seq data, and its thresholding approach for generating binarized doublet calls.\n\nWhile the quality of the manuscript is generally high, we still feel that clarity can be improved, especially in describing methods (see specific comments).\n\nFurther on, as the authors describe, parameters of scDblFinder have been tuned to maximize performance on 16 benchmark data sets used for evaluation. As a consequence, performance comparison with methods that did not perform parameter optimization on the benchmark data is biased in favor of scDblFinder; this should be mentioned in the manuscript’s discussion section.\nSpecific Comments\nTerminology: It would be good to consistently use a term (like “droplet”, for example) for sequenced units of RNA that can contain more than one cell, whereas the term “cell” could be reserved to indicate a single cell.\n\nIn the introduction, the authors comment on drawbacks of multiplexing technologies and that they only identify a fraction of doublets. It would be good to (a) include that these experimental methods incur additional drawbacks, like increased cost and decreased yield and (b) that there are definite benefits of sample multiplexing in the context of experimental design.\n\nMethods, page 3: It would be helpful to streamline the description of scDblFinder's approach/procedure. Specifically, a verbal description would help. In the current version, for example, the authors talk about \"the cluster-based approach\", but it is not at all clear what they mean at that point in the manuscript.\n\nMethods, page 4: The authors state that mislabeled cells can mislead the classifier and use this to motivate their iterative approach (in paragraph 2). It would be helpful to reference Supplemental figure 5 here, which shows the positive effect of removing doublet-classified but singlet-annotated droplets.\n\nFormula on page 5: It is not discussed how the dbr.sd parameter that is used for e_low and e_high is estimated for a given dataset. Is there a motivation for choosing this specific functional form for deviation?\n\nFigure 2: It looks like the dashed line is not at the minimum of the cost function (black line).\n\nFormulae on page 6 and 8: It is not described how difficulty is estimated from misclassification of simulated doublets. In general, it would be good to present a consistent discussion for both models, including motivation, definition of all quantities, and error terms.\n\nFor the dataset used in Figure 3, it would be helpful to give a more in detailed description of the cell lines (organism, type, etc).\n\nMethods page 9. In paragraph 1, how is the desired number of features determined (is it a method parameter)?\n\nResults page 10. It would be helpful to briefly describe cell lines in the Tian et al. 2018 dataset (see previous comment about Figure 3).\n\nResults page 11. It would be helpful to add details about how artificial doublets were generated in paragraph 2. How were contributions \"re-weighted based on the relative median sizes of the composing cell-types”?\n\nResults page 11. In paragraph 4 and Figure 5 panel B: How was the expected rate of homotypic / heterotypic doublets estimated? In the legend of Figure 5, maybe change “truth” to “annotation” (also in the short paragraph 5 on page 11). Further on, a description on how the adjusted AUPRC is calculated should be included. Since doublet prediction is imbalanced, has a non-zero minimum AUPRC (https://dl.acm.org/doi/10.5555/3042573.30427801) been taken into account as well? Finally, does the black dot in Figure 5 B denote a cutoff such that the number of doublets scDblFinder would call corresponds to the expected number of heterotypic doublets?\n\nResults page 11. In paragraph 5 (3 lines), it would be helpful to make explicit what two types errors are accounted for. Further on, it appears the adjustment is based on estimated doublet rates, and it would be good to discuss how reliable these are, and how that, in turn, impacts the adjusted areas under the curve. Finally, the reference should be to supplemental figure 8 (not 9).\n\nFigure 6: It is not clear what the dots in panel A denote. In addition, it is really hard to compare the different points across panels B and C; perhaps sub-panels (one per curve) with both points on each curve would be clearer.\n\nResults page 11. For the last paragraph, it would be good to provide metrics that compare the two approaches in a qualitative way. One possibility would be a table showing for each benchmark dataset the number of annotated doublets, called doublets, false positives and false negatives together with a performance metric (e.g., Matthews correlation coefficient).\n\nResults, page 12. The authors conclude from Figure 7 that “as one” is the “best overall strategy”. Performance seems really close (and the conclusion only holds for AUPRC, not really for AUROC), so it is not clear if (a) the advantage is significant and (b) is expected to generalize to other data sets. This could be discussed.\n\nFigure 8 is very large.\n\nFigure 9: Some colors are different between panels C and D, which makes interpretation of the legend confusing.\n\nSupplemental Figure 1: It would be helpful to better explain the setup in the legend, so it is clear what TRUE/FALSE mean and how differences in AUPRC are defined (e.g., high = better performance without variable, low = worse performance without variable). If the violins are summarizing 16 points, it might be informative to show the points themselves. Does the dot indicate the median or the mean, what interval is denoted?\n\nSupplemental Figure 2: In panel B, maybe show log of elapsed time.\n\nSupplemental Figure 3: Consider using the same type of violin plot as before.\n\nTypo on page 5: “based on the given or estimated doublet rate the dbr.sd parameter” should be “based on the given or estimated doublet rate and the dbr.sd parameter”.\n\nTypo on page 8: “probability of each double type” should be “ probability of each doublet type\n\nType on page 11: “This, in turns, allows” should be “This, in turn, allows”\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "8149",
"date": "16 May 2022",
"name": "Pierre-Luc Germain",
"role": "Author Response",
"response": "We thank the reviewers for their thorough reading and useful comments, and have tried to address all of them in the revised version. A detailed point-by-point version will be made available along with the new version, but here are the main points of response: Bias due to parameter optimization based on the benchmark datasets: The reviewers were absolutely right to raise this important point, we now state it clearly in the discussion, with the note however that a previous version of scDblFinder (developed with only 5 of the datasets) was also found to outperform alternatives in the addendum to Xi and Li’s (2020) original benchmark. Terminology and clarifications: We thank the reviewers for their excellent suggestions regarding terminology and clarifications, which we adopted in the revised version (see the full point-by-point response for details). We also tried to provide a simpler 'verbal' overview of the method in the Results section, as suggested, and to clarify the methods section. AUPRC: We thanks the reviewer for the suggested paper on AUPRC. While it was quite an interesting read, we do not think that either the random or the minimal AUPRC affects any of the claims being made, as it is certainly well below any of those observed, and our main point in this section is that the performance in estimating heterotypic doublets is underestimated in most of the benchmark datasets. This being said, we now added the random expectation in Figure 4B. Finally we also addressed the minor comments."
}
]
}
] | 1
|
https://f1000research.com/articles/10-979
|
https://f1000research.com/articles/10-768/v1
|
06 Aug 21
|
{
"type": "Research Article",
"title": "Marine plant mediated green synthesis of silver nanoparticles using mangrove Rhizophora stylosa: Effect of variable process and their antibacterial activity",
"authors": [
"Nancy Willian",
"Syukri Syukri",
"Zulhadjri Zulhadjri",
"Syukri Arief",
"Nancy Willian",
"Syukri Syukri",
"Zulhadjri Zulhadjri"
],
"abstract": "Background: Most natural plants used in the synthesis of silver nanoparticles are limited to marine plants. To carry out applications, colloidal silver nanoparticles (AgNps) should have appropriate properties such as homogeneous shapes, small and narrow particle size distribution, and long time stability. This study aims to determine the effects of a variable process of AgNps mediated mangrove Rhizophora stylosa (RS) leaf extract, and antibacterial activity. Methods: Synthesis of AgNps was carried out by stirring silver nitrate solution with aqueous extract. The characterization of AgNps was carried out using UV-Vis spectrophotometry, X-ray diffraction (XRD), Dynamic Light Scattering (DLS) zetasizer and Transmission Electron Microscopy (TEM). Evaluation of antibacterial activity was carried out on Escherichia coli and Staphylococcus aureus. Reaction conditions such as the concentration of metal ions (0.001 M, 0.005 M, and 0.01 M), extracts (1%, 3%, and 5% v/v), and the reaction time on the size and stability of nanoparticles were also explored. Results: The UV-Vis spectroscopy showed an absorption of colloidal AgNps in a wavelength range of 403–443 nm. TEM analysis showed that as-synthesized AgNps were spherical in shape with a size range of 5–87 nm. The use of 0.001 M and 0.005 M of Ag+ resulted in a smaller diameter than the synthesized AgNps, using 0.01 M Ag+, in the same extract concentration. The range of zeta potential was -24.9 mV to -27.7 mV. The as-synthesized AgNps were stable for more than one month. The XRD analysis showed four peaks, which were attributed to the face centered cubic crystal structure of metallic silver. The results of the silver nanoparticles synthesis showed good activity on Escherichia coli and Staphylococcus aureus, with an inhibition zone between 4.1–7.2 mm. Conclusions: The AgNps synthesized with RS leaf extract, which is a reducing agent, showed good potential as an antibacterial component.",
"keywords": [
"green synthesis",
"Rhizophora stylosa",
"silver nanoparticles",
"antibacterial activity"
],
"content": "Introduction\n\nNanotechnology has become a new breakthrough in research, as it finds wide application, especially in biomedical fields.1 One of the most studied materials is silver nanoparticles, which have various methods of synthesis from physics, chemistry, and biology techniques. However, most processes have many disadvantages, especially chemical methods, which require the use of hazardous reagents that are not friendly to the environment. Furthermore, an alternative arises in the synthesis of nanoparticles with a biological approach by utilizing phytochemical compounds contained in plants.2 In general, these phytochemical compounds contain hydroxyl groups, which play a crucial role in the formation of silver nanoparticles through the reduction of Ag+ to Ag0.\n\nThe green synthesis of nanoparticles relies on the stability of silver nanoparticles of substances that are non-toxic, as well as solvents and reducing agents. The effectiveness of this product is based on the size and shape of the particles.3 To carry out applications, colloidal silver nanoparticles (AgNps) should have appropriate physical and chemical properties such as homogeneous shapes, small and narrow particle size distribution, and long-time stability. The control of nanoparticle growth from agglomeration is very important in the selection of stabilizers, donor metals, polymers, and surfactants since its potential application strongly depends on the stability. In addition, to reduce the hazardous effect on the environment, the use of natural reagents is being considered. The hydroxyl group in the natural polyphenol component acts as a reducing, as well as capping agent.4 By the double-function utilization of natural plants, the reagent used in the reaction could be diminished.\n\nCurrently, most of the natural plants used in the synthesis of silver nanoparticles are limited to terrestrial plants. Only a few studies report the use of marine plants. Indonesia as an archipelago has a wealth of marine resources such as mangroves. Its extracts are known to have antimicrobial abilities that have long been used by the community.5 One of them is Rhizophora stylosa (RS), which is a member of the Rhizophoraceae family in the Southeast Asian mangrove ecosystem. It is known to have several compounds that play an important role in biomedical applications. Some studies report that Rhizophora has several biological activities such as antibacterial, antioxidant and anti-cancer.6–9 Teraxerol, teraxerone (triterpenoids), sitosterol (steroids), protocatechuic acid and isovanillic acid (phenolic compounds), routine, astilbin, catechin (flavonoids) are the main compounds in RS mangrove plants. Those compounds show extraordinary pharmacological activities and are linked with the presence of –OH.10,11 In this study, RS leaf extract was used as a reducing agent in the production of RS-AgNps as well as a stabilizer.\n\nTo the best of our knowledge, this is the first research on RS mediated synthesis of silver nanoparticles. This study aims to investigate the effects of reaction conditions, such as reaction time, the amount of silver solution, and amount of extract, on the properties of fabricated silver nanoparticles. The antibacterial activity of as-synthesized RS AgNps was evaluated against Escherichia coli and Staphylococcus aureus, which are the main microbes present in wounds.12\n\n\nMethods\n\nFresh leaves of RS were collected from mangrove forest on Bintan Island, Riau Archipelago Indonesia. They were washed with double distilled water (DDW) to remove dust and other impurities. Clean leaves were shade-dried for 10–15 days and then ground to obtain leaf powder. The extraction of RS leaves was done by adding 20 grams of leaf powder into 100 ml of DDW (1:5) followed by heating at 65oC for 30 minutes with a hotplate stirrer. This mixture was then filtered using Whatman filter paper no. 1. The obtained extract was stored at 4°C for further experiments.\n\nSynthesis of silver nanoparticles was carried out by stirring silver nitrate solution with RS leaf extract in a total volume of 50 mL at a constant speed of 500 rpm. The concentration of AgNO3 was varied to be 0.001 M, 0.005 M, and 0.01 M, while RS leaf extract was 1%, 3%, and 5% (v/v). The absorbance of the sample was periodically monitored after one, two, four, and six hours of stirring using UV-Vis spectroscopy. Therefore, all samples were stored in a sealed bottle to measure the absorbance after 24, 72, 168, and 720 hours. In this study, some synthesis variables, such as reaction time, extract, and silver precursor concentration were applied to determine the optimum conditions for fabricating stable colloidal silver nanoparticles.\n\nThe diameter and zeta potential of RS-AgNps were characterized using Dynamic Light Scattering (DLS) Zetasizer HORIBA (SZ-100) at 25 °C. Absorbance intensity and surface plasmon resonance (SPR) uptake were analyzed using UV-Vis spectroscopy (Shimadzu UV-1800 spectrophotometer) in wavelength range of 200-800 nm at 5 nm intervals. The device was fully controlled by the UV Probe version 2.42 software monitor package. The shape and particle size distribution of silver nanoparticles were calculated on the basis of TEM images (JEOL JEM 1400) processed using J software. X-ray diffraction (Shimadzu XRD-7000s, λ 1.5406 Å operated at a voltage of 30kV and current of 30mA) were used to investigate crystal structures of the samples.\n\nAntibacterial activity of the as-synthesized RS-AgNps was tested against Escherichia coli (Gram negative bacteria) and Staphylococcus aureus (Gram positive bacteria) using the agar diffusion method. Firstly, the bacteria were planted in nutrient agar (NA) and then cultivated for 24 hours at 37 °C. The suspended bacteria were transferred into 100 mL NA media and then poured into a petri dish. Sterile cotton with a colloidal nanoparticle sample with a concentration of 100 mg/mL were deposited in the well. DDW and amoxicillin were adopted as negative and positive controls, respectively, and the area of inhibition was measured after 24 hours of precipitation and incubation, tests were carried out in duplicate and the results displayed were averaged.\n\n\nResults and discussion\n\nThe formation of silver nanoparticles in the samples were specifically recognized by color changes from colorless to light yellow right after mixing the silver precursor and leaf extract (Table 1). It was confirmed by UV-Vis spectrophotometry analysis where AgNps provide specific peaks at a wavelength of about 403–443 nm. This analysis was based on the SPR phenomenon of spherical metallic nanoparticles, which is strongly influenced by shape and size.13\n\nFigure 1 shows the UV-Vis spectrum of as-synthesized RS-AgNps in a varied concentration of AgNO3 and RS leaf extract after a one-month reaction. The spectrum of silver nitrate solution (j) and RS leaf extract (k) provided peaks at wavelength 301 and 279 nm, respectively. In general, the peaks were then converted to a wavelength range of 419 to 446 nm, which were specific to spherical AgNps. The inset pictures show laser beam irradiation of the brown-colored samples based on the Tyndal effect. Those results strongly confirmed the formation of metallic silver nanoparticles through the reduction process of Ag+ to Ag0, which consisted of three stages of process i.e. reduction, nucleation, and growth.14 Similar studies on mangrove Rhizophora lamarckii plants have shown that spherical AgNps contribute to absorption bands of around 420 nm in the spectrum of particles.15\n\nThe inset shows the laser beam radiation.\n\nIn this study, RS-AgNps samples were prepared using a varied concentration of silver nitrate (0.001 M, 0.005 M, and 0.01 M) and RS leaf extract (1%, 3%, and 5% v/v) in order to determine the optimum reaction composition. The wavelength and absorbance value based on spectrophotometry analysis are shown in Table 1. It was shown that an increase in extract concentration (1% to 5%) significantly shortened the wavelength, which indicates smaller-sized AgNps were formed. However, based on the wavelength values, AgNps with the addition of 3% leaf extract tended to have less wavelength shift than those of AgNps with 1% and 5%. This suggested that the stability and growth of AgNps were maintained by the addition of 3% extract. This result strongly confirmed that RS leaf extract acted as a capping agent to stabilize and control the growth of AgNps. This was observed in all samples prepared using three different concentrations of silver nitrate.\n\nIn addition, an increase in silver nitrate concentration led to longer wavelength and showed the formation of bigger-sized AgNps. This phenomenon was related to the formation of aggregates due to the excessive amount of silver nitrate in the reaction, resulting in bigger sized AgNps.16 Hence, in order to fabricate stable small-sized AgNps, it is sufficient to apply a low concentration of silver nitrate i.e. 0.001 M and 0.005 M.\n\nThe leaf extract and silver ion concentration significantly affected the absorption intensity as well, as seen in Table 2. The AgNps samples prepared using 5% extract showed a higher absorption intensity than those prepared using 1% and 3%. This was observed both in the use of 0.001 M and 0.005 M silver nitrate. The absorption intensity reflects the number of metallic nanoparticles formed in the reaction. Hence, these results suggest that the more RS leaf extract used in the reaction, the greater the number of metallic nanoparticles formed. This strongly confirmed the role of leaf extract in reducing Ag+ to Ag0 and the formation of AgNps. This result is beneficial in industry because synthesis is carried out on a large scale.\n\nIn addition, the samples prepared using 0.005 M silver nitrate solution exhibited higher absorption intensity than those prepared using 0.001 M. It is assumed that the higher concentration of silver nitrate solution provided more reduction and led to a higher number of formed AgNps. However, the excessive silver nitrate solution in a concentration of 0.01 M resulted in a lower absorption intensity.\n\nIn general, there was no significant decrease in absorbance intensity during the reaction process up to a one-month reaction. This result suggested that the as-synthesized RS showed good stability. Furthermore, the AgNps size data and its correlation with the concentration of extract and silver solution is supported by the TEM data.\n\nFigure 2 shows the TEM images of RS-AgNps, which are spherical in shape with a size range of 5–87 nm. The mean diameter of AgNps prepared using 0.001 M, 0.005 M, and 0.01 M silver nitrate and the addition of 3% extract were 25 nm, 22 nm, and 45 nm, respectively. These results show that the concentration of silver nitrate affects the size of the nanoparticles, where the use of 0.01 M silver nitrate resulted in a larger diameter of AgNps than those prepared using a lower concentration. It was confirmed that there is a strong correlation between the mean particle diameter with absorption wavelength of AgNps. The shift to longer wavelength (red shift) in UV-Vis spectrophotometry analysis indicates a larger mean diameter.17 Figure 2a and 2b show smaller particle size.\n\nTransmission electron microscope images of Rhizophora stylosa silver nanoparticles (RS-AgNps) and particle size distribution: (a, d) AgNps 0.001M 3% with particle size of 5 nm–70 nm and mean diameter 25 nm, (b, e) AgNps 0.005 M 3%, with particle size of 5 nm–77 nm and mean diameter 22 nm (c, f) AgNps 0.01 M 3%, with particle size of 23 nm–87 nm and mean diameter 45 nm.\n\nIn Figure 2c, there was a slight agglomeration at 0.01 M. Particles in this study are ionic silver nanoparticles dispersed in aquades, permanent dipole and induced dipole between particles that are close together so that they undergo aggregation due to the van der Waals force.18,19 Particle aggregation causes the size to become large. Aggregation also indicates the small repulsion force between particles, which causes colloid instability. In previous studies, leaf synthesis for nanoparticles (NP) production in mangrove Rhizophora mucranata,20 Rhizophora apiculata21 and Rhizophora lamarckii17 had successive particle sizes of 60–95, 19–42, 12–28 nm through reduction of silver nitrate compounds. In this study the nanoparticles produced were much smaller in size by controlling the amount of extracts and precursors.\n\nBased on the DLS analysis, the hydrodynamic particle size of colloidal RS-AgNps ranges from 98–125 nm, which is larger than TEM measurements. This is due to the different measurement principles between TEM, and DLS. The latter method measures the hydrodynamic size of nanoparticles in aqueous suspensions including the metal core, and any biological molecule attached to the surface of the particles.22 The zeta potential is an important parameter for assessing the stability of AgNps in aqueous suspensions. When the value is greater, either positive or negative, it suggests that molecules tend to repulse each other, hence it increases the suspension stability. The negative potential values shown by the bio-synthesized AgNps reflect the presence of bio-organic components in the extract as a capping agent.13,23\n\nA zeta potential value of ± 30 mV is required for indication of a stable nanoparticle suspension.24,25 The zeta ability of RS-AgNps colloids range from (−24.9) mV up to (−27.7) mV. In addition, the extract concentration in colloidal AgNps influenced the polydispersity index as well. The polydispersity index showed the dimensions of the particle size distribution, while a polydispersity index value > 0.7 indicates a very wide dispersion.26 AgNps 0.001 M and 0.005 M with addition of 3% extract showed a narrow size distribution (Figure 2d and 2e). It was confirmed by a polydispersity index of 0.37. Similar research was carried out by Nasiriboroumand et al., who synthesized AgNps mediated by pomegranate rind.4 The zeta potential was found to be −37 mV to −32 mV and a PDI value of 0.25. It showed a narrow particle size distribution with good stability.\n\nX-ray diffraction (XRD) analysis was carried out in order to investigate the crystallinity of as-synthesized RS-AgNps. The diffraction pattern (Figure 3) showed diffraction peaks that are well resolved at an angle of 2θ at 38.28, 44.45, 64.53 and 77.53, which correspond to (111), (200), (220), (311) of face-centered cubic structure of metallic silver (ICSD No. 4068). These results confirmed UV-Vis spectroscopy and the TEM analysis result, which showed that AgNps have been successfully obtained by the mediation of RS leaf extract. Some other peaks (marked by asterisks*) were observed in the diffraction pattern. It is assumed that these referred to the presence of reducing, and capping agent on the surface of the AgNps and the additional diffraction peaks in the XRD pattern were due to bio-organic crystallization in the plant extract.27 These results were similar to those found in AgNps synthesized through mediation of other marine plants i.e. Ecklonia cava algae extract.5 This happened in the use of other marine plants like Rhizophora stylosa as well.\n\nX-ray diffraction of Rhizophora stylosa mediated silver nanoparticles. (*) bio-organic crystallization in the plant extract (Khader et al., 2019).\n\nSilver nanoparticles with sizes <100 nm have been of great concern to researchers due to their small particle size and high surface area properties.28 In this study, the antimicrobial activity of RS-AgNps was tested against two types of bacteria i.e. Escherichia coli and Staphylococcus aureus as representatives of Gram negative and Gram-positive bacteria, which were commonly used to evaluate the activity of nanoparticles in previous studies.29,30 The antibacterial testing method uses the agar diffusion method. Amoxcillin and distilled water were used as positive and negative controls, respectively. The test was run in duplicate, and all data presented were averaged.\n\nThe results showed that the three variations in the AgNp concentration significantly affected the inhibition zone. As shown in Table 3 and Figure 4, the area of restriction for a concentration of 0.001 M; 0.005 M and 0.01 M RS-AgNps respectively, are 5.5 mm, 7.2 mm, and 5.1 mm for E. coli and 4.3 mm for S. aureus bacteria. A higher zone of inhibition was found in the 0.005 M concentration of AgNps against E. coli and S. aureus.\n\nAntibacterial activity of silver nanoparticles against: a) Escherichia coli and b) Staphylococcus aureus.\n\nDiameter of inhibition zone of synthesized silver nanoparticles (RS-AgNps) against Escherichia coli and Staphylococcus aureus.\n\nGenerally, it was observed that as-synthesized AgNps showed a greater inhibitory zone diameter against E. coli. than S. aureus. These results suggest that RS-AgNps is more specific against Gram negative bacteria than against Gram positive bacteria. The Gram-positive bacteria have a thick layer of peptidoglycan (80 nm) in the cell wall, and this zone has covalent bonds with teichoic and teichuronic acids, whereas Gram negative bacteria have a thin peptidoglycan layer (~8 nm thick) with a lipopolysaccharide external membrane (1–3 μm thick). Another possible cause for their vulnerability to nanoparticles (NP) are these bacteria are coated with lipopolysaccharides, which are negatively charged. These negative loaded molecules are closer to positive ions, which are mostly released through NP leading to ion uptake and increased intracellular damage. NP exhibit their antibacterial activity by different pathways, which are summarized as a combination of ROS production, altered gene regulation, cell wall penetration, and binding metabolites, among other processes.31\n\nIn addition, the region of maximum inhibition of AgNps was observed based on the TEM results. As corresponding to the average diameter estimated by TEM analysis, there is a correlation between mean diameter of NP and its antibacterial activity. The resulting smaller-sized particles (22 nm) have a larger inhibitory zone, as well as stable colloidal AgNps. Choi and Hu (2008) reported that this phenomenon was due to the easiness of the small-sized NP to penetrate into the bacteria cell. In addition, smaller NP have a larger surface area, resulting in a larger interaction site of NP and bacteria.32\n\nAccording to Aromal and Philip (2012), the mechanism of antibacterial activity of metallic NP is highly dependent on the interaction or bond between NP and compounds in the bacteria cell wall. Firstly, the metallic nanoparticles penetrate into the cell and then interfere with cell metabolism, especially with the organelle involved in protein synthesis.33 From this study, it can be concluded that RS-AgNps may be developed as an antimicrobial agent.\n\nOther types of mangroves have also been used as reducing agents for the synthesis of AgNps against pathogenic bacteria including E. coli and S. aureus, such as Ceriops tagal,34 Exoecaria agallocha,35 Sonneratia apetala,32 and Rhizophora mucranata.33\n\n\nConclusion\n\nSilver nanoparticles with a particle size range of 5–87 nm or an average of 22 nm have been successfully synthesized with a wavelength of 403–443 nm by bioreduction using leaf extracts of the Rhizophora stylosa mangrove plant. The results of UV-Vis spectroscopy and TEM analysis showed the formation of smaller sized nanoparticles. DLS, zeta potential and index polydispersion analysts have demonstrated the stability of nanoparticles within a month of the reaction. The influence of reaction time, silver nitrate dissolution concentration and effect of extract amount showed a joint relationship. A silver nitrate concentration of 0.001 M and 0.005 M was able to produce smaller nanoparticles and the optimal concentration of extract used was 3% (v/v). Antibacterial activity showed that silver nanoparticles mediated by RS mangroves have biomedical potential.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "Acknowledgements\n\nThis research work was supported by Ministry of Finance Indonesia. Funding this works was supported by Pengelola Dana Penelitian (LPDP) of Ministry of Finance Indonesia under Grant No. 201710210211848.\n\n\nReferences\n\nElahi N, Kamali M, Baghersad MH: Recent biomedical applications of gold nanoparticles: A review. Talanta. 2018; 184: 537–556. PubMed Abstract | Publisher Full Text\n\nHembram KC, Kumar R, Kandha L, et al.: Therapeutic prospective of plant-induced silver nanoparticles: application as antimicrobial and anticancer agent. Artif. Cells, Nanomed. Biotechnol. 2018; 0: 1–14. PubMed Abstract | Publisher Full Text\n\nKhader SZA, Syed Zameer Ahmed S, Sathyan J, et al.: A comparative study on larvicidal potential of selected medicinal plants over green synthesized silver nano particles. Egypt. J. Basic Appl. Sci. 2018; 5: 54–62. Publisher Full Text\n\nNasiriboroumand M, Montazer M, Barani H: Preparation and characterization of biocompatible silver nanoparticles using pomegranate peel extract. J. Photochem. Photobiol. B Biol. 2018; 179: 98–104. PubMed Abstract | Publisher Full Text\n\nVenkatesan J, Kim S, Shim MS: Antimicrobial, Antioxidant, and Anticancer Activities of Biosynthesized Silver Nanoparticles Using Marine Algae Ecklonia cava.2016. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKumar J, Hrudaya P, Thatoi N: Metabolic diversity and bioactivity screening of mangrove plants: a review.2011; pp. 1051–1061. Publisher Full Text\n\nRamalingam V, Rajaram R: Enhanced antimicrobial, antioxidant and anticancer activity of Rhizophora apiculata: An experimental report. 3 Biotech. 2018; 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAsmathunisha N, Kathiresan K: A review on biosynthesis of nanoparticles by marine organisms. Colloids Surf B Biointerfaces. 2013; 103: 283–287. PubMed Abstract | Publisher Full Text\n\nKumar SD, Singaravelu G, Ajithkumar S, et al.: Mangrove-Mediated Green Synthesis of Silver Nanoparticles with High HIV-1 Reverse Transcriptase Inhibitory Potential. J. Clust. Sci. 2017; 28: 359–367. Publisher Full Text\n\nLi DL, Li XM, Peng ZY, et al.: Flavanol derivatives from Rhizophora stylosa and their DPPH radical scavenging activity. Molecules. 2007; 12: 1163–1169. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTakara K, Kuniyoshi A, Wada K, et al.: Antioxidative Flavan-3-ol Glycosides from Stems of Rhizophora stylosa. Biosci. Biotechnol. Biochem. 2008; 72: 2191–2194. PubMed Abstract | Publisher Full Text\n\nSyed Zameer Ahmed S, Balu N, Khader SZA, et al.: Fabrication and evaluation of bamboo fabric coated with extracts of Curcuma longa, Centella asiatica and Azadirachta indica as a wound dressing material. Adv. Tradit. Med. 2020. Publisher Full Text\n\nRolim WR, Pelegrino MT, de Araújo Lima B, et al.: Green tea extract mediated biogenic synthesis of silver nanoparticles: Characterization, cytotoxicity evaluation and antibacterial activity. Appl. Surf. Sci. 2019; 463, pp. 66–74. Publisher Full Text\n\nMittal AK, Chisti Y, Banerjee UC: Synthesis of metallic nanoparticles using plant extracts. Biotechnol. Adv. 2013; 31: 346–356. PubMed Abstract | Publisher Full Text\n\nRahman A, Kumar S, Bafana A, et al.: Biosynthetic conversion of Ag+ to highly Stable Ag0 nanoparticles by wild type and cell wall deficient strains of chlamydomonas reinhardtii. Molecules. 2019; 24. PubMed Abstract | Publisher Full Text | Free Full Text\n\nParham S, Wicaksono DHB, Bagherbaigi S, et al.: Antimicrobial Treatment of Different Metal Oxide Nanoparticles: A Critical Review. J. Chinese Chem. Soc. 2016; 63: 385–393. Publisher Full Text\n\nkumar MNSD, Singaravelu G, Ajithkumar S, et al.: Mangrove-Mediated Green Synthesis of Silver Nanoparticles with High HIV-1 Reverse Transcriptase. Clust. Sci. 2016. Publisher Full Text\n\nMajeed A, Ullah W, Anwar AW, et al.: Cost-effective biosynthesis of silver nanoparticles using different organs of plants and their antimicrobial applications: A review.2016; 7857. Publisher Full Text\n\nKharissova OV, Kharisov BI, Oliva González CM, et al.: Greener Synthesis of Chemical Compounds and Materials.2019; 6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUmashankari J, Inbakandan D, Ajithkumar TT: Mangrove plant, Rhizophora mucronata (Lamk, 1804) mediated one pot green synthesis of silver nanoparticles and its antibacterial activity against aquatic pathogens.2012: 1–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGnanadesigan M, Anand M, Ravikumar S, et al.: Biosynthesis of silver nanoparticles by using mangrove plant extract and their potential mosquito larvicidal property. Asian Pac. J. Trop. Med. 4: 799–803. PubMed Abstract | Publisher Full Text\n\nAntony PJJ, Sivalingam P, Siva D, et al.: Comparative evaluation of antibacterial activity of silver nanoparticles synthesized using Rhizophora apiculata and glucose. Colloids Surf B Biointerfaces. 2011; 88: 134–140. PubMed Abstract | Publisher Full Text\n\nSingh P, Kim YJ, Singh H, et al.: Biosynthesis of Anisotropic Silver Nanoparticles by Bhargavaea indica and Their Synergistic Effect with Antibiotics against Pathogenic Microorganisms.2015; 2015: 10. Publisher Full Text\n\nRavichandran V, Vasanthi S, Shalini S, et al.: Green synthesis, characterization, antibacterial, antioxidant and photocatalytic activity of Parkia speciosa leaves extract mediated silver nanoparticles. Results Phys. 2019; 15: 102565. Publisher Full Text\n\nLopes LCS, Brito LM, Bezerra TT, et al.: Silver and gold nanoparticles from tannic acid: Synthesis, characterization and evaluation of antileishmanial and cytotoxic activities. An. Acad. Bras. Cienc. 2018; 90: 2679–2689. PubMed Abstract | Publisher Full Text\n\nBalavandy SK, Shameli K, Biak DRBA, et al.: Stirring time effect of silver nanoparticles prepared in glutathione mediated by green method. Chem. Cent. J. 2014; 8: 1–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhader SZA, Syed Zameer Ahmed S, Ganesan GM, et al.: Rhynchosia rufescens AgNPs enhance cytotoxicity by ROS-mediated apoptosis in MCF-7 cell lines. Environ. Sci. Pollut. Res. 2019; 27: 2155–2164. PubMed Abstract | Publisher Full Text\n\nLakhan MN, Chen R, Shar AH, et al.: Eco-friendly green synthesis of clove buds extract functionalized silver nanoparticles and evaluation of antibacterial and antidiatom activity. J. Microbiol. Methods. 2020; 173: 105934. PubMed Abstract | Publisher Full Text\n\nGirón-Vázquez NG, Gómez-Gutiérrez CM, Soto-Robles CA, et al.: Study of the effect of Persea americana seed in the green synthesis of silver nanoparticles and their antimicrobial properties. Results Phys. 2019; 13. Publisher Full Text\n\nSyukri A, Fri Wardana N, Zulhadjri Z, et al.: High antibacterial properties of green synthesized gold nanoparticles using Uncaria gambir Roxb. leaf extract and triethanolamine. J. Appl. Pharm. Sci. 2020; 10: 124–130. Publisher Full Text\n\nSlavin YN, Asnis J, Häfeli UO, et al.: Metal nanoparticles: Understanding the mechanisms behind antibacterial activity. J. Nanobiotechnology. 2017; 15: 1–20. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChoi O, Hu Z: Size dependent and reactive oxygen species related nanosilver toxicity to nitrifying bacteria. Environ. Sci. Technol. 2008; 42: 4583–4588. PubMed Abstract | Publisher Full Text\n\nAswathy Aromal S, Philip D: Green synthesis of gold nanoparticles using Trigonella foenum-graecum and its size-dependent catalytic activity. Spectrochim. Acta - Part A Mol. Biomol. Spectrosc. 2012; 97: 1–5. PubMed Abstract | Publisher Full Text\n\nPriya Dhas S, Mukerjhee A, Chandrasekaran N: Phytosynthesis of silver nanoparticles using Ceriops tagal and its antimicrobial potential against human pathogens. Int. J. Pharm. Pharm. Sci. 2013; 5: 349–352.\n\nBhuvaneswari MAR, John Xavier R: Facile synthesis of multifunctional silver nanoparticles using mangrove plant Excoecaria agallocha L. for its antibacterial, antioxidant and cytotoxic effects. J. Parasit. Dis. 2016. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "122119",
"date": "18 Feb 2022",
"name": "Manoj Kumar Choudhary",
"expertise": [
"Reviewer Expertise Synthesis",
"Characterization and Environmental Applications of metal nanoparticles",
"carbonaceous materials and photocatalytic materials"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe theory should be more explanatory and well written to improve the readability of this article.\n\nIncorrect inter-relation between the data in the tables and the statements in the text.\n\nLack of consideration of reference materials as the authors of this article directly give statement rather than giving particular reference to that statement.\n\nA statement has been given in the article “these compounds show extraordinary pharmacological activities and are linked with the presence of –OH” What does it referred to?\n\nIn the results and discussion part, the UV-Vis spectrum of synthesized nanoparticles is not clearly explained and hence unjustified.\n\nIn the discussion of table 1 (in results and discussion part), the relation between the size of Nps, wavelength and concentration of extract should be properly explained. Authors may follow a recent article of mine titled, “Evaluation of the kinetic and catalytic properties of biogenically synthesized silver nanoparticles”1.\n\nThe statement made by authors “Ag Nps with addition of 3% leaf extract tend to have less wavelength shift than those of 1% and 5%” needs more elaborated explanation with proper justification and latest reference to support it.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-768
|
https://f1000research.com/articles/11-530/v1
|
16 May 22
|
{
"type": "Software Tool Article",
"title": "The third international hackathon for applying insights into large-scale genomic composition to use cases in a wide range of organisms",
"authors": [
"Kimberly Walker",
"Divya Kalra",
"Rebecca Lowdon",
"Guangyi Chen",
"David Molik",
"Daniela C. Soto",
"Fawaz Dabbaghie",
"Ahmad Al Khleifat",
"Medhat Mahmoud",
"Luis F Paulin",
"Muhammad Sohail Raza",
"Susanne P. Pfeifer",
"Daniel Paiva Agustinho",
"Elbay Aliyev",
"Pavel Avdeyev",
"Enrico R. Barrozo",
"Sairam Behera",
"Kimberley Billingsley",
"Li Chuin Chong",
"Deepak Choubey",
"Wouter De Coster",
"Yilei Fu",
"Alejandro R. Gener",
"Timothy Hefferon",
"David Morgan Henke",
"Wolfram Höps",
"Anastasia Illarionova",
"Michael D. Jochum",
"Maria Jose",
"Rupesh K. Kesharwani",
"Sree Rohit Raj Kolora",
"Jędrzej Kubica",
"Priya Lakra",
"Damaris Lattimer",
"Chia-Sin Liew",
"Bai-Wei Lo",
"Chunhsuan Lo",
"Anneri Lötter",
"Sina Majidian",
"Suresh Kumar Mendem",
"Rajarshi Mondal",
"Hiroko Ohmiya",
"Nasrin Parvin",
"Carolina Peralta",
"Chi-Lam Poon",
"Ramanandan Prabhakaran",
"Marie Saitou",
"Aditi Sammi",
"Philippe Sanio",
"Nicolae Sapoval",
"Najeeb Syed",
"Todd Treangen",
"Gaojianyong Wang",
"Tiancheng Xu",
"Jianzhi Yang",
"Shangzhe Zhang",
"Weiyu Zhou",
"Fritz J Sedlazeck",
"Ben Busby",
"David Molik",
"Daniela C. Soto",
"Fawaz Dabbaghie",
"Ahmad Al Khleifat",
"Medhat Mahmoud",
"Luis F Paulin",
"Muhammad Sohail Raza",
"Susanne P. Pfeifer",
"Daniel Paiva Agustinho",
"Elbay Aliyev",
"Pavel Avdeyev",
"Enrico R. Barrozo",
"Sairam Behera",
"Kimberley Billingsley",
"Li Chuin Chong",
"Deepak Choubey",
"Wouter De Coster",
"Yilei Fu",
"Alejandro R. Gener",
"Timothy Hefferon",
"David Morgan Henke",
"Wolfram Höps",
"Anastasia Illarionova",
"Michael D. Jochum",
"Maria Jose",
"Rupesh K. Kesharwani",
"Sree Rohit Raj Kolora",
"Jędrzej Kubica",
"Priya Lakra",
"Damaris Lattimer",
"Chia-Sin Liew",
"Bai-Wei Lo",
"Chunhsuan Lo",
"Anneri Lötter",
"Sina Majidian",
"Suresh Kumar Mendem",
"Rajarshi Mondal",
"Hiroko Ohmiya",
"Nasrin Parvin",
"Carolina Peralta",
"Chi-Lam Poon",
"Ramanandan Prabhakaran",
"Marie Saitou",
"Aditi Sammi",
"Philippe Sanio",
"Nicolae Sapoval",
"Najeeb Syed",
"Todd Treangen",
"Gaojianyong Wang",
"Tiancheng Xu",
"Jianzhi Yang",
"Shangzhe Zhang",
"Weiyu Zhou"
],
"abstract": "In October 2021, 59 scientists from 14 countries and 13 U.S. states collaborated virtually in the Third Annual Baylor College of Medicine & DNANexus Structural Variation hackathon. The goal of the hackathon was to advance research on structural variants (SVs) by prototyping and iterating on open-source software. This led to nine hackathon projects focused on diverse genomics research interests, including various SV discovery and genotyping methods, SV sequence reconstruction, and clinically relevant structural variation, including SARS-CoV-2 variants. Repositories for the projects that participated in the hackathon are available at https://github.com/collaborativebioinformatics.",
"keywords": [
"Structural variants",
"k-mer",
"Covid-19",
"Long-reads",
"Tomatoes",
"Cancer",
"Viral integration",
"Hackathon",
"NGS"
],
"content": "Introduction\n\nOne of the processes by which genomes incur deleterious changes are commonly linked to the genetic signatures known as structural variants (SVs). SVs are large genomic alterations, where large is typically (and somewhat arbitrarily) defined as encompassing at least 50 base pairs (bp). These genomic variants are typically classified as deletions, duplications, insertions, inversions, and translocations describing different combinations of DNA gains, losses, or rearrangements. Copy number variations (CNVs) are a particular subtype of SVs mainly represented by deletions and duplications. SVs are typically described as single events, although more complex scenarios involving combinations of SV types exist.1,2 Understanding how and why SVs occur can help gain a deeper understanding of evolutionary processes driving species divergence and phenotypic adaptation, genomic processes leading to genetic variation and etiologies of plant and animal diseases.3 With a recent deluge of available genomic data, SVs are an optimal target for computational biology research.4\n\nIn October 2021, 59 researchers from 14 countries participated virtually in the third Baylor College of Medicine & DNAnexus hackathon, focusing on interrelated topics such as SVs, short tandem repeats (STRs), k-mer profiling, viruses, reference refinement and annotation. The hackathon groups addressed questions around: the use of SVs in the localization and understanding of quantitative trait loci (QTL), reference-free analysis of SVs, parallelization of SV workflows, the assessment and refining the quality of detected SVs, use of SVs in the understanding of adaptation in viruses, and understanding genetic signatures of diseases through SVs. The international hackathon focused on nine softwares to answer these questions; eight of which we present in this paper: STRdust, kTom, INSeption, GeneVar2, cov2db, K-var, Imavirus, and a Reference Panel Generator (RPG) for diverse sequencing data analysis. Several emergent themes became apparent over the course of the hackathon.\n\nQTLs link a phenotypic trait to a local genomic region, and in its broadest definition, a molecular change affecting a phenotype.5 A direct connection can be drawn between some SVs and QTLs. Linking traits and their genetic underpinnings is a common practice in the fields of agricultural genomics, molecular evolution, and genetic disease research.6 Structural variation is one possible genomic change that could result in a QTL. This year’s hackathon featured work on tomatoes and other plants which provided an alternative viewpoint to the generally human-focused research of previous hackathons. Such cross-disciplinary research allows disparate groups working on similar problems to push the envelope of what is possible with current technologies.\n\nNucleotide sequence substrings of length k (k-mers) continue to prove useful in SV work and in genomics, however, the time needed to assess the frequency of SVs presents a resource problem.7 The reduction of the computational resources required to complete an SV assessment in a genome would allow greater amounts of SV data to be processed in genomic workflows. Many bioinformatic tools currently used to locate genomic SVs use a sliding window alignment technique, which can be time-consuming.8,9 However, implementing a k-mer based approach to create a pool of reference k-mers of known SVs, the annotation speed of variation in new genomes might be increased.10,11 k-mers have also been used in alignment-free methods, bypassing the need for reference genomes.12\n\nA portion of the hackathon focused on virus work. At the time of the hackathon, the COVID-19 pandemic was ongoing and the question of what SVs are present, and how they might change the behavior of SARS-CoV-2 was unresolved.\n\nTogether the projects of this hackathon represent a range of fields, a range of academic, industry, and government researchers, and a range of desired impacts in the field of SV analysis. Topical introductions to the specific work of each group can be found below, except from “nibSV” which was reported previously11 and did not achieve significant progress.\n\nShort tandem repeats (STRs) (i.e., repeated instances of short 2-6 bp DNA motifs) are widespread in the genomes of most organisms. Due to their highly polymorphic nature, STRs are frequently employed in population and evolutionary genomic studies ranging from genealogy to forensics and disease diagnostics.13 For example, in humans, expansions in functional STRs have been linked to many neurological and developmental disorders14,15 whereas in plants, STRs have been found to impact several traits important to agriculture including growth rate and yield.16 Yet, despite their importance, STRs remain relatively poorly characterized in most species. On the one hand, second-generation sequencing platforms (e.g., Illumina17 (RRID:SCR_010233)) are limiting our view of STR variation within the read length due to both the short length of sequencing reads produced as well as frequent amplification biases (such as GC-biases and over−/under-representation of certain reads on a genome-wide scale). On the other hand, third-generation sequencing platforms (namely, PacBio (PacBio Sequel II System,18 (RRID:SCR_017990)) and Oxford Nanopore Technologies (ONT)19 (RRID:SCR_003756)) allow for the generation of single-molecule reads spanning tens to hundreds of kilobases in length but error rates (~1% in PacBio HiFi reads and ~ 10–15% in ONT20) continue to exacerbate reliable STR detection. To mitigate this issue, several long-read STR calling methods have been developed in recent years, including PacmonSTR21(RRID:SCR_002796), NanoSatellite,22 TRiCoLOR23(RRID:SCR_018801), and Straglr24 – however, their usability remains limited due to platform and/or computational demands. In order to address these shortcomings, we introduce STRdust, a tool to accurately detect and genotype STRs from long reads.\n\nThe success of commercially cultivated vegetables requires a balance of selection for domestication traits while maintaining genomic diversity and quality characteristics, and this is particularly true for tomato breeding programs.25 Many desirable traits for crops are obtained by crossing elite breeding germplasm to wild relatives that carry a trait of interest (e.g., disease resistance or fruit flavor). This process of moving a genomic region from one species or distantly-related species into another is called introgression.25\n\nTomato is an important crop and indispensable in the diet of many cultures and regions. The demand for fresh and processed tomatoes makes them one of the most important vegetables grown globally, with >180 million tons of tomatoes produced in 2019 worldwide (FAOSTAT).26\n\nGenetic traits have been moved into cultivated tomatoes over the past several decades of tomato breeding through trait introgression. Identifying and tracking introgressed traits is a crucial function of modern tomato breeding.25 The introgression of traits often occurs as large presence/absence structural variants with novel genes or sequences. Some introgressions can be completely defined by de novo sequencing and assembly, but this can be expensive for many samples and is not always successful for more complex genomic introgressions.2 These complex structural variation patterns, coupled with the lack of reference genomes for many wild tomato relatives, complicate the efforts to locate or characterize the introgressed traits in the elite germplasm’s genome. Consequently, most marker sets today rely exclusively on SNPs, which do not always track diverse tomato genetics.27\n\nHere we present kTom, a tool to characterize the k-mer content of re-sequenced genomes and to identify k-mers that are unique to traited samples. kTom is a collection of off-the-shelf tools arranged to allow for a tractable characterization of k-mer frequencies in a population. We used re-sequenced tomato accessions for this demonstration, but the same approach can work for any species. Having a reference-free method to characterize and track introgression sequences will give researchers more agility to understand the nature of important traits.28\n\nSome types of SVs, such as insertions, play a crucial role in shaping the genome and thus the function of each gene. For example, more than 50 percent of mammalian genomes include a repeating DNA sequence known as transposable elements.29 Additionally, insertions can indicate an early tumorigenic event,30 demonstrating a role in disease, making it crucial to accurately identify them.\n\nRead-based SV calling methods broadly fall into the categories of alignment- and assembly-based approaches.2 In alignment-based approaches, SVs are inferred from patterns of abnormal read mapping on an existing reference sequence.2 Alignment-based approaches pose a popular method for calling SVs both from short-reads and long-reads, with a multitude of tools developed for both read mapping (e.g., BWA31(RRID:SCR_010910), Minimap232(RRID:SCR_018550), and NGMLR33(RRID:SCR_017620)) and SV detection (e.g., DELLY34(RRID:SCR_004603) and SNIFFLES33(RRID:SCR_004603)). A downside of alignment-based SV detection lies in the incomplete resolution of complex or large genomic rearrangements or insertions exceeding common read lengths.35 By contrast, assembly-based approaches utilize de novo sequence assemblies computed directly on the sampled reads, circumventing any biases introduced by the use of reference sequences.2 SVs are thereby called by aligning such assemblies against a reference and identifying local incongruencies. Commonly used tools include Canu36 (RRID:SCR_015880) and Flye37 (RRID:SCR_017016) for sequence assembly, Minimap2 and BlasR38 for alignment against a reference and SGVar35 and Paftools32 for SV calling. Assembly-based approaches can resolve even complex rearrangements and long insertions, but the construction of high-quality, haplotype-resolved assemblies requires thorough quality control and typically a high quality and diversity of data.39\n\nNext-generation sequencing (NGS) technologies can be a powerful source in uncovering underlying genetic causes of diseases, but significant challenges still remain for SV interpretation and clinical analysis for clinicians.40 Although various tools are available to predict the pathogenicity of a protein-changing variant—a list of these is available at OpenCRAVAT—they do not always agree, further compounding the problem.41\n\nHere we present GeneVar2: an open access, gene-centric data browser to support structural variant analysis. There are two ways to interact with GeneVar2. First, GeneVar2 takes an input of a gene name or an ID and produces a report that informs the user of all SVs overlapping the gene and any non-coding regulatory elements affecting expression of the gene. Second, users can upload variant call format (VCF) files from their analysis pipelines as input to GeneVar2. GeneVar2 will output clinically relevant information as well as provide useful visualizations of disease ontology and enrichment pathway analysis based on SV types.\n\nGlobal SARS-CoV-2 sequencing efforts have resulted in a massive genomic dataset availability to the public for a variety of analyses. However, the two most common resources are genome assemblies (deposited in GISAID41 (RRID:SCR_018251) and GenBank42 (RRID:SCR_002760), for example) and raw sequencing reads. Both of these limit the quantity of information, especially with respect to variants found within the SARS-CoV-2 populations. Genome assemblies only contain common variants, which is not reflective of the full genomic diversity within a given sample (even a single patient derived sample represents a viral population within the host43–46). Raw sequencing reads on the other hand require further analyses in order to extract variant information, and can often be prohibitively large in size.\n\nThus, we propose cov2db; a database resource for collecting low frequency variant information for available SARS-CoV-2 data. As of October 2021 there were more than 1.2 million SARS-CoV-2 sequencing datasets in the Sequence Read Archive (SRA)47(RRID:SCR_004891) and European Nucleotide Archive (ENA)48 (RRID:SCR_006515). Our goal is to provide an easy to use query system, and contribute to a database of VCF files that contain variant calls for SARS-CoV-2 samples. We hope that such interactive databases will speed up downstream analyses and encourage collaboration.\n\nk-mers are commonly used in bioinformatics for genome and transcriptome assembly, error correction of sequencing reads, and taxonomic classification of metagenomes.49,50 More recently, k-mers have been used for genotyping of structural variations in large datasets in a mapping-free manner.51 Sample comparison based on k-mers profiles provides a computationally efficient mapping-free way to address key differences between two biological conditions, avoiding the limitations of reference bias, mappability and sequencing errors.52–54 Of particular interest are case-control studies, that allow to pinpoint genetic loci putatively implicated with a phenotype or a disease.\n\nHere we develop a pipeline that takes a sample’s sequencing data from two distinct conditions (ideally control vs. treatment or two different conditions) as input and compares their k-mer profiles in order to highlight k-mers associated with the phenotype. This approach was tested in a panel of cancer cell lines from the NCI-60 dataset (RRID:SCR_003057) contrasting primary and metastatic tissues to highlight mutational signatures underlying cancer progression.\n\nViral infections impact human health as they can lead to short- and long-term diseases,55 including cancers. Different forms of cancer are caused by viruses such as human papillomaviruses56 and hepatitis B virus capable of integrating into the host genome.57 Other viruses such as human immunodeficiency viruses (HIV) integrate into the host genome as a normal part of viral replication, contributing to cancer indirectly, and less commonly directly through insertional mutagenesis.58 Knowing exactly where the integration events occur can help researchers and ultimately clinicians to better understand the effect of virus integration in disease.\n\nCommon assumptions about integrations are that they are single copy and show an absence of additional structural variability.58 Different mechanisms might lead to different insertion site topology. For example, one would expect a difference between natural HIV-1 p31 integrase-mediated integration (insertion + tandem duplication of five bases of host target site) vs. insertion of viral genomic content (after reverse transcription in case of retroviruses like HIV) with host cell’s DNA repair machinery. Such differences might include conservation of viral terminal repeat elements with virus-specific insertion signatures59 vs. divergence60 from this pattern.\n\nWhen considering model insertion sites for assay evaluation, insertion site location heterogeneity exists to varying degrees in natural infection (with different mechanisms such as virus-dependent integration vs. host-dependent insertion contributing differently) vs. transgenic model organism (in the case of the Tg26 HIV-1 transgenic mouse, pronuclear injection and insertion of restriction enzyme-digested pNL4–3.61 NL4–3 is the most common lab strain of HIV-1.62\n\nWith advances in sequencing technologies,63,64 high-throughput sequencing data is available to explore viral genome integration space. Integration sites can be detected through identification of breakpoints between host and virus genome(s).65 Some integrating viruses can produce run-on transcripts or may participate in trans-splicing between virus exon and downstream host exons.66 Integration events have been previously detected by identifying these and other signatures such as chimeric reads in short-read sequencing (single-end and paired-end) and long-read sequencing.65,67–75\n\nHere, we suggest tools and a general workflow that can be used for virus integration detection and discuss current caveats in using publicly available datasets for this type of analysis.\n\nDespite great advances in our knowledge of NGS data analysis, a diverse complete reference genome sequence is lacking for humans. This leads to lack of sensitivity for detecting small insertions and deletions (INDELs) and structural variation, incomplete architecture of large polymorphic CNVs and correctly calling single nucleotide variants (SNVs) at complex genomic regions. High-quality Telomere-to-Telomere (T2T) CHM13 long-read genome assembly from T2T consortium76 could be utilized as a reference panel to universally improve read mapping and variant calling.\n\nCurrently, we aim to provide a revised version of CHM13 reference panels along with an RPG pipeline based on 1000 Genomes Project77 (RRID:SCR_006828) common allele calls and those abnormally avoided stop codons. Overall, such reference panels will greatly improve future population-scale diverse sequencing data analysis and correctly identify hundreds of thousands of novel per-sample variants in clinical settings.\n\n\nMethods\n\nDNAnexus (RRID:SCR_011884), a cloud platform, was used to run the code developed at the hackathon. It provides flexibility to run a wide array of software applications either on a cloud workstation (default number of cores = 8) or on an interactive environment such as a Jupyter notebook (default number of cores = 16). One of these two resources were used to run the software during the hackathon, unless otherwise specified.\n\nSTRdust142 parses the CIGAR (a compressed representation of an alignment that is used in the SAM file format) of each read, either genome-wide or in user-specified loci, in order to identify sufficiently large (>15 bp) insertions or soft-clipped bases which could indicate the presence of an enlarged STR. The sequence of those candidate-expansions is extracted, along with 50 bp of flanking sequence. Leveraging the phased input data, such insertions are combined per haplotype when multiple of these are found close by (within 50 bp) across multiple reads. The combination is done using spoa 4.0.7,78 which generates a multiple sequence alignment and from that a consensus sequence. The obtained consensus sequence, in which inaccuracies inherent to the long read sequencing technologies should be reduced, is then used in mreps 6.2.01,79 which will assess the repetitive character of the sequence and identify the repeat unit (Figure 1).\n\nDuring the preparation phase, reads (either simulated or sequenced) are aligned to the corresponding reference genome with Minimap232 and the mapped reads are then phased using longshot. Next, STRdust identifies insertions and soft-clips from the Concise Idiosyncratic Gapped Alignment Report (CIGAR) string which identify regions of possible short tandem repeats (STR) expansion. These regions are further analyzed by performing de novo assembly using spoa and assessing the repetitiveness of the region with mreps. STRdust outputs the STR genotype as a tab separated table for further analysis. We evaluated STRdust by comparing the results of simulated STR expansions produced by SimiSTR based on the human (Genome Reference Consortium Human Build 38, GRCh38) and tomato (Solanum lycopersicum 4.0, SL4.0) reference genomes, to two novel tools: Straglr24 and TRiCoLOR.23\n\nSTRdust was tested against simulated STR datasets produced by SimiSTR. SimiSTR modified the GRCh38 (human) and SL4.0 (tomato) reference genome assemblies. Additional variation (SNVs) was introduced with SURVIVOR 1.0.780 at a rate of 0.001.\n\nLong reads were simulated using SURVIVOR80 for the GRCh38 (human) and SL4.0 (tomato) STR-modified genomes. Mapping was performed with Minimap232 2.24 two-fold (with and without the -Y parameter), and phasing was done with longshot 0.4.1.81 Default parameters were used for all tools, if not otherwise mentioned. STRdust results were compared to TRiCoLOR 1.1,23 and Straglr 1.1.124 using default parameters. Figure 1 shows the workflow of STRdust described in this section.\n\nSTRdust is very easy to implement. One can, simply input the bam file after cloning the python script as follows: python3 STRdust/STRDust.py mapped_long_reads.bam -o results_dir. For further details on installation and implementation, review our github page.\n\nkTom (k-mers for profiling Tomato introgressions)143 aims to use k-mers to tag introgressions in elite tomato germplasm.\n\nCurrent implementation\n\nThe kTom workflow (Figure 2a) processes re-sequenced genomes (only tested with Illumina short reads to date) to generate k-mer profiles per sample and calculates the population frequencies of these k-mers. Our use case is focused on k-mers with low-mid range frequencies, which we believe should capture k-mers unique to introgressed traits in our test population. Therefore, we use these k-mers to generate a distance matrix and understand the relatedness of samples.\n\nFrequency of selected k-mers in each accession analyzed. Differential k-mer frequencies are apparent in this view. Depending on the nature of the accessions, this view may provide a first glimpse into genetic sequences underlying structural variations that differentiate the accessions.\n\nTo prototype the kTom workflow, we used 40 Whole Genome Shotgun (WGS) datasets from the 84 tomato or wild species accessions generated by The 100 Tomato Genome Sequencing Consortium82 (BioProject PRJEB5235).\n\nData processing\n\nRaw FASTQ files were quality-checked with FastQC version 0.11.983(RRID:SCR_014583) and trimmed with Flexbar version 1.4.084(RRID:SCR_013001), clipping five bases on 5′ and 3′ ends and keeping reads with quality score > 20 and a minimum length of 50. k-mers were counted using functions in Jellyfish version 2.3.085(RRID:SCR_005491) (jellyfish count followed by jellyfish histo) with kmersize = 21. The k-mers histogram was generated with Genomescope version 1.0.086(RRID:SCR_017014). k-mer counts for individual samples were then aggregated into a k-mer frequency matrix of k-mers as rows and samples as columns. This frequency matrix can be visualized as an interactive heatmap (example Figure 2b) by running kmer_heatmap.R which uses ComplexHeatmap version 2.8.087 (RRID:SCR_017270), InteractiveComplexHeatmap version 1.1.388 and tidyverse v1.3.189 (RRID:SCR_019186) R packages.\n\nINSeption144 was tested using HiFi reads for sample HG002 (RRID:CVCL_1C78) retrieved from the genome in a bottle (GIAB) project.90 The reads were aligned against GRCh37 using Minimap232 and Sniffles 1.01233 was used to call SVs. We filtered out SVs that were supported by less than 10 reads using bcftools 1.1291 (RRID:SCR_005227). We extracted insertions that are larger than 999 nucleotides. No reads span the entire insertion. Additionally, we filtered reads that were not aligned to reference using samtools 1.1491 (RRID:SCR_002105), with the -f 4 option. Finally, we extracted reads that support each insertion studied: first, we extracted read names from the SV file using bcftools and grouped them using SV ID, followed by extracting the FASTA sequence from the binary alignment map (BAM) file using samtools and awk (Figure 3a, left-hand side).\n\nAllele frequency\n\nFor an analysis of the allele frequency (AF) for each mutation type, we created a Python92,93 (RRID:SCR_008394) script (SVStat.py) that takes a VCF as input. For each SV type, it stores the AF and how often this AF was encountered. This data is then being visualized in n different plots (with n representing the number of SV types), where the x-axis represents the AF and the y-axis represents the number of times each SV type occurs.\n\nClustering unmapped reads\n\nTo be able to assemble a sequence from all unmapped reads, we tried several approaches. We attempted to identify clusters of reads using the LROD version 1.094 package, which we found unsuitable for our purposes due to long runtimes. More successfully, we used the program CARNAC-LR version 1.0.095 to build clusters of reads using Minimap2 version 2.22 aligner32 and a subsequent k-mer based clustering approach. As output, for each cluster, all sequences and their IDs were exported into a FASTA file. On our testing dataset, we identified 64 such clusters. These clustered read files are then the basis for the next step for subsequent sequence assembly (Figure 3a right-hand side).\n\nDelegate read clusters to the sequence assembler\n\nAll cluster.fasta files were loaded into the assembler programs (Flye version 2.937 and Spades version 3.15.3,96 see software availability for input parameters) with another python script (clusterAssemble.py). This script has the ability to run a single cluster.fasta file or a whole batch within a directory. The inputs are the program location, program name, an optional flag: multi (for running the batch of clusters), an input directory or an input file, and an output directory (Figure 3a right-hand side continued).\n\nIdentifying integration sites for assembled clusters\n\nHaving successfully assembled contigs for N = 15 read clusters using Canu v2.236(RRID:SCR_015880), we searched for overlap of these contigs with the breakpoint regions of 30 previously identified long insertion sites. We reasoned that for each assembled contig which represents an insertion sequence, reads supporting the insertion breakpoint should also overlap with that specific contig. To find such contigs of interest, we first extracted the sequence reads (n = 604) which support a long inversion and therefore overlap at least one insertion breakpoint. This set of reads was then aligned against all 15 assembled contigs using Minimap2 (parameters: -x map-hifi -P), and using the contigs as a ‘pseudo’ reference. Finally, we manually inspected the resulting alignments to identify long (>3 kbp) contigs overlapping reads (Figure 3b).\n\nGeneVar2145 is an update of GeneVar,11 to help inform clinical interpretation of structural variants (Figure 4). It has expanded options allowing users to upload a VCF file, while maintaining its search functionality—based on gene name-on its web interface. GeneVar2 annotates the uploaded VCF file with a number of items which can then be downloaded by the user. Annotations include: SV allele frequency from gnomAD-SV85(RRID:SCR_014964) and probability of being loss-of-function intolerant (pLI) from gnomAD; transcripts and coding regions of the impacting gene from GENCODE (v35)97; the gene associations with corresponding phenotype annotation from OMIM100; and known clinical SVs and their pathogenicity from dbVar.86\n\nGreen boxes represent the initial features of GeneVar, implemented last year, while blue boxes represent new features implemented in GeneVar2 during this hackathon. (VCF: variant call format, SV: structural variation, CDS: coding sequence).\n\nAdditionally, when a user uploads a VCF file, an option to download graphs for visualizing SVs in the dataset, is available. There is an alternate format, comma-separated values (CSV), available to download with an annotated VCF. GeneVar2, written in R, is available on GitHub (Software availability section) with detailed instructions on installation and usage. GeneVar2 is a web-based application that can also be installed by an individual on their platform to run on the command line and launch locally. Instructions on how to build and run GeneVar2 on DNAnexus can be found here.\n\nWhen users launch GeneVar2 as a web-application, they can enter individual gene names (HGNC98(RRID:SCR_002827)), Ensembl99 (RRID:SCR_002344) gene accession (ENSG) or Ensembl transcript accession (ENST) for extracting various SVs overlapping their gene of choice. GeneVar2 will output the gene-level summary with detailed information about the SVs within the gene. It links the gene information to databases such as OMIM100 (RRID:SCR_006437), GTEx101(RRID:SCR_013042), gnomAD and allele frequency is reported based on gnomAD genomes and exomes.\n\nIf users first need to call SVs on their samples, the developers recommend Parliament2102(RRID:SCR_019187). Parliament2 runs a combination of tools to generate structural variant calls on whole-genome sequencing data. It can run the following callers: Breakdancer103(RRID:SCR_001799), Breakseq2,104 CNVnator105(RRID:SCR_010821), Delly2,34 Manta,106 and Lumpy107(RRID:SCR_003253). Because of synergies in how the programs use computational resources, these are all run in parallel. Parliament2 will produce the outputs of each of the tools for subsequent investigation. See the Parliament2 GitHub page for further details.\n\nAfter users upload a VCF file containing SVs, GeneVar2 annotated each entry with the genes overlapping the SV, allele frequency from gnomAD-SV, and assigns a clinical rank to all the SVs in the VCF relative to each other. This is accomplished using the main annotation script annotate_vcf.R. The final annotated file is available for download as a VCF and CSV format. For Gene and Disease ontology and pathway analysis, GeneAnnotationFromCSV. R supports the enrichment analysis using KEGG108–110(RRID:SCR_012773), Disease Ontology (DO),111 Network of Cancer Gene112 and Disease Gene Network (DisGeNET)113 (RRID:SCR_006178). In addition, several visualization methods were provided by Bioconductor package clusterprofiler114 (RRID:SCR_016884) and enrichplot115 to help interpreting enrichment and disease ontology results.\n\nAlternatively, if users prefer they can run GeneVar2 on the command line, by installing it on their platform. Users should have R version 4.1 or higher installed. In addition, you will need to have sveval, a custom R library, installed which can be accessed via BiocManager using ‘jmonlong/sveval’. Scripts and instructions can be found on GeneVar2’s Github repository in the software availability section.\n\ncov2db146 is implemented as a set of modular scripts which enable the user to annotate and reformat their original VCF files into mongoDB (RRID:SCR_021224) ready JavaScript object notation (JSON) documents. Namely, there are three key components provided within the code repository1: the VCF annotation and processing framework, together with the relevant software and scripts2; a sample set of annotated VCFs that can be used as a starting point for a SARS-CoV-2 iSNV database3; an R Shiny116 (RRID:SCR_001626) app to facilitate a graphical user interface (GUI) for the interactions and quick summaries of the data within the database (Figure 5). The fields to query the cov2db database, such as annotation and variant information, are listed in the readme on our Github page. All of the above can be used to spin up an independent instance of cov2db and provide a user interface to interact with it. Minimal system requirements for a local cov2db instance are dictated by the mongoDB requirements with the key limiting factor being RAM used. Large variant databases will consume substantial amounts of RAM, and we suggest hosting those on dedicated high memory compute servers. Cov2db can run on x86 *nix-style platforms as is. We have not tested the software on ARM architectures or Windows based hosts. End users can interact with a hosted database from any web browser.\n\nUser provided variant call format (VCF) (or iVar output) files are annotated and ultimately converted into JavaScript object notation (JSON). The resulting JSON files serve as the primary input into the database. Secondary input can be provided by supplying any relevant metadata with the sample accession numbers serving as key. The resulting database can be queried directly via mongoDB command-line interface (CLI) or summarized and presented visually via the corresponding R Shiny app. AWS: Amazon web services.\n\nOur current design supports input VCFs generated by LoFreq117 (RRID:SCR_013054) or converted into VCFs from the iVar118 output via provided script. These files are subsequently annotated with snpEff119 (RRID:SCR_005191) using the SARS-CoV-2 reference, and resulting information is recorded as an annotated VCF. Finally, we provide an additional script to convert the annotated VCFs into JSON files that can be directly integrated into the mongoDB database. Metadata intake for the database is separate, and linking between the metadata for the samples and the variant call data is done within the database via the accession number keys.\n\nAs a proof of concept for K-var,147 we used whole exome sequencing of the NCI-60 dataset, a panel of 60 different human tumor cell lines widely used for the screening of compounds to detect potential anticancer activity (Figure 6). k-mer frequencies were obtained for each sample, using the tool Jellyfish version 2.3.0. First, counts of k-mers of size 31 were obtained with jellyfish count. Using a custom script, k-mers sequence and counts were tabulated to facilitate downstream analyses. The frequency distribution was plotted using R v3.6.3120 (RRID:SCR_000432), and low frequency k-mers likely arising from sequencing errors were removed. We measured the relevance of k-mers to the condition using TF-IDF (term frequency-inverse document frequency) with pre-defined control and test datasets. k-mers significantly correlated to the disease are extracted using logistic regression followed by ranking and/or classification of the significant k-mers. The genomic positions of the disease associated k-mers were identified and these positions were run through the ensembl-VEP pipeline to detect probable biological consequences.\n\nThe k-mer composition of whole-genome sequencing (WGS) sequencing data from cases and controls is obtained using Jellyfish. Rare and common k-mers are identified based on their frequency across samples, and mapped to a reference genome to assess their putative functional impact. Selected k-mers are then compared between cases and controls using term frequency-inverse document frequency (TF-IDF) statistical modeling to evaluate association with the phenotype of interest. As a proof of concept, K-var was implemented using cancer samples from the NCI-60 dataset.\n\nThere’s an abundance of public high-throughput sequencing data (e.g. via the National Center for Biotechnology Information Sequence Read Archive). Some integrating viruses can produce run-on transcripts or may participate in trans-splicing between virus exon and downstream host exons.121 Others have shown that it is possible to identify integration events by identifying chimeric reads in single-end short-read and paired-end short-read sequencing, as well as long read sequencing.65,67–75 Others have not yet interrogated available large public datasets with current iterations of mapping.148\n\nWe sought to do so by scoping out the available data and exploring at least one control dataset. We then generated a non-exhaustive list of relevant human pathogenic viruses and evaluated tools for unbiased interrogation of paired-end short-read data. Minimap2 version 2.22,32 HISAT2 version 2.2.1122 (RRID:SCR_015530), and STAR version 2.7.9a123 (RRID:SCR_004463) were evaluated on paired-end short-read RNA-seq from the Tg26 mouse model with HIV believed to be inserted as a transgene. Minimap2 did not work for visual exploration by default, possibly because it treats paired-end reads as single-end. Mapped reads were viewed in IGV colored by orientation and with “view as pairs” selected. HISAT2 and STAR, both split-read mappers, worked to identify at least one previously identified insertion site on mouse chr8.124 Finally, we refined this approach using human plus individual virus genomes (Figure 7).\n\nTo scope out the samples relevant for viral integration studies, human viruses known to integrate were chosen, along with viruses believed not to integrate (negative control set). Not shown, a dataset to contain human immunodeficiency virus (HIV) sequence (Tg26) and to express HIV protein was used as a positive control for pipeline development. Sequence Read Archive (SRA) was evaluated for the presence of RNA-seq (expression) and DNA-seq (host genomic DNA) from relevant viruses. A generic pipeline was evaluated on the positive control dataset with the goal of processing viral samples in SRA. Future work would also evaluate identified insertion/integration sites for possible clinical relevance. (GO: Gene Ontology).\n\nThe mouse model used includes two “insertion sites” on chr8, one on chr18, two on chrX, and a camouflaged one on chr4 embedded in a LINE element (the last site validated by long-read sequencing and deep paired-end 150 genomic DNA sequencing). These sites segregated together when multiple animals were genotyped and sequenced.125,126 This behavior is suggestive of a yet to be defined complex structural variation encompassing multiple HIV transgene “copies” together with parts of different mouse chromosomes. The Tg26 HIV-1 transgenic mouse model61 illustrates the current limitations of using short-read sequencing, which may only capture virus:host junctions (insertion/integration half-sites) in the absence of recapitulating the entire insertion site unambiguously. When deriving putative viral integration sites from RNA-seq, sites may be more likely to be detected if coming from highly expressed loci.\n\nRPG149 is a scalable and easy to apply pipeline that utilizes input genome assembly (FASTA format) and gene annotations (GFF3 format), and outputs reference panels based on the 1000 Genomes Project (1KGP) common allele calls and those abnormally avoided stop codons. Currently, the RPG pipeline is tested on the T2T-CHM13 genomic data set provided by T2T consortium in an effort to provide high-quality reference panels for diverse sequencing data analysis (Figure 8). The generation of this panel is described in Figure 8 and the accompanying figure legend.\n\nCHM13 genome sequence (FASTA), gene annotations (GFF3), and combined 1000 Genomes Project single nucleotide variants (SNVs) and insertion/deletion (INDEL) call sets in variant call format (VCF) are retrieved from Amazon-AWS127 (RRID:SCR_012854) cloud. Only common alleles (>5% allele frequency (AF)) in the variant call set are retained. ClinVar128 database was used to annotate variant calls with any clinical significance. Subsequently, common allele calls are replaced with CHM13 rare alleles in CHM13 FASTA genome sequence. Finally, screen-out in-frame stop-codon sites from genome sequence in order to generate the final reference panel files in FASTA format.\n\nThe resultant output T2T genome features completeness (i.e. filled gaps in its genomic sequence) compared to previously available GRCh38 releases. It further harbors 1KGP common alleles and avoids stop codons. Such T2T genomic sequence can be utilized in the ‘read mapping’ and ‘variant calling’ steps while processing whole genome sequencing (WGS) data and has important applications in improving structural variant identification. The output files generated by RPG pipeline are available in GitHub repository (Software availability section) along with supplementary pre-processing scripts.\n\n\nUse cases\n\nPlease refer to the Methods section for implementation details of the software including its input/output options and dependencies.\n\nIdentification and characterization of STR using short-read sequencing data have been met with shortcomings including biases introduced by polymerase chain reaction (PCR) amplification. Long-read sequencing can identify STRs more accurately than short-read sequencing as reads can span across the entire repeat region, however, they still exhibit a high error rate. Although tools have been developed to address this problem, they still have limitations such as not being able to consider multiple STRs in a single read. To address this, our tool STRdust is capable of detecting and genotyping STRs in long-read sequencing data in both mammals and plants without prior genome annotation. As a proof of concept we simulated STRs expansions using the human and tomato reference genomes and current annotations and applied STRdust, which only requires a long read sequence alignment (see Methods). This tool can be used by plant breeders to accurately genotype STRs and develop linkage maps, which are essential for mapping quantitative trait loci and intelligently selecting for combinations of traits of interest in the offspring.\n\nIn plant breeding, important traits are often moved into elite breeding material through traditional plant breeding methods of crossing and back-crossing with phenotypic selection to retain the trait of interest. In the era of genomics, genotype markers can be used to track the introgression of traits into different lines. However, for traits with complex underlying genome biology, including structural variations, SNP-based markers are often insufficient to discover or track traits reliably in a breeding pipeline. This is particularly relevant for identifying and tracking disease resistance loci, which have been introgressed from wild tomato relatives into elite tomatoes over decades of breeding25 and higher-resolution tracking of those loci could accelerate tomato breeding. To circumvent the SNP-based limitations for finding and following trait introgressions, the kTom tool uses a k-mer approach to characterize re-sequenced genomes and identify potential k-mer tags for trait introgressions. The kTom tool enables the user to understand the k-mer profile of the resequenced genome (from Illumina WGS reads) and compare that to a background k-mer profile (e.g. the reference genome for that line or a known genome without the trait of interest) to identify novel k-mers. kTom can enable population-level analysis of structural variation, including establishing an alternate (non-SNP) genotyping method to profile introgressions within a population and investigating and visualizing the history of introgressions. A derivation of kTom data can facilitate understanding tomato population structure with a data type more able to account for SVs. In addition, the output of kTom should be able to form the basis for a k-mer GWAS approach.28 The kTom tool was designed with plant breeding problems in mind, but it can be applied to any resequencing dataset without the need for a reference genome.\n\nInsertions play an important role in human genetic variability and diseases, and therefore their accurate identification is key for genetic analyses and clinical studies. However, comprehensively identifying sequence-resolved insertions can be challenging, especially when the read length is not sufficient to span the whole inserted sequence. In those cases, SV callers will identify the insertion’s location but not its sequence. INSeption is a bioinformatics workflow that addresses this issue by reconstructing the inserted sequence utilizing the unaligned portions of reads (i.e. hanging reads). After retrieving a sample’s unaligned reads, INSeption builds a consensus sequence to provide sequence-resolved insertions. This information allows scientists to better assess the impact of an insertion on gene function and genome organization.\n\nSVs account for more genetic differences between humans than other types of variation and are the underlying genetic cause of several traits and diseases.33,129 Although SV discovery has become more readily available, its interpretation is particularly challenging for those outside the immediate field of genetics.40,41 GeneVar2 is an extremely fast and computationally efficient platform for the analysis, visualization, and interpretation of structural variation data. It is designed to provide a powerful and easy-to-use tool for applications in biomedical research and diagnostic medicine at minimal computational cost. Its comprehensive approach brings the analyses of structural variation within the reach of non-specialist laboratories and to centers with limited computational resources available.\n\nCataloging viral mutations within a sample (intra-host variation) and across samples (inter-host variation) provides critical insights to understanding the dynamics of viral evolution during the COVID-19 pandemic.130 The SARS-CoV-2 virus has been shown to have high genomic diversity45,131), and mutations can change the fitness of the virus132 by increasing its transmission or pathogenicity potential.133,134 SNVs can also result in dramatically different protein function and recognition,135,136 and studies have shown persistent intra-host evolution of SARS-CoV-2 in immunocompromised hosts.137 cov2db represents an integrative platform and complementary database for active monitoring of SARS-CoV-2 strain variants specific to circulating SARS-CoV-2 lineages and will facilitate efficient and sensitive tracking of both inter-host and intra-host SARS-CoV-2 variation.\n\nInput to cov2db consists of a single or multiple VCF file(s) in the format output by the LoFreq variant caller. Cov2db does not provide an output, but allows its users to interact with a mongoDB database instance containing the variant calling information provided by the users.\n\nThe identification of phenotype-associated biomarkers is crucial for precision medicine, crop breeding, and answering evolutionary questions. Based on the area of interest, K-var can be applied to identify mutational signatures that help distinguish between conditions using phenotype associations with low bias. Short-read sequencing data is used as input to estimate k-mer frequencies per sample, followed by statistical correlation to a known phenotype across two distinct conditions. The output is a ranked table of significant phenotype-associated k-mers that can be used to fish for genomic regions experiencing mutations. Precisely identifying these genomic locations will help in downstream analysis to infer biological consequences. During the hackathon, we ran K-var using as input metastatic and non-metastatic breast cancer whole-exome sequencing (non-metastatic n = 7; metastatic n = 5) from the NCI-60 dataset. K-var delivered a ranked list of 44,884 k-mers, where the score indicates the relevance of each sequence (calculated by TF-IDF analysis) in differentiating metastatic and non-metastatic (primary) sequences. The top-ranked k-mer identified by K-var impacted methyl-methanesulfonate sensitivity 19 (MMS19), a component of the Fe-S assembly machinery involved in the production of proteins associated with genomic stability, such as DNA polymerase and DNA repair proteins. This gene has been reported as a breast cancer candidate gene in familial studies in Tunisian individuals.138 The next highest-ranked k-mer impacted 1-Acylglycerol-3-Phosphate O-Acyltransferase 4 (AGPAT4), which has been proposed as required for triple-negative breast cancer progression.139 This ranked k-mer list and genes impacted provide a resource to “fish” for genes relevant to breast cancer metastasis.\n\nWhen deriving putative viral integration sites from RNA-seq, sites may be more likely to be detected if coming from highly expressed loci. The Tg26 mouse reanalyzed in the present study was made from pronuclear injection of pNL4–3 restriction products.61 Such insertion depends entirely on host DNA repair machinery on nuclear DNA with nuclear topology distinct from human cells which HIV more easily infects. As such, many of the sites missed during the RNA-seq interrogation may have been missed due to low levels of expression at those loci, or those parts of the complex insertion site. Many viruses have the capability of integrating into host genomes, leading to DNA damage and gene disruption. Accurately identifying virus integration sites and potentially disrupted genes is important to fully understand their impact on disease severity. However, identifying virus integration sites from genomic DNA is challenging and there are not many bioinformatics tools available to reliably detect viral presence or integration events. Here, we developed Imavirus, a bioinformatics approach that identifies putative virus integration sites (pIS) in public data. Using unbiased RNA-seq datasets, Imavirus aimed to identify pIS and to pinpoint clinically relevant viral integration sites, especially those that may affect cell function and possibly contributing to disease and/or antiviral responses and possibly contributing to virus fitness. Imavirus is a community resource that aids researchers by enhancing our knowledge of viral infection and improving disease severity prediction of viral infections. During the hackathon we were able to verify a previously reported integration site on mouse chr8 which can be seen in our GitHub repository cited in the Software Availability section.\n\nFuture work should explore the datasets we scoped out in SRA for more physiological systems such as animal models or stable cell lines to identify more putative insertion sites. Another important limitation of the positive control set explored here is that the Tg26 mouse has approximately 15 copies of HIV integrated at the same loci.125,126 While HIV signal may be coming from multiple loci, when considering junctions, most of the signal seemed to be coming from an HIV copy with run-on transcripts in chr8. Natural human infections would have distinct insertion sites, making them harder to spot with these approaches.\n\nThe human reference genome has served as a foundation for human genetics and genomics studies. Despite its countless applications, the current human reference genome assembly (GRCh38) harbors several gaps and missing nucleotides (‘N’ characters) that hinder comprehensive analysis. Therefore, complete T2T genome references are essential to make sure all the genomic variants are discovered and analyzed. Here, we implemented a pipeline that incorporates 1000 Genome Project common alleles and avoids stop codons into the T2T-CHM13 genome sequence, in order to provide a complete human reference sequence for diverse sequencing data analyses.\n\n\nConclusions\n\nThe results of the 2021 Baylor College of Medicine/DNAnexus hackathon described here represent novel work that pushes the field forward for human, plant, and viral genome SV detection. All are needed to further current findings about diversity and the complexity of organisms and their genotypes. To further facilitate this progress in a FAIR-compliant manner, 59 people, across the world with different professional backgrounds, came together in October 2021 to complete or further eight groundbreaking prototypes.\n\n\nNext steps\n\nSome directions that we think will be impactful in the future are:\n\nk-mer analyses avoid reference and mapping biases through a reference-free approach. We endeavor to create tools for k-mer analysis which work with both short- and long- read sequencing technologies. An example use case is the identification of rare variants can help in diagnostic purposes to identify disease biomarkers and therapeutic targets for personalized medicine. Along similar lines, crop breeding research can benefit from identifying markers associated with disease resistance.\n\nSpecifically, we would improve the kTom tool to enable quantification of k-mers to detect potential copy-number changes, and this would be particularly relevant for disease resistance loci, which often contain gene copy-number variations.140\n\nTo achieve these outcomes, additional modules can be added to the kTom code base. For example, for disease-resistance introgression that is known to be in some but not all of samples in a collection, the k-mer frequency matrix can be filtered to keep low-middle frequency k-mers. With or without this filtering step, a distance matrix can be computed from the k-mer frequency matrix and used for hierarchical clustering to suggest sets k-mers introgressed together. The resulting output can then be used for validation complemented by curated and known loci, and later for phenotypic association.\n\nFor clearer virus integration site mapping, long read DNA sequencing is preferable to short reads, but these types of data are sparse in major public repositories. The present hackathon scoped out sequences from the Sequence Read Archive and subset viruses and controls relevant for integration studies. Therefore, future work is needed to compare short-read datasets to long-read generated stable vs transient insertion sites in order to improve our understanding of the effects on viral replication, host gene regulation, and disease.\n\nTo inform clinical significance of SVs for clinicians and researchers, GeneVar2 is a comprehensive tool for understanding the impact of SVs on disease. To expand users’ ability to identify and communicate key SV findings, Samplot,141 a multi-sample structural variant visualizer, will be integrated with GeneVar2. Subsequent development will focus on further cloud integration and new output options, such as research reports and the ability to use the application off-line.\n\nThe annual nature of this hackathon has seeded teams and projects that are often ongoing for multiple years, resulting in mature software products. Other annual hackathons, particularly the NBDC/DBCLS (Japan) and ELIXIR (Europe) bio-hackathons, have seen the same. In this vein, we expect to see many of the projects that have been seeded here continue next year, and possibly in other hackathons.\n\n\nData availability\n\nThe data used for these projects were obtained from publicly accessible repositories and are available in Table 1.\n\n\nSoftware availability\n\nSource code available from: https://github.com/collaborativebioinformatics/STRdust\n\nRelease version: 0.2.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.6467829.142\n\nLicense: MIT.\n\nSource code available from: https://github.com/collaborativebioinformatics/kTom\n\nRelease version: 0.2.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.6467823.143\n\nLicense: MIT.\n\nSource code available from: https://github.com/collaborativebioinformatics/InSeption\n\nRelease version: 0.2.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.6467818.144\n\nLicense: MIT.\n\nSource code available from: https://github.com/collaborativebioinformatics/GeneVar2\n\nRelease version: 0.2.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.6467837.145\n\nLicense: MIT.\n\nSource code available from: https://github.com/collaborativebioinformatics/cov2db\n\nRelease version: 0.2.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.6467825.146\n\nLicense: MIT.\n\nSource code available from: https://github.com/collaborativebioinformatics/kvar\n\nRelease version: 0.2.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.6467850.147\n\nLicense: MIT.\n\nSource code available from: https://github.com/collaborativebioinformatics/imavirus\n\nRelease version: 0.2.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.6467774.148\n\nLicense: MIT.\n\nSource code available from: https://github.com/collaborativebioinformatics/RPG_Pikachu\n\nRelease version: 0.2.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.6467816.149\n\nLicense: MIT.",
"appendix": "Acknowledgements\n\nThe hackathon was sponsored by Pacific Biosciences of California, Inc. and Oxford Nanopore Technologies Limited. We’d like to thank Richard Gibbs and the Baylor College of Medicine Human Genome Sequencing Center for hosting the hackathon. Computation was performed on the DNAnexus platform, which donated compute and storage to the hackathon.\n\nThe U.S. Department of Agriculture is an equal opportunity lender, provider, and employer.\n\nMention of trade names or commercial products in this report is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture.\n\n\nReferences\n\nHo SS, Urban AE, Mills RE: Structural variation in the sequencing era. Nat. Rev. Genet. 2020 Mar; 21(3): 171–189. PubMed Abstract | Publisher Full Text\n\nMahmoud M, Gobet N, Cruz-Dávalos DI, et al.: Structural variant calling: the long and the short of it. Genome Biol. 2019 Nov 20; 20(1): 246. PubMed Abstract | Publisher Full Text\n\nSanchis-Juan A, Stephens J, French CE, et al.: Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing. Genome Med. 2018 Dec 7; 10(1): 95. PubMed Abstract | Publisher Full Text\n\nHurles ME, Dermitzakis ET, Tyler-Smith C: The functional impact of structural variation in humans. Trends Genet. 2008 May; 24(5): 238–245. PubMed Abstract | Publisher Full Text\n\nSerba DD, Daverdin G, Bouton JH, et al.: Quantitative trait loci (QTL) underlying biomass yield and plant height in switchgrass. Bioenerg. Res. 2015 Mar; 8(1): 307–324. Publisher Full Text\n\nHartl DL: A primer of population genetics and genomics. Oxford University Press; 2020. Publisher Full Text\n\nGe J, Guo N, Meng J, et al.: K-mer Counting for Genomic Big Data. Chin FYL, Chen CLP, Khan L, et al., editors. Big data – bigdata 2018. Cham: Springer International Publishing; 2018. p. 345–51.\n\nTajima F: Determination of window size for analyzing DNA sequences. J. Mol. Evol. 1991 Nov; 33(5): 470–473. PubMed Abstract | Publisher Full Text\n\nWellenreuther M, Mérot C, Berdan E, et al.: Going beyond SNPs: The role of structural genomic variants in adaptive evolution and species diversification. Mol. Ecol. 2019 Mar; 28(6): 1203–1209. PubMed Abstract | Publisher Full Text\n\nEbler J, Clarke WE, Rausch T, et al.: Pangenome-based genome inference. BioRxiv. 2020 Nov 12.\n\nMc Cartney AM, Mahmoud M, Jochum M, et al.: An international virtual hackathon to build tools for the analysis of structural variants within species ranging from coronaviruses to vertebrates. F1000Res. 2021 Mar 26; 10: 246. Publisher Full Text\n\nZielezinski A, Vinga S, Almeida J, et al.: Alignment-free sequence comparison: benefits, applications, and tools. Genome Biol. 2017 Oct 3; 18(1): 186. Publisher Full Text\n\nFan H, Chu J-Y: A brief review of short tandem repeat mutation. Genomics Proteomics Bioinformatics. 2007 Feb; 5(1): 7–14. Publisher Full Text\n\nPearson CE, Nichol Edamura K, Cleary JD: Repeat instability: mechanisms of dynamic mutations. Nat. Rev. Genet. 2005 Oct; 6(10): 729–742. Publisher Full Text\n\nMirkin SM: Expandable DNA repeats and human disease. Nature. 2007 Jun 21; 447(7147): 932–940. Publisher Full Text\n\nZhu L, Wu H, Li H, et al.: Short Tandem Repeats in plants: Genomic distribution and function prediction. Electron. J. Biotechnol. 2021 Mar; 50: 37–44. Publisher Full Text\n\nBentley DR, Balasubramanian S, Swerdlow HP, et al.: Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008 Nov 6; 456(7218): 53–59. PubMed Abstract | Publisher Full Text\n\nWenger AM, Peluso P, Rowell WJ, et al.: Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome. Nat. Biotechnol. 2019 Oct; 37(10): 1155–62. PubMed Abstract | Publisher Full Text\n\nShafin K, Pesout T, Lorig-Roach R, et al.: Nanopore sequencing and the Shasta toolkit enable efficient de novo assembly of eleven human genomes. Nat. Biotechnol. 2020 Sep; 38(9): 1044–1053. PubMed Abstract | Publisher Full Text\n\nDohm JC, Peters P, Stralis-Pavese N, et al.: Benchmarking of long-read correction methods. NAR Genom Bioinform. 2020 Jun; 2(2): lqaa037. PubMed Abstract | Publisher Full Text\n\nUmmat A, Bashir A: Resolving complex tandem repeats with long reads. Bioinformatics. 2014 Dec 15; 30(24): 3491–3498. PubMed Abstract | Publisher Full Text\n\nDe Roeck A, De Coster W, Bossaerts L, et al.: NanoSatellite: accurate characterization of expanded tandem repeat length and sequence through whole genome long-read sequencing on PromethION. Genome Biol. 2019 Nov 14; 20(1): 239. PubMed Abstract | Publisher Full Text\n\nBolognini D, Magi A, Benes V, et al.: TRiCoLOR: tandem repeat profiling using whole-genome long-read sequencing data. Gigascience. 2020 Oct 7; 9(10). PubMed Abstract | Publisher Full Text\n\nChiu R, Rajan-Babu I-S, Friedman JM, et al.: Straglr: discovering and genotyping tandem repeat expansions using whole genome long-read sequences. Genome Biol. 2021 Aug 13; 22(1): 224. PubMed Abstract | Publisher Full Text\n\nLin T, Zhu G, Zhang J, et al.: Genomic analyses provide insights into the history of tomato breeding. Nat. Genet. 2014 Nov; 46(11): 1220–6. PubMed Abstract | Publisher Full Text\n\nFAOSTAT: Choice Reviews Online.2011 Jan 1; 48(05): 48–2430–48–2430.\n\nSchouten HJ, Tikunov Y, Verkerke W, et al.: Breeding has increased the diversity of cultivated tomato in the netherlands. Front. Plant Sci. 2019 Dec 10; 10: 1606. PubMed Abstract | Publisher Full Text\n\nVoichek Y, Weigel D: Identifying genetic variants underlying phenotypic variation in plants without complete genomes. Nat. Genet. 2020 May; 52(5): 534–540. PubMed Abstract | Publisher Full Text\n\nHancks DC, Kazazian HH: Roles for retrotransposon insertions in human disease. Mob. DNA. 2016 May 6; 7: 9. PubMed Abstract | Publisher Full Text\n\nCajuso T, Sulo P, Tanskanen T, et al.: Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival. Nat. Commun. 2019 Sep 6; 10(1): 4022. PubMed Abstract | Publisher Full Text\n\nLi H, Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009 Jul 15; 25(14): 1754–1760. PubMed Abstract | Publisher Full Text\n\nLi H: Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics. 2018 Sep 15; 34(18): 3094–3100. PubMed Abstract | Publisher Full Text\n\nSedlazeck FJ, Rescheneder P, Smolka M, et al.: Accurate detection of complex structural variations using single-molecule sequencing. Nat. Methods. 2018 Jun; 15(6): 461–468. PubMed Abstract | Publisher Full Text\n\nRausch T, Zichner T, Schlattl A, et al.: DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012 Sep 15; 28(18): i333–i339. PubMed Abstract | Publisher Full Text\n\nTian S, Yan H, Klee EW, et al.: Comparative analysis of de novo assemblers for variation discovery in personal genomes. Brief Bioinformatics. 2018 Sep 28; 19(5): 893–904. PubMed Abstract | Publisher Full Text\n\nKoren S, Walenz BP, Berlin K, et al.: Canu: scalable and accurate long-read assembly via adaptive k-mer weighting and repeat separation. Genome Res. 2017 May; 27(5): 722–736. PubMed Abstract | Publisher Full Text\n\nKolmogorov M, Yuan J, Lin Y, et al.: Assembly of long, error-prone reads using repeat graphs. Nat. Biotechnol. 2019 May; 37(5): 540–546. PubMed Abstract | Publisher Full Text\n\nChaisson MJ, Tesler G: Mapping single molecule sequencing reads using basic local alignment with successive refinement (BLASR): application and theory. BMC Bioinformatics. 2012 Sep 19; 13: 238. PubMed Abstract | Publisher Full Text\n\nEbert P, Audano PA, Zhu Q, et al.: Haplotype-resolved diverse human genomes and integrated analysis of structural variation. Science. 2021 Apr 2; 372(6537). PubMed Abstract | Publisher Full Text\n\nIacoangeli A, Al Khleifat A, Sproviero W, et al.: ALSgeneScanner: a pipeline for the analysis and interpretation of DNA sequencing data of ALS patients. Amyotroph Lateral Scler Frontotemporal Degener. 2019 May; 20(3–4): 207–215. PubMed Abstract | Publisher Full Text\n\nIacoangeli A, Al Khleifat A, Sproviero W, et al.: DNAscan: personal computer compatible NGS analysis, annotation and visualisation. BMC Bioinformatics. 2019 Apr 27; 20(1): 213. PubMed Abstract | Publisher Full Text\n\nSayers EW, Cavanaugh M, Clark K, et al.: GenBank. Nucleic Acids Res. 2020 Jan 8; 48(D1): D84–D86. PubMed Abstract | Publisher Full Text\n\nLythgoe KA, Hall M, Ferretti L, et al.: SARS-CoV-2 within-host diversity and transmission. Science. 2021 Apr 16; 372(6539). PubMed Abstract | Publisher Full Text\n\nWang Y, Wang D, Zhang L, et al.: Intra-host variation and evolutionary dynamics of SARS-CoV-2 populations in COVID-19 patients. Genome Med. 2021 Feb 22; 13(1): 30. PubMed Abstract | Publisher Full Text\n\nSapoval N, Mahmoud M, Jochum MD, et al.: SARS-CoV-2 genomic diversity and the implications for qRT-PCR diagnostics and transmission. Genome Res. 2021 Apr; 31(4): 635–644. PubMed Abstract | Publisher Full Text\n\nArmero A, Berthet N, Avarre J-C: Intra-Host Diversity of SARS-Cov-2 Should Not Be Neglected: Case of the State of Victoria, Australia. Viruses. 2021 Jan 19; 13(1). PubMed Abstract | Publisher Full Text\n\nLeinonen R, Sugawara H, Shumway M: International Nucleotide Sequence Database Collaboration. The sequence read archive. Nucleic Acids Res. 2011 Jan; 39(Database issue): D19–D21. PubMed Abstract | Publisher Full Text\n\nLeinonen R, Akhtar R, Birney E, et al.: The european nucleotide archive. Nucleic Acids Res. 2011 Jan; 39(Database issue): D28–D31. PubMed Abstract | Publisher Full Text\n\nCompeau PEC, Pevzner PA, Tesler G: How to apply de Bruijn graphs to genome assembly. Nat. Biotechnol. 2011 Nov 8; 29(11): 987–991. PubMed Abstract | Publisher Full Text\n\nZhao L, Xie J, Bai L, et al.: Mining statistically-solid k-mers for accurate NGS error correction. BMC Genomics. 2018 Dec 31; 19(Suppl 10): 912. PubMed Abstract | Publisher Full Text\n\nBreitwieser FP, Baker DN, Salzberg SL: KrakenUniq: confident and fast metagenomics classification using unique k-mer counts. Genome Biol. 2018 Nov 16; 19(1): 198. PubMed Abstract | Publisher Full Text\n\nRahman A, Hallgrímsdóttir I, Eisen M, et al.: Association mapping from sequencing reads using k-mers. elife. 2018 Jun 13; 7. PubMed Abstract | Publisher Full Text\n\nMehrab Z, Mobin J, Tahmid IA, et al.: Reference-free Association Mapping from Sequencing Reads Using k-mers. Bio Protoc. 2020 Nov 5; 10(21): e3815. PubMed Abstract | Publisher Full Text\n\nWang Y, Chen Q, Deng C, et al.: KmerGO: A Tool to Identify Group-Specific Sequences With k-mers. Front. Microbiol. 2020 Aug 25; 11: 2067. PubMed Abstract | Publisher Full Text\n\nWoolhouse M, Scott F, Hudson Z, et al.: Human viruses: discovery and emergence. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2012 Oct 19; 367(1604): 2864–2871. PubMed Abstract | Publisher Full Text\n\nNkili-Meyong AA, Moussavou-Boundzanga P, Labouba I, et al.: Genome-wide profiling of human papillomavirus DNA integration in liquid-based cytology specimens from a Gabonese female population using HPV capture technology. Sci. Rep. 2019 Feb 6; 9(1): 1504. PubMed Abstract | Publisher Full Text\n\nTu T, Budzinska MA, Vondran FWR, et al.: Hepatitis B Virus DNA Integration Occurs Early in the Viral Life Cycle in an in vitro Infection Model via Sodium Taurocholate Cotransporting Polypeptide-Dependent Uptake of Enveloped Virus Particles. J. Virol. 2018 Jun 1; 92(11). PubMed Abstract | Publisher Full Text\n\nBushman FD: Retroviral insertional mutagenesis in humans: evidence for four genetic mechanisms promoting expansion of cell clones. Mol. Ther. 2020 Feb 5; 28(2): 352–356. PubMed Abstract | Publisher Full Text\n\nMarchand C, Johnson AA, Semenova E, et al.: Mechanisms and inhibition of HIV integration. Drug Discov. Today Dis. Mech. 2006 Jul 1; 3(2): 253–260. PubMed Abstract | Publisher Full Text\n\nHuang R, Zhou P-K: DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct. Target. Ther. 2021 Jul 9; 6(1): 254. PubMed Abstract | Publisher Full Text\n\nDickie P, Felser J, Eckhaus M, et al.: HIV-associated nephropathy in transgenic mice expressing HIV-1 genes. Virology. 1991 Nov; 185(1): 109–119. PubMed Abstract | Publisher Full Text\n\nGener AR, Zou W, Foley BT, et al.: Reference Plasmid pHXB2_D is an HIV-1 Molecular Clone that Exhibits Identical LTRs and a Single Integration Site Indicative of an HIV Provirus. Res Sq. 2021 Apr 6.\n\nShendure J, Balasubramanian S, Church GM, et al.: DNA sequencing at 40: past, present and future. Nature. 2017 Oct 19; 550(7676): 345–353. PubMed Abstract | Publisher Full Text\n\nStark R, Grzelak M, Hadfield J: RNA sequencing: the teenage years. Nat. Rev. Genet. 2019 Nov; 20(11): 631–656. Publisher Full Text\n\nCameron DL, Jacobs N, Roepman P, et al.: Virusbreakend: viral integration recognition using single breakends. Bioinformatics. 2021 May 11; 37: 3115–3119. PubMed Abstract | Publisher Full Text\n\nDesfarges S, Ciuffi A: Viral integration and consequences on host gene expression. Witzany G, editor. Viruses: essential agents of life. Dordrecht: Springer Netherlands; 2012. p. 147–75.\n\nArtesi M, Hahaut V, Cole B, et al.: PCIP-seq: simultaneous sequencing of integrated viral genomes and their insertion sites with long reads. Genome Biol. 2021 Apr 6; 22(1): 97. PubMed Abstract | Publisher Full Text\n\nZhuo Z, Rong W, Li H, et al.: Long-read sequencing reveals the structural complexity of genomic integration of HBV DNA in hepatocellular carcinoma. NPJ Genom. Med. 2021 Oct 12; 6(1): 84. PubMed Abstract | Publisher Full Text\n\nStephens Z, O’Brien D, Dehankar M, et al.: Exogene: A performant workflow for detecting viral integrations from paired-end next-generation sequencing data. PLoS One. 2021 Sep 22; 16(9): e0250915. PubMed Abstract | Publisher Full Text\n\nRamirez R, van Buuren N , Gamelin L, et al.: Targeted Long-Read Sequencing Reveals Comprehensive Architecture, Burden, and Transcriptional Signatures from Hepatitis B Virus-Associated Integrations and Translocations in Hepatocellular Carcinoma Cell Lines. J. Virol. 2021 Sep 9; 95(19): e0029921. PubMed Abstract | Publisher Full Text\n\nYang W, Liu Y, Dong R, et al.: Accurate detection of HPV integration sites in cervical cancer samples using the nanopore minion sequencer without error correction. Front. Genet. 2020 Jun 26; 11: 660. PubMed Abstract | Publisher Full Text\n\nPatro SC, Brandt LD, Bale MJ, et al.: Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors. Proc. Natl. Acad. Sci. USA. 2019 Dec 17; 116(51): 25891–25899. PubMed Abstract | Publisher Full Text\n\nIwase SC, Miyazato P, Katsuya H, et al.: HIV-1 DNA-capture-seq is a useful tool for the comprehensive characterization of HIV-1 provirus. Sci. Rep. 2019 Aug 23; 9(1): 12326. PubMed Abstract | Publisher Full Text\n\nNguyen N-PD, Deshpande V, Luebeck J, et al.: ViFi: accurate detection of viral integration and mRNA fusion reveals indiscriminate and unregulated transcription in proximal genomic regions in cervical cancer. Nucleic Acids Res. 2018 Apr 20; 46(7): 3309–3325. PubMed Abstract | Publisher Full Text\n\nXia Y, Liu Y, Deng M, et al.: Detecting virus integration sites based on multiple related sequencing data by VirTect. BMC Med. Genet. 2019 Jan 31; 12(Suppl 1): 19. PubMed Abstract | Publisher Full Text\n\nAganezov S, Yan SM, Soto DC, et al.: A complete reference genome improves analysis of human genetic variation. BioRxiv. 2021 Jul 13.\n\n1000 Genomes Project ConsortiumAuton A, Brooks LD, et al.: A global reference for human genetic variation. Nature. 2015 Oct 1; 526(7571): 68–74. PubMed Abstract | Publisher Full Text\n\nVaser R, Sović I, Nagarajan N, et al.: Fast and accurate de novo genome assembly from long uncorrected reads. Genome Res. 2017 May; 27(5): 737–746. PubMed Abstract | Publisher Full Text\n\nKolpakov R, Bana G, Kucherov G: mreps: Efficient and flexible detection of tandem repeats in DNA. Nucleic Acids Res. 2003 Jul 1; 31(13): 3672–3678. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJeffares DC, Jolly C, Hoti M, et al.: Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast. Nat. Commun. 2017 Jan 24; 8: 14061. PubMed Abstract | Publisher Full Text\n\nEdge P, Bansal V: Longshot enables accurate variant calling in diploid genomes from single-molecule long read sequencing. Nat. Commun. 2019 Oct 11; 10(1): 4660. PubMed Abstract | Publisher Full Text\n\n100 Tomato Genome Sequencing ConsortiumAflitos S, Schijlen E, et al.: Exploring genetic variation in the tomato (Solanum section Lycopersicon) clade by whole-genome sequencing. Plant J. 2014 Oct; 80(1): 136–148. Publisher Full Text\n\nAndrews S: FastQC: a quality control tool for high throughput sequence data.2010. Reference Source\n\nDodt M, Roehr JT, Ahmed R, et al.: FLEXBAR-Flexible Barcode and Adapter Processing for Next-Generation Sequencing Platforms. Biology (Basel). 2012 Dec 14; 1(3): 895–905. PubMed Abstract | Publisher Full Text\n\nMarçais G, Kingsford C: A fast, lock-free approach for efficient parallel counting of occurrences of k-mers. Bioinformatics. 2011 Mar 15; 27(6): 764–770. PubMed Abstract | Publisher Full Text\n\nVurture GW, Sedlazeck FJ, Nattestad M, et al.: GenomeScope: fast reference-free genome profiling from short reads. Bioinformatics. 2017 Jul 15; 33(14): 2202–2204. PubMed Abstract | Publisher Full Text\n\nGu Z, Eils R, Schlesner M: Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016 Sep 15; 32(18): 2847–2849. PubMed Abstract | Publisher Full Text\n\nGu Z, Hübschmann D: Make interactive complex heatmaps in R. Bioinformatics. 2021 Dec 2.\n\nWickham H, Averick M, Bryan J, et al.: Welcome to the tidyverse. JOSS. 2019 Nov 21; 4(43): 1686. Publisher Full Text\n\nZook JM, McDaniel J, Olson ND, et al.: An open resource for accurately benchmarking small variant and reference calls. Nat. Biotechnol. 2019 May; 37(5): 561–566. PubMed Abstract | Publisher Full Text\n\nDanecek P, Bonfield JK, Liddle J, et al.: Twelve years of SAMtools and BCFtools. Gigascience. 2021 Feb 16; 10(2). PubMed Abstract | Publisher Full Text\n\nVan Rossum G, Drake FL Jr: Python reference manual. Centrum voor Wiskunde en Informatica Amsterdam; 1995.\n\nVan Rossum G, Drake FL: Python 3 Reference Manual. Scotts Valley, CA: CreateSpace; 2009.\n\nLuo J, Chen R, Zhang X, et al.: LROD: An Overlap Detection Algorithm for Long Reads Based on k-mer Distribution. Front. Genet. 2020 Jul 11; 11: 632. PubMed Abstract | Publisher Full Text\n\nCARNAC-LR: Clustering coefficient-based Acquisition of RNA Communities in Long Reads - Archive ouverte HAL.[cited 2022 Feb 15]. Reference Source\n\nPrjibelski A, Antipov D, Meleshko D, et al.: Using SPAdes de novo assembler. Curr. Protoc. Bioinformatics. 2020; 70(1): e102. PubMed Abstract | Publisher Full Text\n\nFrankish A, Diekhans M, Jungreis I, et al.: GENCODE 2021. Nucleic Acids Res. 2021 Jan 8; 49(D1): D916–D923. PubMed Abstract | Publisher Full Text\n\nTweedie S, Braschi B, Gray K, et al.: Genenames.org: the HGNC and VGNC resources in 2021. Nucleic Acids Res. 2021 Jan 8; 49(D1): D939–D946. PubMed Abstract | Publisher Full Text\n\nHowe KL, Achuthan P, Allen J, et al.: Ensembl 2021. Nucleic Acids Res. 2021 Jan 8; 49(D1): D884–D891. PubMed Abstract | Publisher Full Text\n\nSayers EW, Beck J, Bolton EE, et al.: Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 2021 Jan 8; 49(D1): D10–D17. PubMed Abstract | Publisher Full Text\n\nGTEx Consortium: The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 2013 Jun 1; 45(6): 580–585.\n\nEnglish AC, Salerno WJ, Hampton OA, et al.: Assessing structural variation in a personal genome-towards a human reference diploid genome. BMC Genomics. 2015 Apr 11; 16: 286. PubMed Abstract | Publisher Full Text\n\nFan X, Abbott TE, Larson D, et al.: BreakDancer: Identification of Genomic Structural Variation from Paired-End Read Mapping. Curr. Protoc. Bioinformatics. 2014; 45: 15.6.1–15.6.11. Publisher Full Text\n\nJoshi I, DeRycke J, Palmowski M, et al.: Genome-wide mapping of DNA double-strand breaks from eukaryotic cell cultures using Break-seq. STAR Protocols. 2021 Jun 18; 2(2): 100554. PubMed Abstract | Publisher Full Text\n\nAbyzov A, Urban AE, Snyder M, et al.: CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 2011 Jun; 21(6): 974–984. PubMed Abstract | Publisher Full Text\n\nChen X, Schulz-Trieglaff O, Shaw R, et al.: Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016 Apr 15; 32(8): 1220–1222. PubMed Abstract | Publisher Full Text\n\nLayer RM, Chiang C, Quinlan AR, et al.: LUMPY: a probabilistic framework for structural variant discovery. Genome Biol. 2014 Jun 26; 15(6): R84. PubMed Abstract | Publisher Full Text\n\nKanehisa M, Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000 Jan 1; 28(1): 27–30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKanehisa M: Toward understanding the origin and evolution of cellular organisms. Protein Sci. 2019 Nov; 28(11): 1947–1951. PubMed Abstract | Publisher Full Text\n\nKanehisa M, Furumichi M, Sato Y, et al.: KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2021 Jan 8; 49(D1): D545–D551. PubMed Abstract | Publisher Full Text\n\nSchriml LM, Arze C, Nadendla S, et al.: Disease Ontology: a backbone for disease semantic integration. Nucleic Acids Res. 2012 Jan; 40(Database issue): D940–D946. PubMed Abstract | Publisher Full Text\n\nRepana D, Nulsen J, Dressler L, et al.: The Network of Cancer Genes (NCG): a comprehensive catalogue of known and candidate cancer genes from cancer sequencing screens. Genome Biol. 2019 Jan 3; 20(1): 1. PubMed Abstract | Publisher Full Text\n\nPiñero J, Queralt-Rosinach N, Bravo À, et al.: DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes. Database (Oxford). 2015 Apr 15; 2015: bav028. PubMed Abstract | Publisher Full Text\n\nWu T, Hu E, Xu S, et al.: clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (N Y). 2021 Aug 28; 2(3): 100141. PubMed Abstract | Publisher Full Text\n\nYu G: enrichplot: Visualization of Functional Enrichment Result. R package version 1.14.1.2021. Reference Source\n\nChang W, et al.: \"Shiny: web application framework for R.\" R package version 1.5 (2017).2017.\n\nWilm A, Aw PPK, Bertrand D, et al.: LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets. Nucleic Acids Res. 2012 Dec; 40(22): 11189–11201. PubMed Abstract | Publisher Full Text\n\nGrubaugh ND, Gangavarapu K, Quick J, et al.: An amplicon-based sequencing framework for accurately measuring intrahost virus diversity using PrimalSeq and iVar. Genome Biol. Jan 8, 2019; 20(1): 8. PubMed Abstract | Publisher Full Text\n\nCingolani P, Platts A, Wang LL, et al.: A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012 Jun; 6(2): 80–92. PubMed Abstract | Publisher Full Text\n\nR Core Team: R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2017. Reference Source\n\nTelwatte S, Morón-López S, Aran D, et al.: Heterogeneity in HIV and cellular transcription profiles in cell line models of latent and productive infection: implications for HIV latency. Retrovirology. 2019 Nov 11; 16(1): 32. PubMed Abstract | Publisher Full Text\n\nKim D, Paggi JM, Park C, et al.: Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 2019 Aug 2; 37(8): 907–915. PubMed Abstract | Publisher Full Text\n\nDobin A, Davis CA, Schlesinger F, et al.: STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013 Jan 1; 29(1): 15–21. PubMed Abstract | Publisher Full Text\n\nGharavi AG, Ahmad T, Wong RD, et al.: Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3. Proc. Natl. Acad. Sci. USA. 2004 Feb 24; 101(8): 2488–2493. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlejandroR G, Washington T, Hyink D, et al.: 3264 - The Multiple HIV-1 Transgenes in the Murine Model of HIV-Associated Nephropathy Fail to Segregate as Expected. American Society of Human Genetics Annual Meeting. 2020 Jan 1.\n\nGener A, Fan Y, Das GC, et al.: PEA0011 - Insights from HIV-1 Transgene Insertions in the Murine Model of HIV-Associated Nephropathy. 23rd International AIDS Conference (AIDS2020).2020 Jan 1.\n\nAmazon Web Services, Inc: Amazon Web Services.Reference Source\n\nLandrum MJ, Lee JM, Benson M, et al.: ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018 Jan 4; 46(D1): D1062–D1067. PubMed Abstract | Publisher Full Text\n\nAl Khleifat A, Iacoangeli A, van Vugt JJFA , et al.: Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis. NPJ Genom. Med. 2022 Jan 28; 7(1): 8. PubMed Abstract | Publisher Full Text\n\nvan Dorp L , Acman M, Richard D, et al.: Emergence of genomic diversity and recurrent mutations in SARS-CoV-2. Infect. Genet. Evol. 2020 Sep; 83: 104351. PubMed Abstract | Publisher Full Text\n\nKaramitros T, Papadopoulou G, Bousali M, et al.: SARS-CoV-2 exhibits intra-host genomic plasticity and low-frequency polymorphic quasispecies. J. Clin. Virol. 2020 Oct; 131: 104585. PubMed Abstract | Publisher Full Text\n\nPlante JA, Liu Y, Liu J, et al.: Spike mutation D614G alters SARS-CoV-2 fitness. Nature. 2021 Apr; 592(7852): 116–121. PubMed Abstract | Publisher Full Text\n\nHou YJ, Chiba S, Halfmann P, et al.: SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science. 2020 Dec 18; 370(6523): 1464–1468. PubMed Abstract | Publisher Full Text\n\nDavies NG, Jarvis CI; CMMID COVID-19 Working Group et al.: Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Nature. 2021 May; 593(7858): 270–274. PubMed Abstract | Publisher Full Text\n\nSyed AM, Taha TY, Tabata T, et al.: Rapid assessment of SARS-CoV-2-evolved variants using virus-like particles. Science. 2021 Dec 24; 374(6575): 1626–1632. PubMed Abstract | Publisher Full Text\n\nTeng S, Sobitan A, Rhoades R, et al.: Systemic effects of missense mutations on SARS-CoV-2 spike glycoprotein stability and receptor-binding affinity. Brief. Bioinformatics. 2021 Mar 22; 22(2): 1239–1253. PubMed Abstract | Publisher Full Text\n\nChoi B, Choudhary MC, Regan J, et al.: Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N. Engl. J. Med. 2020 Dec 3; 383(23): 2291–2293. PubMed Abstract | Publisher Full Text\n\nHamdi Y, Boujemaa M, Ben Rekaya M, et al.: Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases. J. Transl. Med. 2018 Jun 7; 16(1): 158. PubMed Abstract | Publisher Full Text\n\nLee ST, Feng M, Wei Y, et al.: Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis. Proc. Natl. Acad. Sci. USA. 2013 Jul 2; 110(27): 11121–11126. PubMed Abstract | Publisher Full Text\n\nvan Wersch S , Li X: Stronger When Together: Clustering of Plant NLR Disease resistance Genes. Trends Plant Sci. 2019 Aug; 24(8): 688–699.\n\nBelyeu JR, Chowdhury M, Brown J, et al.: Samplot: a platform for structural variant visual validation and automated filtering. Genome Biol. 2021 May 25; 22(1): 161. PubMed Abstract | Publisher Full Text\n\nWouter De Coster A, Paulin L, Avdeyev P, et al.: collaborativebioinformatics/STRdust: Release 0.2 (0.2). Zenodo. 2022. Publisher Full Text\n\nLiew CS, Busby B, Rlowd: collaborativebioinformatics/kTom: Release 0.2 (0.2). Zenodo. 2022. Publisher Full Text\n\nMedhat DM, Philippe S, Busby B: collaborativebioinformatics/INSeption: Release 0.2 (0.2). Zenodo. 2022. Publisher Full Text\n\nIlovericenoodle K, Kesharwani R, Al Khleifat A, et al.: collaborativebioinformatics/GeneVar2: Release 0.2 (0.2). Zenodo. 2022. Publisher Full Text\n\nAgustinho DP, Sapoval N, Ramanandan SKM, et al.: collaborativebioinformatics/cov2db: Release 0.2 (0.2). Zenodo. 2022. Publisher Full Text\n\nAlbin D, Rohit K, Soto DC, et al.: collaborativebioinformatics/kvar: Release 0.2 (0.2). Zenodo. 2022. Publisher Full Text\n\nGener G, Busby B, Peralta C: collaborativebioinformatics/imavirus: Release 0.2 (0.2). Zenodo. 2022. Publisher Full Text\n\nLo CH, Zhang S, Xu T, et al.: collaborativebioinformatics/RPG_Pikachu: Release 0.2 (0.2). Zenodo. 2022. Publisher Full Text"
}
|
[
{
"id": "139299",
"date": "22 Jun 2022",
"name": "Rodolfo Aramayo",
"expertise": [
"Reviewer Expertise Genetics",
"Genomics",
"Computational Genomics",
"Epigenetics",
"Fungal Genetics and Biology",
"Metazoan Genome Organization and Digital Biology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction: In this manuscript, Kimberly Walker and colleagues describe and summarize the results of \"The third hackathon for applying insights into large-scale genomic composition to use cases in a wide range of organisms.\"\nThis virtual hackathon took place in October 2021 and encompassed a total of 59 scientists from 14 countries and 13 U.S. states.\nIn this manuscript, the authors describe the evaluation of eight software packages aimed at identifying Structural Variants (SVs) by using mainly k-mers-based tools, among others.\nThis manuscript addresses key problems in Computational Genomics. Importantly, unlike before, the 2021 hackathon features work on plants, which provides an important alternative point of view to the human-focused research of previous hackathons.\nBelow you will find a series of general and specific recommendations that will, in my opinion, significantly improve the readability and overall quality of this work, while correcting a series of issues I have found associated with both the online version and the downloaded PDF version of the manuscript.\nGeneral Comments: I hope you will agree with me that this is, by no means, a \"standard\" manuscript. Yet, the manuscript was written trying to adjust the logic of the text to that of a \"standard\" manuscript. It is very hard to follow the logic of what was described in the text, as the text is presented.\nLet me explain: any potential reader that is trying to learn, understand and follow what was done with any one of the software packages here described would have an extremely hard time trying follow the logic of a given tool under the current manuscript format.\nThe current format is fragmented. Information related to a given software package is scattered around the text. It is hard to follow.\nThis is why I strongly suggest to reorganize the text of the manuscript as follows:\n1. Abstract 2. Introduction to the general topic only (not to the different packages used) 3. Methods. Describe the methods general to all the work (Cloud Computing) 4. STRdust: Detect and genotype short tandem repeats 4.1. Introduction to STRdust 4.2. Experimental Rationale, Methods and Discussion for STRdust 4.3. Next Steps or Recommended Future Directions for STRdust 5. kTom: k-mers for profiling tomato introgressions 5.1. Introduction to kTom 5.2. Experimental Rationale, Methods and Discussion for kTom 5.3. Next Steps or Recommended Future Directions for kTom 6. cov2db 6.1. Introduction to cov2db 6.2. Experimental Rationale, Methods and Discussion for cov2db 6.3. Next Steps or Recommended Future Directions for cov2db ... ... ... X. Conclusions Y. Tables Y.1. Table 1. Lists the data source utilized by each tool developed during the hackathon. Y.2 Table 2. A table compiling the Data, and Software Availability and others. V. Acknowledgements Z. References\nRegarding what I call in the example above section Y.2, I would like to see the data associated Data, Software availability, and others organized as a single table with the following format or something similar:\n========================= Table 2. Software availability\n\nRow 1\n\nRow 2 Column 1: Tool Name\n\nSTRdust Column 2: Source code\n\nhttps://github.com/collaborativebioinformatics/STRdust Column 3: Version No.\n\n0.2 Column 4: Link to Archive\n\nhttps://doi.org/10.5281/zenodo.6467829 Column 5: License\n\nMIT =========================\nIn summary, I think that the format described will be easier to read, as it will contain all the information and figures relating to a piece of software together. It will follow a logical flow. As far as I am concerned, this is a better way to present this work. It is not a \"conventional\" way, but then again, this is not a \"conventional\" manuscript.\nSpecific Comments:\nComment 01: The paragraph: \"These genomic variants are typically classified as deletions, duplications, insertions, inversions, and translocations describing different combinations of DNA gains, losses, or rearrangements. Copy number variations (CNVs) are a particular subtype of SVs mainly represented by deletions and duplications. SVs are typically described as single events, although more complex scenarios involving combinations of SV types exist.1,2\"\nShould read: These genomic variants are typically classified as deletions, duplications, insertions, inversions, and translocations describing different combinations of DNA losses, gains and/or rearrangements. SVs are typically described as single events, although more complex scenarios involving combinations of SV types exist. Copy number variations (CNVs) are a particular subtype of SVs mainly represented by deletions and duplications. 1,2\nRationale: As originally written, the paragraph starts describing Structural Variants (SVs), then switches to Copy Number Variations (CNVs), and the returns to SVs. I would like to see the ideas of SVs presented together.\nComment 02: The paragraph: \"In October 2021, 59 researchers from 14 countries participated virtually in the third Baylor College of Medicine & DNAnexus hackathon, focusing on interrelated topics such as SVs, short tandem repeats (STRs), k-mer profiling, viruses, reference refinement and annotation.\"\nShould read: In October 2021, 59 researchers from 14 countries participated virtually in the third Baylor College of Medicine & DNAnexus hackathon, focusing on interrelated topics such as k-mer profiling, short tandem repeats (STRs), SVs, reference refinement, annotation and viruses.\nRationale: I would like to see the presented topics sorted according to those that are related to large genomes and then small genomes (i.e., viruses). This order should also be applied to the rest of the manuscript.\nComment 03: The paragraph: \"The international hackathon focused on nine softwares to answer these questions; eight of which we present in this paper: STRdust, kTom,INSeption, GeneVar2, cov2db, K-var, Imavirus, and a Reference Panel Generator (RPG) for diverse sequencing data analysis. Several emergent themes became apparent over the course of the hackathon.\"\nShould read: The international hackathon focused on nine software packages (eight of which we present in this paper), to answer these questions: K-var, kTom, STRdust, INSeption, GeneVar2, cov2db, RPG, and Imavirus. Several emergent themes became apparent over the course of the hackathon.\nRationale: I think it reads better and lists the virus-related package last (see Comment 02).\nComment 04: The paragraph:\n\"Nucleotide sequence substrings of length k (k-mers) continue to prove useful in SV work and in genomics, however, the time needed to assess the frequency of SVs presents a resource problem.7 The reduction of the computational resources required to complete an SV assessment in a genome would allow greater amounts of SV data to be processed in genomic workflows. Many bioinformatic tools currently used to locate genomic SVs use a sliding window alignment technique, which can be time-consuming.8,9 However, implementing a k-mer based approach to create a pool of reference k-mers of known SVs, the annotation speed of variation in new genomes might be increased.10,11 k-mers have also been used in alignment-free methods, bypassing the need for reference genomes.12\"\nNeeds serious rearrangement. I read this paragraph as follows:\nHere you are telling me that k-mers are useful for SV work:\n\"Nucleotide sequence substrings of length k (k-mers) continue to prove useful in SV work and in genomics,\"\nHere you are telling me that generating SV is computationally expensive:\n\"however, the time needed to assess the frequency of SVs presents a resource problem.7\"\nHere you are telling me that if we were to reduce the time it takes to compute them, they would then be more likely to be incorporated in genomic workflows:\n\"The reduction of the computational resources required to complete an SV assessment in a genome would allow greater amounts of SV data to be processed in genomic workflows.\"\nHere you are describing that time consuming sliding windows alignment techniques are currently used to locate genomic SVs:\n\"Many bioinformatic tools currently used to locate genomic SVs use a sliding window alignment technique, which can be time-consuming.8,9\"\nHere you are telling me that if we were to implement a k-mer-based approach, the annotation speed would increase:\n\"However, implementing a k-mer based approach to create a pool of reference k-mers of known SVs, the annotation speed of variation in new genomes might be increased.10,11\"\nHere you are stating that k-mer have been used in alignment-free methods:\n\"k-mers have also been used in alignment-free methods, bypassing the need for reference genomes.12\"\nI would like to see these ideas presented as follows (re-do the text):\nFirst, introduce k-mers and how k-mers are being used in genomics:\n\"k-mers have also been used in alignment-free methods, bypassing the need for reference genomes.12\"\nSecond, state that k-mers are useful:\n\"Nucleotide sequence substrings of length k (k-mers) continue to prove useful in SV work and in genomics,\"\nState that the way SV are calculated is time-consuming:\n\"Many bioinformatic tools currently used to locate genomic SVs use a sliding window alignment technique, which can be time-consuming.8,9\"\nThird, state that calculating SV is expensive:\n\"however, the time needed to assess the frequency of SVs presents a resource problem.7\"\nFourth, tell us why using k-mers might be better:\n\"However, implementing a k-mer based approach to create a pool of reference k-mers of known SVs, the annotation speed of variation in new genomes might be increased.10,11\"\nFinally, conclude how faster calculation is likely to result on SV data to be readily incorporated in existing genomic workflows, thus improving the overall genome annotation:\n\"The reduction of the computational resources required to complete an SV assessment in a genome would allow greater amounts of SV data to be processed in genomic workflows.\"\nSTRdust Specific Comments:\nComment 05:\nIn following Resource IDs:\n(RRID:SCR_010233) (RRID:SCR_017990) (RRID:SCR_003756) (RRID:SCR_002796) (RRID:SCR_018801)\ntheir links do not work because the RESEARCH RESOURCE IDENTIFICATION PORTAL has changed. The only way I have found to access the resource is by accessing the legacy RRID website (https://scicrunch.org/resources-legacy/).\nRegarding resource SCR_002796, it points to a github repository (https://github.com/alibashir/pacmonstr), which, in my opinion is the link it should be used (added as a reference?). The same can be said about resource SCR_018801, that points to the https://github.com/davidebolo1993/TRiCoLOR, repository.\nIn general, I think that GitHub repositories that have not been archived via databases like Zenodo, should be linked directly to GitHub.\nComment 06:\nIn the following paragraph:\n\"To mitigate this issue, several long-read STR calling methods have been developed in recent years, including PacmonSTR21(RRID:SCR_002796), NanoSatellite,22 TRiCoLOR23(RRID:SCR_018801), and Straglr24 -- however, their usability remains limited due to platform and/or computational demands\"\nYou state that either the usability or computational demands of the packages: PacmonSTR, NanoSatellite, TRiCoLOR, and Straglr, are problematic.\nIn fairness to the authors of those packages, you should provide data supporting that statement.\nIn the legend of Figure 1 you clearly state:\n\"We evaluated STRdust by comparing the results of simulated STR expansions produced by SimiSTR based on the human (Genome Reference Consortium Human Build 38, GRCh38) and tomato (Solanum lycopersicum 4.0, SL4.0) reference genomes, to two novel tools: Straglr24 and TRiCoLOR.23\"\nAnd in the text, you state:\n\"STRdust results were compared to TRiCoLOR 1.1,23 and Straglr 1.1.124 using default parameters.\"\nBut you never really showed any data that would allow an independent observer to reach the same conclusion you claim to have reached.\nIn my opinion, this is not fair to the developers of the other packages and should be corrected.\nkTom Specific Comments:\nComment 07:\nPlease define: \"k-mers with low-mid range frequencies\"\nComment 08:\nPlease state the length or range of lengths of the Illumina reads used in these experiments.\nIt is not clear to me how the read length affects the outcome of this analysis (has anyone tested this parameter?).\nComment 09:\nAlso, it is important to state the k-mer length or k-mer length range that was used for this analysis.\nWhat is the minimum k-mer length that is calculated/used by this package?\nComment 10:\nAs I suspect that the read coverage will have a profound effect on these experiments, therefore, I would like to see a table (or Supplementary table), where the coverage for the different datasets analyzed is presented.\nComment 11:\nWhere the FastQ read lengths normalized in these experiments?\nIf they were not, then it is hard for me to evaluate the meaning of the results displayed in Figure 2. Again, data requested in Comment 09 is important.\nComment 12:\nThe link to resource RRID:SCR_014583, is not working. Also, this resource should link directly to the FastQC web site (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/).\nComment 13:\nSimilarly, link to resources SCR_013001, SCR_005491, SCR_017014, and SCR_017270 are not working.\nComment 14:\nWhen searched manually, resource SCR_013001 links to the Sourceforge link: https://sourceforge.net/projects/flexbar/, but in there the Flexbar version 1.4.0, used in the work is not present. The oldest version present there is for version 2.2. Also, the official Flexbar website has been moved to GitHub (https://github.com/seqan/flexbar). Version 1.4.0, is not available there either, thus a person wanting to reproduce these results using the exact same versions presented in this manuscript, would be unable to do so.\nThis needs to be corrected.\nComment 15:\nResources SCR_005491 and SCR_017014, should link directly to GitHub (https://github.com/gmarcais/Jellyfish and https://github.com/schatzlab/genomescope, respectively), and resources SCR_017270 and SCR_019186, should link directly to Bioconductor (https://bioconductor.org/packages/release/bioc/html/ComplexHeatmap.html) and CRAN (https://cran.r-project.org/web/packages/tidyverse/index.html), respectively.\nComment 15:\nThe resolution of Figure 2 must be increased. When the PDF file is displayed on a large screen the figure is extremely pixelated and hard to interpret.\nINseption Specific Comments:\nComment 16: The resources for SCR_010910 - BWA, SCR_018550 - Minimap2, SCR_017620 - NGMLR, SCR_004603 - DELLY, SCR_004603 - SNIFFLES \\<==Note wrong ID!, SCR_015880 - Canu, SCR_017016 - Flye, SCR_005227 - BCFTools, SCR_002105 - SamTools, SCR_008394 - Python, and SCR_015880 - Canu\nHave links not working and, again, in my opinion should point to their GitHub or SourceForge repositories.\nI really appreciate the work of trying to make uniform the web addresses citations, but in the long term, as the repositories get updated, it will create a problem.\nPlease consider adding these links as part of the references.\nModern Reference Managers like Paperpille (https://paperpile.com/app), do an excellent job doing this.\nComment 17: You state that: \"We filtered out SVs that were supported by less than 10 reads using bcftools 1.12\"\nBcftools is a complex set of scripts. Please provide the exact command used.\nComment 18: Figure 3 is very hard to understand. The problem is that you are using lower-case letters and upper-case letters to refer to the different panels. Do not do that. Use Panel A, SubPanel I, etc.\nThis figure needs to be edited or replaced and the figure legend needs to be re-written so as to make it digestible. It is not clear what are you trying to show: are you showing haplotypes? Are you showing reference and experimental regions? Why is the F panel on the right? And the C, D, and E panels on the left? This is confusing. I understand you are trying to save space, but the logic must be presented sequentially.\nComment 19: In the section: \"Clustering unmapped reads\"\nYou state:\n\"To be able to assemble a sequence from all unmapped reads, we tried several approaches. We attempted to identify clusters of reads using the LROD version 1.094 package, which we found unsuitable for our purposes due to long runtimes. More successfully, we used the program CARNAC-LR version 1.0.095 to build clusters of reads using Minimap2 version 2.22 aligner32 and a subsequent k-mer based clustering approach.\"\nHere, you need to define what you mean by \"due to long runtime\".\nAlso, you need to define and describe what you mean by:\n\"and a subsequent k-mer based clustering approach.\"\nYou need a reference to a publication or to a script name or to a repository.\nComment 20:\nIn the section: \"Identifying integration sites for assembled clusters\"\nYou state:\n\"Having successfully assembled contigs for N = 15 read clusters using Canu v2.236(RRID:SCR_015880), we searched for overlap of these contigs with the breakpoint regions of 30 previously identified long insertion sites.\"\nHow were those 30 regions previously identified?\nComment 21:\nAlso related to Comment 20, are you stating that you re-identified regions that were previously identified as containing insertions?\nIf this is the case, can your experimental logic be applied to identify unknown insertion points?\nIf the answer is yes, then why have you not done that?\nCan you expand Figure 3 to clarify this point?\nComment 22:\nPlease comment on the Genome Coverage needed for INseption to work as expected.\nHas anyone tested the effects of Genome Coverage on INseption's performance?\nComment 23: The most important part that must be addressed in this section is the fact that while you have explained the logic of using sample reads to detect insertions in the reference genome, by definition, in comparing genomes from the same population, an insertion in Genome A is a deletion in Genome B and an insertion in Genome B, is a deletion in Genome A. So, it is not clear to me how your experimental logic would be applied to a deletion present in the reference genome and an insertion in the sample reads. As things are explained here, it looks to me that you seem to have only solved 50% of the problem.\nGeneVar2 Specific Comments:\nComment 16 applies to this section.\nComment 24: How is GeneVar2 different or better or what are its advantages when compared to seeing this same information in a good old genome browser like Ensembl? Please elaborate.\nComment 25: Also, I think it would really help if you could add a figure showing the how a gene like BRCA2 (ENSG00000139618), displays in GeneVar2. That would help people not familiar with the GeneVar2 browser to be able to see it in action.\ncov2db Specific Comments:\nComment 16 applies to this section.\nComment 26: In the statement: \"Minimal system requirements for a local cov2db instance are dictated by the mongoDB requirements with the key limiting factor being RAM used. Large variant databases will consume substantial amounts of RAM, and we suggest hosting those on dedicated high memory compute servers.\"\nYou need to be more specific. Define large database, and be more specific about RAM usage. Also, when recommending to use dedicated high memory compute servers, please be more specific on the minimal requirements needed.\nComment 27: In the statement: \"Our current design supports input VCFs generated by LoFreq117 (RRID:SCR_013054) or converted into VCFs from the iVar118 output via provided script.\"\nPlease give the name of the \"provided script\".\nComment 28: To truly appreciate the package cov2db in action, I would recommend the authors present a screenshot of an actual data display of a region of the virus in the R Shiny app.\nK-var Specific Comments:\nComment 16 applies to this section.\nComment 29: The URL (http://www.dtp.nci.nih.gov/) present in the resource RRID:SCR_003057 (when searched manually, because the link does not work...) point to a dead web site.\nComment 30: The statement: \"k-mer frequencies were obtained for each sample, using the tool Jellyfish version 2.3.0.\"\nNeeds clarification. What kind of data was used to obtain the k-mers? FastQ files? BAM files? Tables?\nComment 31: You mention that you used \"whole exome sequencing of the NCI-60 dataset\", but based on the data you gave me I was unable to find that dataset. Even when I searched the NCBI-SRA website using the terms \"NCI-60 cancer\" I was not able to easily identify the exome datasets in question.\nPlease give specific links to the data you used in these experiments.\nComment 32: It is totally unclear to me how the data coming from these different samples compare to each other in terms of coverage/number of reads.\nIt would help if you were to provide a table with this data. K-mer frequency is dependent on coverage.\nComment 33: Please provide the name of the \"custom script\" used to tabulate the data.\nIs this script part of your submission?\nComment 34: Please define \"low frequency k-mers\"\nComment 35: How were the control and test datasets pre-defined? And how you implemented the TF-IDF test? (R Script?, Python Script?).\nImavirus Specific Comments:\nComment 16 applies to this section.\nComment 36: The statement: \"During the hackathon we were able to verify a previously reported integration site on mouse chr8 which can be seen in our GitHub repository cited in the Software Availability section.\"\nHow did you do this? What commands did you use? Where is your computational pipeline?\nComment 37: The statement: \"Using unbiased RNA-seq datasets, Imavirus aimed to identify pIS...\"\nPlease define \"unbiased\"\nComment 38: The statement: \"Future work should explore the datasets we scoped out in SRA for more physiological systems such as animal models or stable cell lines to identify more putative insertion sites.\"\nWhat do you mean by: \"more physiological systems such as animal models or stable cell lines to identify more putative insertion sites\"\nThis statement makes no sense to me. A bacterial cell does not have less Physiology than a Human Liver cell. It has a different physiology. Please rephrase this idea.\nComment 39: Based on what was presented in this manuscript Imavirus is an idea, not a tool. The authors are not presenting a logical code-based pipeline to complete this analysis.\nThe Zenodo repository contains tables and figures, not code, and although this is a nice idea, I cannot understand why this was included on this manuscript. The tool Imavirus as presented is an idea and should not be part of this report. Alternatively, the authors should provide a viable computational pipeline that can be used to perform a similar analysis. I was unable to find not a single draft text page containing a list of commands.\nAs this \"pipeline\" is presented is completely unreproducible and useless.\nThis section is by far below the standards of the other tools presented. It should either be removed or re-done. As it is, it hurts the manuscript as it does not follow the F1000 Condition for publication:\n\"Are sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others?\"\nIn addition, the authors make no mention of competing tools like ViFi, VirTect, and VIRUSBreakend.\nIn fact, when they mention: \"However, identifying virus integration sites from genomic DNA is challenging and there are not many bioinformatics tools available to reliably detect viral presence or integration events.\"\nWithout mentioning competing tools, is not fair to the authors of those other competing tools and, in my opinion, it is misleading.\nI have to conclude that, after reading this section I am left with the taste that Imavirus is an idea that is being presented so as to be \"sold\" to be incorporated into a commercial product.\nRPG Specific Comments:\nComment 16 applies to this section.\nComment 40: In the legend of Figure 8 you state: \"Only common alleles (\\>5% allele frequency (AF)) in the variant call set are retained.\" and \"Subsequently, common allele calls are replaced with CHM13 rare alleles in CHM13 FASTA genome sequence.\"\nPlease elaborate how you did that.\nAlso elaborate if you do that for both haplotypes or not.\nComment 41: It would help to have a table with the actual numbers of variants calls, non-pathogenic variants, pathogenic variants, number of in-frame stop codons, etc.\nComment 42: It is not clear to me the origin of the list of 1KGP common alleles. Where those downloaded or calculated? And, if they were calculated, can you provide their list?\nConclusion: This is a good piece of work. Here, I am offering a series of suggestions that, I am sure, will improve the overall quality of this work.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? No\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "8919",
"date": "20 Oct 2022",
"name": "Rodolfo Aramayo",
"role": "Reviewer Response",
"response": "As requested from the authors, I am expanding some of my previous comments so as to make them more clear. Below, I will post the original comment and its associated expanded comment(s). kTom Specific Comments: Comment 10: As I suspect that the read coverage will have a profound effect on these experiments, therefore, I would like to see a table (or Supplementary table), where the coverage for the different datasets analyzed is presented. Expanded Comment. After Quality Control, where the resulting read lengths distributions observed for the different genome samples equivalent? After Quality Control, was the Sample Coverage (No. Reads x Length per Read) equivalent between the different samples? My main concern is with the possibility of some genomes having a significantly lower Sample Coverage, which could result in under-counting Kmers for that particular genome. The requested table in question should present the result of adding the lengths of all the reads corresponding to a given genomic dataset, divided by the total number of reads for such dataset. This “Sample Coverage” calculation should be performed for each genome and the results summarized on a table. These numbers could also be ‘normalized’ in relation to the genome with the lowest sample coverage. INseption Specific Comments: Comment 22: Please comment on the Genome Coverage needed for INseption to work as expected. Has anyone tested the effects of Genome Coverage on INseption's performance? Expanded Comment. As presented, the authors first aligned HiFi reads to GRCh37 using Minimap2 and then used Sniffles to call SVs. The authors also report that they filtered out SVs that were supported by less than 10 reads using bcftools. My question about the Genome Coverage needed for INseption to work as expected, is: How did you test or controlled for chromosomal regions that were either not-covered or had low coverage after Minimap2 mapping? Given that the existence of such regions could potentially be the source of false negatives SV in your analysis. Related to the question, if anyone has tested the effects of Genome Coverage on INseption's performance, I would like to know how many HiFi reads spanning a SV are needed for Sniffles to call an SV. Also, given that the shorter the read, the higher the probability that the read in question could be assigned to two different genomic positions by Minimap2, thus generating different SAM flags, has anyone tested how these parameters affect Inseption’s performance? What was the minimal insert size accepted for analysis? Comment 23: The most important part that must be addressed in this section is the fact that while you have explained the logic of using sample reads to detect insertions in the reference genome, by definition, in comparing genomes from the same population, an insertion in Genome A is a deletion in Genome B and an insertion in Genome B, is a deletion in Genome A. So, it is not clear to me how your experimental logic would be applied to a deletion present in the reference genome and an insertion in the sample reads. As things are explained here, it looks to me that you seem to have only solved 50% of the problem. Expanded Comment. This is related to the potential existence of regions in the reference genome that have no mappers, not because of low coverage, but because the donor genome of the reads in question have a deletion in a region that is present in the reference genome. Like I said before: For the same synthenic region, if those regions have deletions/insertions, an insertion in Genome A is a deletion in Genome B and an insertion in Genome B, is a deletion in Genome A. Both genomes could have a deletion (in relation to a third genome), or an insertion (again in relation to a third genome), and, despite that, be considered to be identical. But if Genome A has an insertion in relation to Genome B, it is also possible that Genome B has an insertion in relation to Genome A. Detecting insertions in Genome A in relation to Genome B, does not detect insertions in Genome B in relation to Genome A. The way the data was presented, it was not clear to me your approach took both possibilities into consideration. K-var Specific Comments: Comment 32: It is totally unclear to me how the data coming from these different samples compare to each other in terms of coverage/number of reads. It would help if you were to provide a table with this data. K-mer frequency is dependent on coverage. Expanded Comment. The calculation of Kmers starts with Short-read sequencing data. The authors state they used: 7 non-metastatic and 5 metastatic samples. My question is: How those different samples compare in terms of number of reads and the total number of bases present in that particular sample. To answer that question, the authors need to calculate the result of adding the lengths of all the reads corresponding to a given sample, divided by the total number of reads for such dataset. Such calculation will reveal the theoretical “sample coverage” (not genome coverage), of each sample and allow us to compare if such coverage between different samples is equivalent. For example, I can see how a given sample whose sample coverage is half of that another sample, could potentially generate a different number of Kmers. It follows that if one were to compare two samples one metastatic with one non-metastatic both having exactly the same sample coverage, would you be able to re-identify the same genes? And, how reducing sample coverage would affect the resulting kmer table? RPG Specific Comments: Comment 41: It would help to have a table with the actual numbers of variants calls, non-pathogenic variants, pathogenic variants, number of in-frame stop codons, etc. Expanded Comment. What I am requesting is a table, similar to the one you presented in your github repository (3. Biologically annotated variants (CHM13 based).), where you would summarize the percentage of common variants that resulted from your annotation. Imavirus Specific Comment: In re-reading the manuscript I became concerned about how potentially misleading is to present a GITHUB repositiory that supposedly present a computational pipeline, when in fact such said repository does not contain a single line of code."
},
{
"c_id": "9102",
"date": "12 Dec 2022",
"name": "Kimberly Walker",
"role": "Author Response",
"response": "The authors would like to thank the reviewer for their comments and questions. The purpose of this paper is to present the work completed during a 3-day hackathon. Each tool presented in this paper is still in progress and, therefore, this paper does not contain many typical elements of a publication. The goal is to highlight the use-cases and potential of each tool. Additionally, because these tools serve multiple purposes and organisms, they can’t necessarily be compared to each other either. As each application matures, the different teams are expected to submit a final publication of the software. Regarding comments that asked for additional work on the tool, improvements, or data analysis – the comments have been passed to each team so they can be addressed at the next hackathon. Finally, the authors are aware that many reviewers found the format and style of the paper to be fragmented, however, the authors are simply following the F1000 format for hackathon collections."
}
]
},
{
"id": "149878",
"date": "23 Sep 2022",
"name": "Nguyen Quoc Khanh Le",
"expertise": [
"Reviewer Expertise Genomics analysis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this study, the authors briefly went through all algorithms in the third international hackathon for applying insights into large-scale genomics composition. Overall, it is well-written and holds potential for indexing. I just have some minor comments as follows:\nI'm wondering whether the authors included all projects from the hackathon or not. Any reasons to exclude the other projects out of this analysis?\n\nAdding more use cases to each algorithm would be more interesting.\n\nThe authors should add more discussions to show the biological insights of each tool/algorithm.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Yes\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "9103",
"date": "12 Dec 2022",
"name": "Kimberly Walker",
"role": "Author Response",
"response": "The authors would like to thank the reviewer for their comments and questions. The purpose of this paper is to present the work completed during a 3-day hackathon. Each tool presented in this paper is still in progress and, therefore, this paper does not contain many typical elements of a publication. The goal is to highlight the use-cases and potential of each tool. Additionally, because these tools serve multiple purposes and organisms, they can’t necessarily be compared to each other either. As each application matures, the different teams are expected to submit a final publication of the software. Regarding comments that asked for additional work on the tool, improvements, or data analysis – the comments have been passed to each team so they can be addressed at the next hackathon. Finally, the authors are aware that many reviewers found the format and style of the paper to be fragmented, however, the authors are simply following the F1000 format for hackathon collections."
}
]
},
{
"id": "149876",
"date": "12 Oct 2022",
"name": "Pedro G. Ferreira",
"expertise": [
"Reviewer Expertise Transcriptomics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nKimberly Walker and colleagues presents a manuscript that reports the results of a workshop meeting where different groups have applied their developed tools for the analysis of genomic variation.\nThe manuscript is written in an unconventional way, which is hard to follow.\nMy main concern with the manuscript is that I did not find a conducting line or a specific goal, rather than reporting the methods that were applied. The title mentions a wide range of organisms. In the introduction, it is mentioned a focus on tomatoes, plants, Sars-cov2, and some methods like INSeption analyse human data from Genome in a Bottle project. Overall, that is too confusing.\nThe text focuses on describing the tools and their workflows. It would be interesting to discuss the results from a qualitative and quantitative point-of-view. This way, one would obtain a better intuition of the relevance and utility of the tool.\nWhat are the results of applying these tools in tomato genome? It would be very interesting to summarize the novel findings on the tomato genome or the human genome from the different views of applying all these tools. For instance, in the INSeption section it is mentioned allele frequency analysis. I’m very curious about these results, but these were not discussed at all.\nFrom the quantitative point of view, what are the computational demands of these tools? What are the performance gains of using a k-mer approach when compared with other approaches?\nOverall, without a clear focus on the goals and the reporting of the insights gained, the manuscript is of little use. Therefore, I recommend a substantial re-organization and improvement of the manuscript.\n\nIs the rationale for developing the new software tool clearly explained? No\n\nIs the description of the software tool technically sound? Partly\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? No\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? No",
"responses": [
{
"c_id": "9104",
"date": "12 Dec 2022",
"name": "Kimberly Walker",
"role": "Author Response",
"response": "The authors would like to thank the reviewer for their comments and questions. The purpose of this paper is to present the work completed during a 3-day hackathon. Each tool presented in this paper is still in progress and, therefore, this paper does not contain many typical elements of a publication. The goal is to highlight the use-cases and potential of each tool. Additionally, because these tools serve multiple purposes and organisms, they can’t necessarily be compared to each other either. As each application matures, the different teams are expected to submit a final publication of the software. Regarding comments that asked for additional work on the tool, improvements, or data analysis – the comments have been passed to each team so they can be addressed at the next hackathon. Finally, the authors are aware that many reviewers found the format and style of the paper to be fragmented, however, the authors are simply following the F1000 format for hackathon collections."
}
]
},
{
"id": "149877",
"date": "19 Oct 2022",
"name": "Quan Long",
"expertise": [
"Reviewer Expertise Genomics",
"Genetics",
"Machine Learning"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the manuscript, the authors have reported “The third hackathon for applying insights into large-scale genomic composition to use cases in a wide range of organisms” that happened in Baylor College of Medicine in 2021.\n\nDetailed descriptions of eight software packages focusing on structural variation detection have been provided. The data for benchmarking are also mentioned. However, I do not see any quantitative results regarding to the evaluation of the software. For instances: what are the true/false positives for the tools? What are the advantages/disadvantages of different tools when comparing to each other? The manuscript focuses more on describing the algorithms and the data, which are important. However, without an evaluation, this seems to be an unfinished work. If the evaluation could be added, this looks an excellent review and comparison of SV tools.\n\nAlso it is clear that different authors have written their pieces and then submitted. The work looks quite segmented without smoothing.\n\nIs the rationale for developing the new software tool clearly explained? Partly\n\nIs the description of the software tool technically sound? Partly\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? No\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? No",
"responses": [
{
"c_id": "9105",
"date": "12 Dec 2022",
"name": "Kimberly Walker",
"role": "Author Response",
"response": "The authors would like to thank the reviewer for their comments and questions. The purpose of this paper is to present the work completed during a 3-day hackathon. Each tool presented in this paper is still in progress and, therefore, this paper does not contain many typical elements of a publication. The goal is to highlight the use-cases and potential of each tool. Additionally, because these tools serve multiple purposes and organisms, they can’t necessarily be compared to each other either. As each application matures, the different teams are expected to submit a final publication of the software. Regarding comments that asked for additional work on the tool, improvements, or data analysis – the comments have been passed to each team so they can be addressed at the next hackathon. Finally, the authors are aware that many reviewers found the format and style of the paper to be fragmented, however, the authors are simply following the F1000 format for hackathon collections."
}
]
}
] | 1
|
https://f1000research.com/articles/11-530
|
https://f1000research.com/articles/11-152/v1
|
07 Feb 22
|
{
"type": "Research Article",
"title": "Testosterone level correlates significantly with luteinizing hormone to follicle-stimulating hormone ratio among women with polycystic ovary syndrome: A cross sectional study",
"authors": [
"Samia Mohammed Alhassan",
"Abdelgadir Elmugadam",
"Nuha Eljaili Abubaker",
"Ghada A. Elfadil",
"Samia Mohammed Alhassan",
"Abdelgadir Elmugadam",
"Nuha Eljaili Abubaker"
],
"abstract": "Background: Polycystic ovary syndrome (PCOS), an endocrinological problem among women in the reproductive age, is characterized by chronic ovulatory dysfunction, hyperandrogenism, and elevated luteinizing hormone: follicle stimulating hormone (LH-FSH) ratio. The goal of this study was to examine if the blood LH-FSH ratio and total testosterone (TT) levels in Sudanese women with PCOS were linked. Methods: This cross-sectional study included 300 women with confirmed PCOS based on Rotterdam criteria. PCOS women mean (standard deviation): age 29.1(5.8) years; body mass index (BMI) 27.9±4.6 kg/m2. Each participant underwent a clinical history, physical examination, and ovaries ultrasonogram. ASYS Expert Plus Microplate was used to quantify serum LH, FSH, and TT levels in fasting blood specimen drawn during the follicular phase of the menstrual cycle of women with PCOS. Results: More than two-thirds of the participants (71.0%) had an aberrant LH-FSH ratio (cut-off>1.0), and 58.3% had hyperandrogenemia (TT>109.5 ng/dL). Hyperandrogenemic women had significantly increased LH-FSH ratio (P= 0.000). The LH-FSH ratio and serum TT were significantly positive correlated (r= 0.329, P= 0.000). Overall, 52.0% of women with PCOS exhibited menstrual cycle irregularity, and 59.0 % had a positive family history of PCOS. On logistic regression analysis, the LH-FSH ratio (odds ratio (OR) (95% confidence interval (CI)): 2.308 (1.698- 3.139, P= 0.000) was found to be positively related to hyperandrogenemia independently. Furthermore, when the LH-FSH ratio is greater than one, hyperandrogenemia can be distinguished from normoandrogenemia, area under the curve (AUC) = 0.726, P= 0.000, 95% CI: (0.668-0.785) with a serum TT threshold of 109.5 ng/dL (sensitivity 70.0%, specificity 77.1%). Conclusions: In women with PCOS, the serum LH-FSH ratio and TT have a strong relationship. Furthermore, LH-FSH ratio of greater than one can be used to distinguish between hyperandrogenic and non-hyperandrogenic PCOS women.",
"keywords": [
"PCOS",
"LH-FSH ratio",
"total testosterone",
"Hyperandrogenemia",
"Sudan"
],
"content": "Introduction\n\nPolycystic ovary syndrome (PCOS) is a prevalent endocrine condition affecting women of reproductive age, with a reported frequency of 6 to 15%.1,2 PCOS is characterized by a female sex hormone imbalance and increased androgen production, which results in irregular or extended menstrual periods, obesity, and excessive hair growth.3 Genetic and epigenetic factors, as well as environmental variables have been identified as risk factors for intra-ovarian hyperandrogenism.3 PCOS is a challenging disorder to diagnose since it is a diverse condition with different characteristics. It is currently diagnosed using revised Rotterdam criteria, which has been recently approved by an international evidence-based PCOS guideline.4,5\n\nAccording to certain studies, the brain is both a regulator and an impacted organ in PCOS (the brain phenotype). The brain, which contains multiple receptors, and neurons with their neurotransmitters, produces a higher pulse frequency of gonadotropin. As a result, people with PCOS have more luteinizing hormone (LH) than follicle-stimulating hormone (FSH) secretion.6 Increased ovarian androgen production is caused by a change in the LH-FSH ratio. Furthermore, hyperandrogenemia lowers estrogen's negative feedback to the hypothalamus, resulting in increased LH pulse frequency. As a result, a vicious cycle is set in motion, causing a variety of clinical symptoms of PCOS, including hyperandrogenism.7 The goal of this study was to see possible link between the LH-FSH ratio and total testosterone levels in Sudanese women with PCOS.\n\n\nMethods\n\nThis was an observational study with a cross-sectional design. The study was conducted between October 2020 and September 2021 in Khartoum- Sudan. Various infertility centers clinics were visited to select the study sample, using a convenience sampling method. The inclusion criteria were women with confirmed PCOS based on Rotterdam criteria,5 where at least two of the following criteria were fulfilled: oligomenorrhoea/anovulation (delayed menses >35 days or <8 spontaneous hemorrhagic episodes/year), hyperandrogenism (clinical hirsutism using modified Ferriman-Gallwey score of ≥8 or biochemical) and morphology of polycystic ovaries on ultrasonography (12 or more follicles in each ovary measuring 2 to 9 mm in diameter, and/or increased ovarian volume>10 mL3). Women with systemic disease (cardiovascular disease and diabetes mellitus), on medication prior to the study (oral contraceptives, glucocorticoids, ovulation induction agents, and estrogenic or anti-androgenic) were excluded from the study.4,5\n\nAt the time of the study, there was no published data about the prevalence of PCOS in Sudan. For this, the prevalence of PCOS in unspecified populations 3–10%.8 The sample size was determined based on the following equation9:\n\nn = sample size\n\nZ1-α/2 = 1.96 for 95% confidence level\n\nd = Desired margin of error, expressed as a decimal (0.05)\n\nP = Prevalence of the disease (10.0%)\n\nn = 138\n\nThe study protocol was approved by the Federal Ministry of Health at Khartoum- Sudan. This study was conducted in compliance with the ethical standards of the responsible institution on human subjects as well as with the Helsinki Declaration. The study objective was explained to potential participants, and those who agreed to participate provided a signed consent before the start of the study.\n\nAfter signing an informed consent form, the socio-demographic characteristics, medical and gynecological history were taken from each patient using a questionnaire. The detailed medical and gynecological history (menstrual pattern, fertility, hirsutism) were taken from all patients included in the study. Then full general and pelvic examinations were performed.\n\nFollowing standard protocols, weight was measured twice. After calibration, OMRON BF508l Body Fat Scales (China) were utilized. Women were told to remove their bulky attire. The weights were calculated to within 0.1 kg. After calibration, ladies were requested to remove their shoes and a portable stadiometer (SECA-213 model, Germany) was used to measure their height twice. Quetelet's BMI was estimated using a conventional formula (weight in kilograms divided by height in meters2). Underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (30 kg/m2) were the BMI categories used by the WHO.10 During the follicular phase, ultrasonography was performed by Mindray (model: DP-50, Germany) and vaginal transducer where presence or absence of ovarian cysts were conformed or excluded. If cysts were seen, then the volume as well as the number of small follicles were determined, in each ovary.\n\nWomen were asked to come back on days 2-5 after a spontaneous menstruation or on a convenient day if they had amenorrhea. In a fasting state, 5 mL venous blood was collected between the hours of 8 a.m. and 9 a.m. The blood was centrifuged using Hettich (D-78532 Tuttlingen: Germany), then plasma obtained, and kept at -20 °C until the assay. Enzymes linked immunosorbent assay (ELISA); ASYS (model: Expert Plus; type G020150; serial nr: 28382; Austria) was used to quantify serum LH, FSH by indirect method, and TT competitive methods.\n\nData was coded, and statistical analysis was performed with social package of statistical science version 26.0 (SPSS Inc., IBM, Chicago, IL, USA). The Kolmogorov–Smirnov was used for testing the normality of continuous data. All data was skewed. Continuous variables were presented as mean with standard deviation, and median with interquartile ranges. Whereas qualitative data was expressed with frequency (%). Mann-Whitney U test, and Chi-square test for qualitative variables were used to assess the relationship between LH-FSH ratio groups and androgen status. The association between the LH-FSH ratio, serum TT, and BMI was tested using Spearman's correlation test. The link between the LH-FSH ratio>1 and other factors was investigated using binary logistic regression analysis. The serum LH-FSH ratio was studied using a receiver-operating characteristic (ROC) curve to see if it might distinguish androgen status.\n\n\nResults\n\nIn total, 350 Women were screened; 300 of them fulfilled the inclusion criteria.11 Their mean (SD) age was 29.1 (5.8) years, and BMI 27.9 (4.6) kg/m2. Overall; 30.3% (n=91) of women were obese based on their BMI, and 59.0% (n=117) had positive family history to PCOS. More than half (52.3%, n=157) of women had menstrual cycle irregularity. More than two-thirds of them (71.0%, n= 213) had altered LH-FSH ratio with cut-off > 1.0. According to their serum TT (> 109.5 ng/dL), 58.3% (n= 175) had hyperandrogenemia.\n\nWomen with LH- FSH ratio >1 (based on their serum LH-FSH ratio) had significantly increased serum TT level (P = 0.000), and 70.0% of them had TT> 109.5 ng/dL. 55.4% (n= 118) of them had positive family history to PCOS, compared with counterpart. There were no significant differences in age, BMI, and menstrual cycle frequency irregularity between groups (Table 1).\n\n# Mean= Geometric mean; SD= standard deviation;\n\n† = Median; S.E.M= Standard Error of Mean, Q1-Q3= Interquartile Ranges,\n\n‡ Values are numbers and percentages;\n\n* P-value were obtained using Mann-Whitney test; and P# were obtain using Chi- Square test.\n\nIn comparison to their counterpart, women with hyperandrogenemia (serum TT > 109.5 ng/dL) had significant increase in LH-FSH ratio (P= 0.000). Furthermore; obesity was found in 30.9% (n= 54) of them based on their BMI (Table 2).\n\n# Mean= Geometric mean; SD= standard deviation;\n\n† = Median; SEM= Std. Error of Mean, Q1-Q3= Interquartile Ranges,\n\n‡ Values are numbers and percentages;\n\n* P-value were obtained using Mann-Whitney test; and #P were obtain using Chi- Square test. BMI: body mass index; FC: family history; M.C; Menstrual cycle; TT: total testosterone; AMH: anti mullein's hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone\n\nAs shown in Figure 1, the Spearman’s correlation revealed that serum LH-FSH ratio was significantly correlated with serum TT (ng/dL) (r= 0.329, P= 0.000). However; both LH-FSH ratio and TT were insignificantly correlated with BMI among women with PCOS (results not shown on figure).\n\nLH-FSH: luteinizing hormone to follicle-stimulating hormone, TT: total testosterone.\n\nAs shown in Table 3, the serum LH-FSH ratio (odds ratio (OR) (95% confidence interval (CI)): 2.308 (1.698-3.139, P = 0.000) was independently related to androgen status and can be used as a predictor in women with PCOS.\n\nAccording to the ROC curve analysis; LH-FSH ratio>1 can distinguish hyperandrogenemia from normoandrogenemia in women with PCOS (AUC = 0.726, P=0.000, 95% CI: 0.668-0.785; sensitivity 70.0%, specificity 77.1%) at TT threshold 109.5 ng/dL (Figure 2).\n\n\nDiscussion\n\nIn the present study, the link between serum LH-FSH ratio and total testosterone level were investigated in a cross-sectional analysis of 300 Sudanese women with PCOS. The study revealed that 30.3% of women were obese based on their BMI. Obesity was found in 50–80 % of women with PCOS, according to McCartney and Marshall.12 This may differ depending on race, ethnicity, location, and environmental factors (physical activity, diet, stress).\n\nThe most common clinical symptom of women diagnosed with PCOS, according to Malini and George,13 is a greater LH-FSH ratio. The LH-FSH ratio in healthy women is 1:1. In PCOS, the LH level is higher than the FSH level, resulting in increased ovarian androgen production and ovulatory failure. Various LH-FSH ratio cut-offs have been proposed. However, the cut-off more than 1.0 was found to be the most successful in diagnosing PCOS in terms of sensitivity and specificity.14,15\n\nAccording to our findings, 71.0% of women with PCOS exhibited an abnormal LH-FSH ratio with a cut-off of >1. Morshed et al. reported that 71.0% PCOS patients (cut-off more than1.0) exhibited an aberrant LH-FSH ratio.16 According to Nath et al.,17 70.58% of women with PCOS have an increased LH-FSH ratio. As a result, the authors proposed that the LH-FSH ratio is one of the defining characteristics of PCOS women.17\n\nStudy revealed 58.3% of women with PCOS had hyperandrogenemia (cut-off TT more than 109.5 ng/dL). Furthermore, the findings showed a statistically significant difference in the frequency of hyperandrogenemia between the changed and normal LH-FSH ratio groups demonstrated that an altered LH-FSH ratio with a cut-off of 1.0 was associated with androgen status in women with PCOS. Moreover, the LH-FSH ratio was linked to a higher level of serum TT. Alexiou et al., reported hyperandrogenemia was present in 78.2% of PCOS.18 Livadas and his colleagues reported that prevalence of hyperandrogenemia was 58.8%.19 The imbalance in LH: FSH causes proliferation of ovarian theca cells leading to increased steroidogenesis, and ultimately leading to hyperandrogenemia in PCOS women.20\n\nIn the hyperandrogenic group LH-FSH ratio was higher and differed significantly from the value of the normoandrogenic group. This may suggest that LH-FSH ratio has an independent relation with TT, which is consistent with previous studies.13,21\n\nIn regression analysis our study observed that LH-FSH ratio>1 was significantly positive independently associated to hyperandrgenemia. Moreover, ROC analysis indicated that serum LH-FSH ratio>1 was significantly discriminate androgen statuses among PCOS women with cut-off to serum TT 109.5 ng/dL. The studies13,21 also demonstrate that an LH-FSH ratio greater than 1.0 is enough to generate significant testosterone production from the ovaries, resulting in hyperandrogenemia.\n\nThere are several solid points in the present research. A high sample size was used in this study. It looked at the relationship between the LH-FSH ratio>1 and TT in Sudanese women PCOS. It is the first study to use an LH-FSH ratio greater than 1 to distinguish hyperandrogenic status in PCOS Sudanese individuals. Our research can be used as a starting point for further research. To compute the free testosterone index, serum sex hormone binding globulin or free testosterone were not assessed. Furthermore, we lack population-specific data on serum TT reference ranges.\n\n\nConclusions\n\nSudanese women with PCOS are prone to androgenemia. Furthermore, among women with PCOS, the LH-FSH ratio was found to be substantially linked with total testosterone. The finding of this study may aid in a better understanding of the pathophysiology and management of hyperandrogenemia in PCOS women of Sudanese descent.\n\n\nData availability\n\nFigshare: PCOS in Sudan. https://doi.org/10.6084/m9.figshare.19102715.11\n\n- Note: FH: family history; MC: menstrual cycle; AMH: anti mullein's hormone\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThe authors are most grateful to all the women who agreed to take part in this study. Also, our gratitude to the physicians who assessed the participants.\n\n\nReferences\n\nAversa A, La Vignera S, Rago R, et al.: Fundamental Concepts and Novel Aspects of Polycystic Ovarian Syndrome: Expert Consensus Resolutions. Front. Endocrinol. 2020; 11: 516. PubMed Abstract | Publisher Full Text\n\nTola H, Abbas M, Alhassan EA, et al.: Assessment of the Role of the Anti-Mullerian Hormone, Luteinizing Hormone/Follicle Stimulating Hormone Ratio in the Diagnosis of Polycystic Ovary Syndrome in Sudanese Women. Open Access Maced J Med Sci. 2018; 6: 1244–1247. Publisher Full Text\n\nGoodarzi MO, Dumesic DA, Chazenbalk G, et al.: Polycystic ovary syndrome: aetiology, pathogenesis and diagnosis. Nat. Rev. Endocrinol. 2011; 7(4): 219–231. Publisher Full Text\n\nTeede H, Misso M, Costello M, et al.: International evidence-based guideline for the assessment and management of polycystic ovary syndrome. National Health and Medical Research Council (NHMRC); 2018; 1–198.\n\nRotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil. Steril. 2004; 81: 19–25. Publisher Full Text\n\nCoutinho EA, Kauffman AS: The role of the brain in the pathogenesis and physiology of polycystic ovary syndrome (PCOS). Med Sci (Basel). 2019; 7(8): 84.\n\nAshraf S, Nabi M, Rasool S u A, et al.: Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review. Egypt J Med Hum Genet. 2019; 20(1): 25. Publisher Full Text\n\nWolf WM, Wattick RA, Kinkade ON, et al.: Geographical Prevalence of Polycystic Ovary Syndrome as Determined by Region and Race/Ethnicity. Int J Environ Res Public Health. 20. 2018; 15(11): 2589. PubMed Abstract | Publisher Full Text\n\nCharan J, Biswas T: How to calculate sample size for different study designs in medical research?. Indian J. Psychol. Med. 2013; 35(2): 121–126. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report. Series No. 894. Geneva, Switzerland: WHO; 2000.\n\nElfadil G, Elmugadam A: PCOS in Sudan. figshare. Dataset. 2022. Publisher Full Text\n\nMcCartney CR, Marshall CJ: Polycystic Ovary Syndrome. N. Engl. J. Med. 2016; 375(1): 54–64. PubMed Abstract | Publisher Full Text\n\nMalini NA, George KR: Evaluation of different ranges of LH:FSH ratios in polycystic ovarian syndrome (PCOS) - Clinical based case control study. Gen. Comp. Endocrinol. 2018; 260: 51–57. PubMed Abstract | Publisher Full Text\n\nEscobar-Morreale HF, Carmina E, Dewailly D, et al.: Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum. Reprod. Update. 2012; 18(2): 146–170. PubMed Abstract | Publisher Full Text\n\nHsu MI, Liou TH, Liang SJ, et al.: Inappropriate gonadotropin secretion in polycystic ovary syndrome. Fertil. Steril. 2009; 91(4): 1168–1174. PubMed Abstract | Publisher Full Text\n\nMorshed M, Banu H, Akhtar N, et al.: Luteinizing Hormone to Follicle-Stimulating Hormone Ratio Significantly Correlates With Androgen Level and Manifestations Are More Frequent With Hyperandrogenemia in Women With Polycystic Ovary Syndrome. Journal Of Endocrinology And Metabolism. 2021; 11(1): 14–21. Publisher Full Text\n\nNath CK, Barman B, Das A, et al.: Prolactin and thyroid stimulating hormone affecting the pattern of LH/FSH secretion in patients with polycystic ovary syndrome: A hospital-based study from North East India. J Family Med Primary Care. 2019; 8(1): 256–260.\n\nAlexiou E, Hatziagelaki E, Pergialiotis V, et al.: Hyperandrogenemia in women with polycystic ovary syndrome: prevalence, characteristics and association with body mass index. Horm. Mol. Biol. Clin. Invest. 2017; 29(3): 105–111.\n\nLivadas S, Pappas C, Karachalios A, et al.: Prevalence and impact of hyperandrogenemia in 1,218 women with polycystic ovary syndrome. Endocrine. 2014; 47(2): 631–638. PubMed Abstract | Publisher Full Text\n\nNisenblat V, Norman RJ: Androgens and polycystic ovary syndrome. Curr. Opin. Endocrinol. Diabetes Obes. 2009; 16(3): 224–231. Publisher Full Text\n\nSuresh S, Vijayakumar T: Correlations of insulin resistance and serum testosterone levels with LH:FSH ratio and oxidative stress in women with functional ovarian hyperandrogenism. Indian J. Clin. Biochem. 2015; 30(3): 345–350. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "127132",
"date": "13 Apr 2022",
"name": "Małgorzata Szczuko",
"expertise": [
"Reviewer Expertise I am an expert in the field of nutrition",
"including PCOS. I have written a total of over 10 papers on various aspects of PCOS"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe scientific study was well ignited and carried out. However, the following requests need to be corrected. In addition, some suggestions should be clarified in the introduction and discussion.\nDifferent scientific articles give different cut-off values of 2: 1 or 3: 1 in the introduction, as is the case with other populations. And since other values have emerged, the reasons for this should be discussed in the discussion\n\nIn premenopausal women, the LH / FSH ratio is typically 1: 1 does the ratio change with age? should be referred to in the discussion\n\nWomen with PCOS in European populations tend to be overweight or obese with occasional normal body weight, how does this apply to Sudanese women?\n\nDoes body fat affect LH and FSH levels? I recommend the Figure 2 in (Szczuko et al. 2014) 1. It is also worth checking PCOS phenotypes\n\nAuthors should explore the biochemical evidence of an increase in testosterone levels as well as a high free androgen index (FAI index)\n\nCorrect the level of testosterone and FAI index2 and briefly write down if there are differences in the cut-off point\n\nThe conclusion should apply to women from Sudan. The LH / FSH ratio in other populations in the PCOS female group was already known\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8128",
"date": "16 May 2022",
"name": "Ghada Elfadil",
"role": "Author Response",
"response": "Reviewer comment: The conclusion should apply to women from Sudan. The LH / FSH ratio in other populations in the PCOS female group was already known. Author response: Tola et al found that in Sudanese women with PCOs the cut- off more than 1 has a diagnostic power of PCOS with sensitivity and specificity 72%, 76% respectively (Tola H, Abbas M, Alhassan EA, et al.: Assessment of the Role of the Anti-Mullerian Hormone, Luteinizing Hormone/Follicle Stimulating Hormone Ratio in the Diagnosis of Polycystic Ovary Syndrome in Sudanese Women. Open Access Maced J Med Sci. 2018; 6:1244–1247). Reviewer comment: Correct the level of testosterone and FAI index2 and briefly write down if there are differences in the cut-off point. Author response: Hyperandrogenemia based on estimation of TT level, while the gold standard is serum free testosterone by equilibrium dialysis, which is complex, expensive and labor-intensive. Therefore, surrogate markers such as the free androgen index (Szczuko, M., Zapałowska-Chwyć, M., Maciejewska, D., Drozd, A., Starczewski, A., & Stachowska, E. (2017). Significant Improvement Selected Mediators of Inflammation in Phenotypes of Women with PCOS after Reduction and Low GI Diet. Mediators of inflammation, 2017, 5489523) or calculated free and bioavailable testosterone can be used to assess hyperandrogenemia (Ożga, K., Krzyczkowska-Sendrakowska, M., Hubalewska-Dydejczyk, A., Gilis-Januszewska, A., Ratajczak, M., Ratajczak, M., Chaykivska, Z., & Jach, R. (2019). The value of the free androgen index depends on the phenotype of polycystic ovary syndrome - a single-centre experience. Endokrynologia Polska, 70(4), 330–335) Reviewer comment: Does body fat affect LH and FSH levels? I recommend the Figure 2 in (Szczuko et al. 2014) 1. It is also worth checking PCOS phenotypes. Author comment: Obesity augments the androgen production by stimulating LH, which in turn leads to hyperandrogenism (Glueck, C.J., Goldenberg, N., 2019 Mar 1. Characteristics of obesity in polycystic ovary syndrome: etiology, treatment, and genetics. Metabolism 92, 108–120). Leptin, an appetite-controlling adipokine has a direct impact on the neuroendocrine and reproductive function of obese PCOS women( Szczuko, M., Zapałowska-Chwyć, M., Maciejewska, D., Drozd, A., Starczewski, A., & Stachowska, E. (2016). High glycemic index diet in PCOS patients. The analysis of IGF I and TNF-α pathways in metabolic disorders. Medical hypotheses, 96, 42–47) Reviewer comment: Women with PCOS in European populations tend to be overweight or obese with occasional normal body weight, how does this apply to Sudanese women? Author Response: Among Sudanese PCOS women in this study we found that 30.3% were obese and 46.7% were overweight. Reviewer comment: In premenopausal women, the LH / FSH ratio is typically 1: 1 does the ratio change with age? should be referred to in the discussion. Author response: No diagnostic criteria are presently available for PCOS for premenopausal and menopausal women, the condition can still be suspected in case of a previous diagnosis of the condition, a chronic history of irregular menstrual cycles and hyperandrogenism, and/or polycystic ovarian morphology during the reproductive period (Çelik, Ö., & Köse, M. F. (2021). An overview of polycystic ovary syndrome in aging women. Journal of the Turkish German Gynecological Association, 22(4), 326–333) . Reviewer comment :Different scientific articles give different cut-off values of 2: 1 or 3: 1 in the introduction, as is the case with other populations. And since other values have emerged, the reasons for this should be discussed in the discussion. Author response: A number of studies have proposed appropriate cut-off values for the LH:FSH ratio in PCOS patients. however, the optimal cut-off threshold remains unclear because of the varying sensitivity and specificity. Hsu et al. suggested that an LH/FSH ratio of >1 offered the best combination of sensitivity and specificity for the diagnosis of PCOS (Hsu MI, Liou TH, Liang SJ, Su HW, Wu CH, Hsu CS. Inappropriate gonadotropin secretion in polycystic ovary syndrome. Fertil Steril 2009;91:1168-74). while, in contrast, Papaleo et al ; postulated that an LH/FSH ratio of ≥2 is the characteristic feature of abnormal gonadotropin secretion in PCOS patients ( Papaleo E, Doldi N, De Santis L, Marelli G, Marsiglio E, Rofena S, et al. Cabergoline influences ovarian stimulation in hyperprolactinaemic patients with polycystic ovary syndrome. Hum Reprod 2001;16:2263-6)."
}
]
}
] | 1
|
https://f1000research.com/articles/11-152
|
https://f1000research.com/articles/11-523/v1
|
16 May 22
|
{
"type": "Research Article",
"title": "Analysis of the paddy fields to support community and tourism activities in Ciemas District, Indonesia",
"authors": [
"Lely Syiddatul Akliyah",
"Hilwati Hindersah",
"Muhammad Hanif Fikri",
"Hilwati Hindersah",
"Muhammad Hanif Fikri"
],
"abstract": "Ciletuh Geopark Tourism Area (UNESCO Global Geopark Ciletuh Palabuhanratu) is now one of the main tourist attractions in the Sukabumi Regency, West Java province of Indonesia. The geopark area is in the Ciemas District. Based on the Regional Spatial Planning of the Sukabumi Regency, the Ciemas District is designated as the center of the agricultural sector activities for paddy rice plants in the Sukabumi District. Through the development of tourism activities, Ciletuh Palabuhanratu Geopark will undoubtedly threaten the rice farming sector in the area. In the disruption era, as technology changes, information and knowledge become more accessible. The development of these tourism activities will grow faster in Ciemas District, causing many changes, especially in physical space and regional economics. One change would be in the rice fields in this area, which has been transformed into built-in land in villas, inns, and homestays. If this is allowed, then the function of the sustainability of agricultural activities in the Ciemas District will be threatened. For this reason, control efforts are needed so that paddy fields that must be maintained do not change function quickly. This study analyzes the land use and land cover for paddy fields in Ciemas District. The method of this study is the quantitative method. The analytical methods include population projection, ArcGIS analysis, and Land Potential Index. The findings contribute to supporting the development of tourism while maintaining food security. The results indicate that there are protected areas from being prioritized, which are not prioritized for paddy fields, can be used for the development of tourism activities. Thus, this can be used as a source for the government to make policies for fulfilling food requirements and developing tourism activities in the region.",
"keywords": [
"land-use change",
"paddy fields",
"agriculture land"
],
"content": "Introduction\n\nSome of the Sustainable Development Goals (SDGs) are relevant to the issue of land change. In this research, SDGs that are included are: no poverty (SDG 1), zero hunger (SDG 2), sustainable cities and communities,15 responsible consumption, and production (SDG 12).1 Agriculture land use as a source of food for the community is essential. Especially, for Indonesians who consume rice as their daily staple food, therefore, the existence of rice fields has a vital role. Thus, these goals can be achieved if food sustainability is fulfilled.\n\nDetermination of the Ciletuh Palabuhanratu area as UNESCO Global Geopark at the beginning of 2018 increased visits by local and foreign tourists to this region. This results in an increase in villas, homestays, cottages which leads to a decrease in agricultural land use in this region. Based on the Central Statistics Agency of Sukabumi Regency’s data during 2011-2016, the area of paddy fields has decreased. In 2011, the area of paddy fields in the Ciemas District was 4,684 Ha, while in 2016, it was reduced to 4,225 Ha.\n\nThe research on Land-use change has been widely studied in various countries. Kleiman RE and Erickson DL2 explain the factors influencing landscape change in the USA central watershed. The study showed that the increasing trend in riparian forest areas increased land parcelization at the municipal scale.2 Additionally, this study revealed that the number of cultivated agricultural areas and the number of farmers had decreased. The land had been further divided, and the remaining forest existed only along the rivers. According to this study, the causes of the landscape phenomenon are land-use policies, government programs, agricultural mechanization, and agricultural economics. Rau A-L et al. stated that the drivers of change are human-induced.3\n\nGupta R4 stated that land-use change is caused by population growth. This study examined the complexity of the dynamics of changes in land use, patterns of urban expansion, and population growth. Some indicators were examined using Geomatica, Erdas, and Arc-GIS software. By using these softwares, they were able to show land changes in three cities in India. The same was also done by Iryadi R and Sadewo MN5 in studying the influence of the existence of the Bali Botanical Gardens in the Bedugul basin using Landsat images.5 Thus, there are a lot of research that use Arc-GIS software to investigate land-use changes based on image data.\n\nOne of the researches on the relationship between tourism and settlements was carried out by Lakshmi SR and Shaji TL.6 The findings show the impact of tourism development in Varkala on the coastal environment, including urban sprawl, linear urbanization, environmental degradation, waste, habitat transformation, and changes in the social environment. Moreover, Lanya I et al. indicated that land-use changes happen because of rapid tourism development in Bali.7 GIS showed that land use was reclaimed as vacant land, built areas, annual crops, and settlements. This study stated that sustainable tourism strategies need to be done for tourism development through various environmental assessment tools such as Carrying Capacity Assessment (CCA), Strategic Environmental Assessment (SEA), Environmental Impact Assessment (EIA), and sustainability indicators.\n\nBased on these studies, analysis of changes in land use in an area or city is critical because it has various impacts. It is stated by Zhang X et al.8 that analyzing land change can provide a lot of important information for decision making. Liao H et al.9 stated that Land-use change can be predicted by quantitative and spatial simulation models. In research, changes in land use also need to be reviewed because the research area is a geopark area that functions not only as an attractive area for scientific and technological exploration but also as geotourism. A function of the study area as a tourist area is contrary to the Regional Spatial Planning of the Sukabumi Regency. The Ciemas District, as a research area, has been designated as a center for livestock, fisheries, and agriculture activities, especially rice fields. The increasing tourism activities will threaten agricultural land use in this region. However, Hindersah et al.10 stated that the Ciletuh Geopark, which is a typical tourist attraction has prospects to increase regional income. The functioning paddy fields have become villas, bungalows, restaurants, and other facilities built to support tourism activities. Therefore, for the land to be functionally controlled and tourism activities continue to develop, it is necessary to study efforts to control changes in agricultural land due to the development of tourism activities. This research aims to analyze the supply and demand of people's food needs such as rice. Based on the number of demands, this research analyzed the area of rice fields that had to be maintained, so that community needs were still met. After obtaining the area of paddy fields, the priority areas of rice fields were analyzed so that they were not converted to the development of tourism activities.\n\n\nMethods\n\nIn this study, a survey, and data collection from two government institutions, namely the Regional Development Planning Research, and Development Agency of Sukabumi Regency, and the Central Bureau of Statistics of Sukabumi Regency were taken (Figure 1). The data is analyzed to create a Suitability Analysis of Paddy Fields.\n\nThe data needed for this study was collected through secondary data. Secondary data in Landsat images are processed with ARC GIS 10.8 to obtain land use data for physical analysis such as: topographic map, lithological map, soil types of maps, hydrogeological maps, and natural disaster map obtained from Regional Development Planning, Research, and Development of Sukabumi Regency. While population data, paddy fields production, and paddy fields area were obtained from the Central Statistics Agency of Sukabumi Regency (BPS) from 2016 to 2020.11–15\n\nAnalysis of paddy field that need to fulfill the community's rice needs is obtained by carrying out the following: first step, calculating future projections of the population to obtain an estimated population in the future using the polynomial method. This method was chosen because the population of the Ciemas District experienced fluctuations. The second step is to calculate the required paddy fields using the following formula.16\n\nLR = land requirements (Acre)\n\nCS = consumption standard (kg/hectare/year)\n\nTP = total population (person)\n\nCCR = coefficient of conversion of rice to paddy (1.918)\n\nALP = average land production (ton/Ha)\n\nACI = average cropping index\n\nGandes H et al.17 said that Analysis of Land Potential Index (LPI) is an analysis to produce land that has the potential to become food agriculture, with assessment parameters in the form of slope, soil type, hydrogeology, lithology, and landslide susceptibility. This analysis technique is carried out by overlaying parameters that have their respective scores to form the LPI class. The LPI class covers very low, medium, high, and very high classes. The formulas used are as follows:\n\nLPI = Land Potential Index\n\nR = Relief\n\nS = Slope\n\nLi = Litology\n\nT = Land Type\n\nH = Hydrogeology\n\nB = Disaster\n\nThe suitability analysis of paddy fields was carried out according to FAO (1985)18 evaluation of land for irrigated agriculture. The analysis of delineation of priority paddy field protection aims to delineate which paddy fields have the potential to be protected. This analysis uses parameters in wetland use based on the irrigation, irrigation networks, potential indices of food agriculture, and suitability of wetland paddy fields.\n\nThis analysis was carried out by overlaying wetland maps based on the type of irrigation and irrigation networks, with a map of potential agricultural land indexes and a suitability map of rice fields. The conditions for priority paddy fields to be protected are irrigated paddy fields and non-irrigated paddy fields. Those paddy fields have a high to moderate index of food agriculture land potential.\n\n\nResults\n\nThe Ciemas District is one of the regions in West Java, Indonesia. Based on the results of processed SIG from the 2017 Indonesian Earth map, land use in this region (Figure 2) are dryland forests (33%), savannas (29%), plantations (17%), paddy fields (14%), settlement (2%), and others (5%). Based on GIS processing, rice fields in this region in 2017 amounted to 4.276 ha, while paddy fields in 2018 decreased to 4.184 ha (BPS, 2018) [12].\n\nPaddy fields production in the region has fluctuated from year to year because rice cultivation in this area is irrigated and rainfed. Therefore, the intensity of rain dramatically affects the amount of rice production in this region. Based on BPS data [10-15], rice production from 2012 to 2020 can be seen in Table 1.\n\nThis area is dominated by farmers. The population from 2011 to 2016 has fluctuated. Table 2. Shows data on the population of the Ciemas District.\n\nTo increase rice production in the Ciemas District, the government made 11 irrigation areas, each irrigating the fields with a particular water discharge. The area of paddy fields covered by irrigation is 3,241 ha. The condition of the irrigation canal in the Ciemas District has an average width of 2-3 meters, which is sourced from springs, rivers, and waterfalls. The area of irrigation and water discharge can be seen in Table 3 and the distribution can be seen in Figure 3.\n\nThe rice fields that needed to fulfill the community needs can be calculated by projecting the population first (Table 4).\n\nThe need for paddy fields per person for the Ciemas Subdistrict community is calculated using formulas 1. Compared to the increase in the estimates of the Ciemas population, the need for paddy fields is also increasing. The rice field needs for the next 20 years has been shown in Table 5, assuming that the actual rice field area in 2016 was 4,225.46 Ha, and it will not decrease until the next 20 years.\n\nBased on Table 5, the needs of paddy fields until the year 2035 could be achieved. The rice field area in Ciemas is surplus. However, the existence of the Ciletuh Geopark as a geotourism area in Ciemas will certainly have an impact on the increasing number of residents who come and turn the land into built-up land for villas, cottages, homestays, and others.\n\nCiemas District, which functions as one of the sustainable food agriculture areas, must be able to guarantee the availability of food for Ciemas and other regions. Thus, it is necessary to delineate paddy fields that must be protected so that the sustainability of food agriculture in this region is guaranteed. This delineation is carried out by overlaying paddy field maps based on the type of irrigation and irrigation networks, with a map of potential agricultural land indexes and a suitability map of rice fields.\n\nLand Potential Index analysis (LPI)\n\nLPI analysis was carried out scoring from relief, slope, lithology, soil type, hydrogeology, and disaster-prone ground movement. Furthermore, each factor that has been given a score is overlaid to produce 172 types of land, each of which has its own characteristics. Based on the analysis, the classification of the potential of food agriculture, the Ciemas District can be divided into three classes, namely medium, low, and deficient class. The following table are the results of the LPI analysis:\n\nFrom Table 6 the dominant land of potential food agriculture is the low potential class reaching 68% of total area. The low potential class of land is caused by the main factor of the hydrogeological conditions of the region, where 87.72% of the total area of Ciemas District is included in the minor productive aquifers.\n\nThe existence of three types of potential agricultural land classes in Ciemas District will impact the diversity of types of agricultural businesses. The agricultural business must be adapted to the existing potential index of land. Areas that have a moderate land potential class can be said to be suitable for all agricultural businesses but with a record of having a high risk of damage. This class has a slight slope, or it is at a risk of erosion, poor drainage, very slow soil permeability, shallow solum, low water-holding capacity, low soil fertility, and it is not easily repaired.\n\nAreas with a low potential class of land can still be planted with crops, but the choice of plants is minimal and less suitable to be planted by rice plants. This land class has steep slope conditions, sensitivity to significant erosion, low water-holding capacity, and high salinity.\n\nAreas with a deficient potential class of land are not suitable for cultivation, therefore it is recommended for these areas to be protected. This class of land has a high erosion hazard, and often experiences flooding, rocky soil, and soils in swampy areas that are difficult to drain.\n\nJudging from its distribution, the area that has the LPI class is spread in lowland areas, precisely in Ciwaru Village and several other villages, especially in coastal areas Almost all villages have undulating to hilly and mountainous landscapes, therefore they are categorized as low to very low LPI class. More details about the distribution of the IPL class can be seen in Table 6.\n\nLand suitability analysis of rice paddy crop agriculture\n\nAnalysis of the suitability of wetland rice fields will result in the delineation of any area that has the potential to be used as paddy fields. Based on the results of overlaying the suitability of paddy fields in the Ciemas District, it produces 20 polygons that have their own characteristics. Furthermore, the 20 polygons can be further classified into actual and potential land suitability. The actual and potential land suitability maps can be seen in Figures 4 and 5.\n\nPriority map of wetland rice is produced by overlaying irrigated paddy field map, land potential index analysis map, and suitability analysis map. The criteria for priority rice fields to be protected are rice fields that have been irrigated and rainfed rice fields that have a land suitability class of S1. In comparison, those that are not a priority to protect are rainfed lowland rice fields with medium, low, and deficient potential land types and land suitability other than S1. The results of the overlay of the three maps produce 40 land types that have different characteristics (Table 7).\n\nAs seen in Table 7 priority paddy fields to be protected are spread over 3,559.72 ha, or 84% of the total paddy field area. In comparison, paddy fields that are not a priority to be protected are spread with 665.74 ha or 16% of the total wetland area.\n\nJudging from its distribution, many priority paddy fields that should be protected are scattered in the middle of the sub-district along the Ciletuh, Cikanteh, and Cimarinjung River stream precisely in Ciwaru, Mekarsakti, Tamanjaya, Cibenda, Sidamulya, and Mandrajaya Villages. In comparison, rice paddy fields that are not a priority to be protected are widely spread in the north, namely in the villages of Girimukti, Ciemas, Mekarjaya, and Tamanjaya. More details about the form and distribution of delineation of priority and non-priority paddy fields have been shown in Figure 6.\n\n\nDiscussion\n\nIn Indonesia, rice is the main staple food. To meet the demand for rice, the Indonesian government has established a policy to make rice fields sustainable. Food sustainability is becoming essential so that one of the SDGs regarding zero hunger could be achieved. However, making the rice supply sustainable is not easy. Sometimes food needs can result in reduced forest land or competition with other development needs, which can cause land use conflicts.19 It is challenging to keep paddy fields in Ciletuh Geopark, as it is recognized globally as Geotourism.\n\nThe development of Ciletuh Geopark in Ciemas District as a tourism area will change land use/land cover in this region. Lakshmi SR et al6 and Lanya I et al.7 stated that many regions with tourism development have the same experience with function changes on their land. Zhu H et al.20 stated that other tourist destination experiences facing conflict to gain sustainable development in heritage tourist site. On the other hand, this research calculates the limited rice paddy areas that are needed so that there are other areas that still meet tourism development. Therefore, Ciemas, which is defined as an area that has a sustainable supply of agricultural food for the provision of rice for the community, can still develop as a tourist destination without turning rice fields into a tourist area.\n\nThis research employed a quantitative method with a supply-demand and suitability analysis approach. These two approaches are the way to give a solution for the competing interest. The paddy field area will be the land-use supporting the Ciletuh Geopark Tourism and food security of the Ciemas community. The availability of paddy fields in this region is still surplus. However, control efforts must be made so that the paddy field area would not decrease.\n\n\nConclusion and recommendations\n\nThe analysis showed two priority classifications of paddy fields to be protected and not protected. Following the discussion, it can be concluded that:\n\n1. The policy of land-use change from agricultural to other purposes must begin with calculating the food consumption needs of the community so that their needs are guaranteed.\n\n2. Efforts to control the functioning of agricultural land use for tourism activities must be carried out from the outset. There needs to be strong participation and commitment between the community, government, and private sector to implement and control agricultural and tourism activities to develop well and work together.\n\n3. Zoning regulation must be implemented through policies accompanied by control tools in clear incentives, disincentives, and sanctions.\n\nBased on the conclusion of the study, several recommendations can be proposed:\n\n1. Applying the concept of agrotourism as part of the Ciletuh Geopark tourist attraction by making paddy fields a medium for farming learning for tourists.\n\n2. Involving local farmers and agriculture and tourism communities such as Gapoktan and Paguyuban Alam Pakidulan Sukabumi (PAPSI) in Ciemas District to manage agro-tourism activities.\n\n3. Provision of irrigation networks for paddy fields that have not been irrigated.\n\n4. Improve the limiting factor for potential paddy fields.\n\n5. The regional government to immediately draws up regulations on land conversion concerning the direction of future food security programs. The zoning of productive land that must be maintained is based on binding regulations and sanctions if violated.\n\n6. Incentive and disincentive policies. The policy of providing incentives is given to residents who maintain their productive land through reduced land and building tax payments, ease of obtaining capital assistance, assistance for agricultural production facilities, counseling assistance, post-harvest management, marketing assistance, all of which are carried out by maintaining the stability of agricultural commodity prices. Disincentive policy is given if the citizens do the land conversion that conflicts with their designation or it is against the regulations that apply, e.g., Regional Spatial Plan. However, the residents are free to sell their land.\n\n7. Licensing tourism development must be based on the results of environmental impact analysis through various appropriate analytical tools.\n\n\nData availability\n\nPhysical maps are private data that cannot be published by the Regional Development Planning, Research, and Development Agency of the Sukabumi Regency. Researchers have permission from the institution to use the data for this research. However, information from the map can be seen in the Regional Spatial Planning of Sukabumi Regency document and it can be accessed at https://jdihn.go.id/files/308/5822.-rtrw-kabupaten-sukabumi.pdf. Data from the Central Bureau of Statistics of Sukabumi Regency can be accessed at Badan Pusat Statistik Kabupaten Sukabumi (bps.go.id).\n\n\nAuthor contributions\n\nLely Syiddatul Akliyah\n\nRoles: conceptualization, data curation, methodology, formal analysis, Writing – Original Draft Preparation\n\nHilwati Hindersah\n\nRoles: methodology, formal analysis, Writing – Original Draft Preparation\n\nM. Hanif Fikri\n\nRoles: data curation, visualization, software, Writing – review, and editing",
"appendix": "Acknowledgement\n\nWe thank The Ministry of Research, Technology, and Higher Education of the Republic of Indonesia for funding this research.\n\n\nReferences\n\nViana CM, Freire D, Abrantes P, et al.: Agricultural Land Systems Importance for Supporting Food Security and Sustainable Development Goals: A Systematic Review. Sci. Total Environ. 2022; 806: 150718. PubMed Abstract | Publisher Full Text\n\nKleiman RE, Erickson DL: Landscape Change In An Agricultural Watershed: The Effect of Parcelization on Riparian Forest Cover. Environ. Plan. B Plan. Des. 1996; 23(1): 25–36. Publisher Full Text\n\nRau A-L, Bickel MW, Rathgens J, et al.: Linking Concepts of Change and Ecosystem Services Research: A systematic review. Chang. Adapt. Socio-Ecological Syst. 2019; 4(1): 33–45.\n\nGupta R: The Pattern of Urban Land-use Changes: A Case Study of The Indian Cities. Environ. Urban. ASIA. 2014; 5(1): 83–104. Publisher Full Text\n\nIryadi R, Sadewo MN: Influence the Existence of the Bali Botanical Garden for Land Cover Change in Bedugul Basin Using Landsat Time Series. Procedia Environ. Sci. 2015; 24(January): 158–164. Publisher Full Text\n\nLakshmi SR, Shaji TL: Transformation of Coastal Settlements Due to Tourism. Procedia Technol. 2016; 24: 1668–1680. Publisher Full Text\n\nLanya I, Dibia IN, Diara IW, et al.: Analysis of Subak Land Use Change Due to Tourism Accommodation Development in North Kuta Sub-district, Badung Regency, Indonesia. IOP Conf Ser Earth. Environ. Sci. 2017; 98(1): 012024. Publisher Full Text\n\nZhang X, Kang T, Wang H, et al.: Analysis on Spatial Structure of Land Use Change Based on Remote Sensing and Geographical Information System. Int. J. Appl. Earth Obs. Geoinf. 2010; 12(SUPPL. 2): S145–S150. Publisher Full Text\n\nLiao H, Liu M, He H, et al.: Application of Land Use Change and Prediction in Urban Planning Evaluation and Formulation. J. Comput. Commun. 2021; 09(06): 230–237. Publisher Full Text\n\nHindersah H, Asyiawati Y, Akliyah LS, et al.: Tantangan Pembangunan Pariwisata Inklusif Geopark Ciletuh, Desa Ciwaru Kabupaten Sukabumi – Provinsi Jawa Barat. In: Prosiding Seminar Nasional: Perencanaan Pembangunan Inklusif Desa - Kota.2017; p. 125–34. Reference Source\n\nSukabumi BPSK: Kecamatan Cemas Dalam Angka 2016.2016. Reference Source\n\nSukabumi BPSK: Kecamatan Ciemas Dalam Angka 2017.2017. Reference Source\n\nSukabumi BPSK: Kecamatan Ciemas Dalam Angka 2018.2018. Reference Source\n\nSukabumi BPSK: Kecamatan Ciemas Dalam Angka 2019.2019.\n\nSukabumi BPSK: Kecamatan Ciemas Dalam Angka Tahun 2020.2020.\n\nAfif ZF: Analisis Prioritas Perlindungan Lahan Sawah Pada Kawasan Strategis Perkotaan Di Kabupaten Garut. Library of IPB University; 2020. Reference Source\n\nGandes H, Dwi Priyono K, Tjahjono T: Analisis Potensi Lahan Pertanian Sawah Berdasarkan Indeks Potensi Lahan (IPL) Di Kabupaten Wonosobo. UMS Library. Universitas Muhamadiyah Surakarta; 2014.\n\nOrganization FA. FAO: Land Evaluation For Irrigated Agriculture. 1985.1985.\n\nde Jong L , De Bruin S, Knoop J, et al.: Understanding Land-use Change Conflict: A Systematic Review of Case Studies. J. Land Use Sci. 2021; 16(3): 223–239. Publisher Full Text\n\nZhu H, Zhang J, Yu X, et al.: Sustainable Tourism Development Strategies and Practices of World Heritage Sites in China: A Case Study of Mt. Huangshan. Int. J. Sustain. Dev. Plan. 2019; 14(4): 297–306. Publisher Full Text"
}
|
[
{
"id": "145447",
"date": "09 Aug 2022",
"name": "Abdelkader Ababneh",
"expertise": [
"Reviewer Expertise Tourism management",
"heritage management and interpretation",
"tour guiding"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nREVIEW STATEMENT JOURNAL: F1000Research PAPER TITLE: Analysis of the paddy fields to support community and tourism activities in Ciemas District, Indonesia\n\nMANUSCRIPT ID: Thank you for letting me read this article. I think the manuscript needs to be restructured, better organized and better crafted. I recommend the approval and indexing of this work after the adjustment of the following concerns.\nI wish you good luck with your work.\nAbstract and key words:\n\nThe abstract is well drafted, the background is long, it needs to be summarized, more details regarding the methods is advised.\n\nThis statement \"The findings contribute to supporting the development of tourism while maintaining food security\" needs to be replaced at the end of the abstract.\n\nI suggest to add the name of the case study and the country as part of the key words.\nIntroduction:\n\nWhile the introduction section seems well articulated the purposes of the study need to be clearly stated and explained. This section is brief, further, this section has to demonstrate clearly the problem of the study, and thus the purpose of the study needs to be expanded. In addition, the introduction in its current form is a sort of literature review, why you don’t have your own separated sub section dedicated to the literature review. However, the literature review must be critical and demonstrate the gaps and the trends.\nMethods:\n\nThis part and its sub sections are well detailed.\nResults:\n\nThis section is also well articulated with good maps and tables.\n\nBut why is there no background about the case study? A section or anything else may introduce the case study to the readership.\nDiscussion:\nThis section needs to be revised for repetition and further the discussion in a more critical approach.\nConclusion and recommendations are clear and concise\n\nSummary statement: A very worthy subject, it needs to be thoroughly reorganized, using the suggestions provided; I recommend indexing of this manuscript after addressing the concerns.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "175308",
"date": "12 Jul 2023",
"name": "Mitiku Badasa Moisa",
"expertise": [
"Reviewer Expertise GIS and Remote sensing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nComments for “Analysis of the paddy fields to support community and tourism activities in Ciemas District, Indonesia”\nDear Authors Your manuscript is interesting and high potential for publication, but it needs major revision before acceptance for indexing.\nGeneral comments\nThe abstract critical needs rewrite. It is not follow the rule of abstract writing. So revise by considering, introduction, objective, methods, result, conclusion and recommendation.\n\nResearch gap of your study should be discussed in the end paragraph of introduction part by comparing with previous similar studies.\n\nAll methods need rearrangement as:\n2. Materials and methods\n2.1 Description of the study area - Location map of the study area - Study area map for this study should be mapped - Climate - Elaborate temperature and rainfall of the study area - Land use types - List and discuss the current Land use land cover types of the study area - Socio economic status\n2.2. Data source and descriptions\n2.3. Data analysis\n\nThe quality of all maps should be improved.\n\nDiscussion should be strong by elaborating and comparing previous studies.\n\nConclusion should separate from recommendation and rewrite it.\n\nRecommendation does not need independent title and it should be written at the end line of conclusion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-523
|
https://f1000research.com/articles/11-521/v1
|
13 May 22
|
{
"type": "Research Article",
"title": "The effects of silkworm cocoon (Bombyx mori) wound dressing applications to the COX-2 expression and the number of neutrophils after skin excision wounds (in vivo research on Wistar rats)",
"authors": [
"Efron Andre Tarigan",
"Cahya Yustisia Hasan",
"Pingky Krisna Arindra",
"Efron Andre Tarigan",
"Pingky Krisna Arindra"
],
"abstract": "Background: Silkworm cocoons are materials that have fine regenerating abilities for the human body. Fibroin and sericin present in silkworm cocoons (Bombyx mori) are thought to have anti-inflammatory effects. This study aimed to know the effects of the use of wound dressing from silkworm cocoons toward COX-2 expression and neutrophils number in the inflammatory phase after skin excision. Methods: Twelve male Wistar rats according to inclusion criteria were randomly divided into 4 groups, each group of 6, based on the decapitation time (the 3rd day and the 6th day) and based on the dressing material (moist gauze dressing as the control group and silkworm cocoons as the treatment group). Each group was performed an excision on the dorsal skin with subcutaneous depth using a 4 mm-round punch biopsy. Neutrophil cell observations were performed by Hematoxylin eosin staining (HE). COX-2 expression was found in preparations for immunohistochemical staining using rabbit monoclonal COX-2 antibody at sacrificed period on the 3rd and the 6th day after wound dressing application. Results: The number of neutrophils and expression of COX-2 were analyzed using Two-way ANOVA and Independent t-test. The results showed a significant decrease in the number of COX-2 expression on inflammatory cells as well as the number of neutrophils (p<0.005) in the groups treated with wound dressing from silkworm cocoons on both the 3rd and 6th day. Conclusions: It was concluded that the use of wound dressing from silkworm cocoons can inhibit COX-2 expression (p=0,000) and decrease the number of neutrophils in the inflammatory phase after skin excision (p=0,001).",
"keywords": [
"COX-2",
"fibroin",
"neutrophil",
"sericin",
"silkworm cocoons",
"skin excision"
],
"content": "Introduction\n\nWound healing is a complex dynamic process that results in restoration of anatomic continuity and tissue function after injury. Wound healing is divided into three stages that are interconnected and overlapped in time of occurrence, namely: 1) inflammation; 2) tissue formation (proliferation); and 3) tissue remodelling.1 Inflammation causes many substances to be released endogenously, known as inflammatory mediators. Arachidonic acid is one of the important inflammatory mediators. Arachidonic acid plays a role in the biosynthesis of prostaglandins through the cyclooxygenase pathway. Cyclooxygenase-1 (COX-1) plays a role in normal physiological functions such as mucus secretion to protect the digestive mucosa and to maintain kidney function. Cyclooxygenase-2 (COX-2) is an enzyme whose presence is influenced by tissue stimulation. These stimuli can be in the form of cytokines, bacterial lipopolysaccharides, inflammation, or other pathological conditions.2\n\nInflammation also results in the accumulation of white blood cells, especially neutrophils and monocytes, at the site of injury to eliminate or limit the causative agent of injury. Neutrophils will perform margination, emigration, chemotaxis and phagocytosis. The short lifespan of neutrophils and the process of phagocytosis by neutrophils will affect the timing of the acute inflammatory phase and continue with the next phase of the healing process.3\n\nThe wound care method that is currently developing is using the principle of moisture balance known as modern wound dressing, which is stated to be more effective in wound healing.4 Modern wound dressing is one of the wound care methods in a closed and moist way that is focused on keeping the wound from dehydration and improving wound healing process.5 Wounds with a moist condition can accelerate fibrinolysis, angiogenesis, reduce the risk of infection, form growth factors, and form active cells. Modern wound dressings that have been developed are made of synthetic polymers and are classified as passive, interactive and bioactive6 products, in the form of hydrocolloids, alginates, hydrogels, films, and foams.7\n\nSilkworms (Bombyx mori) produce cocoons that have many benefits, especially as a basic material for silk products. Silkworm cocoons have a structure, function and protection mechanism that is almost similar to human skin.8 Silkworm cocoons have been used for a long time as a medical basis and mainly as a suturing material, namely silk thread. Many studies have shown that the main proteins that make up the cocoon structure of silkworms, namely fibroin and sericin, are highly biocompatible materials and have fine regenerating abilities for human tissues.9 In vitro studies have also shown that fibroin helps cell migration and proliferation by acting as cellular and molecular modulators.6\n\nIn vitro and in vivo studies on the use of silkworm cocoons as the base material for wound dressings have been carried out, but their use in skin excision wounds has never been proven and no studies have been conducted to determine whether or not there is an effect of using silkworm cocoons wound dressing on the inflammatory phase after skin excision. Based on these reasons, the idea emerged about the research on the effects of using silkworm cocoon wound dressing on wound healing after skin excision on Wistar rats in terms of the COX-2 expression and the number of neutrophils.\n\n\nMethods\n\nThe making of wound dressings from silkworm cocoons was carried out by following the guidelines made by Yu, et al. (Figure 1).6 The cocoons used were oval in shape, then they were cut at both ends so that they became tubular and cut back on one side of the tube to form a rectangular sheet measuring 4×1.5cm. The silkworm cocoons that had been cut were then immersed in a beaker containing a solution of CaCl2-ethanol- H2O with a molar mass ratio of 1:2:8. The beaker containing the cocoon sheets was then placed in a water bath at 58oC for 90 minutes. The silkworm cocoons were then rinsed with sterile distilled water at room temperature four times and dried with silica gel desiccant for 24 hours. Sheets of silkworm cocoons that had been processed were formed into pieces of transparent film measuring 4×1.5 cm with a thickness of 0.7 mm and were ready to be used as wound dressings on wounds. The wound dressing was then sterilized using a sterilization pack and ethylene oxide gas (EOG) at 36°C for seven hours.\n\nThis research was approved by the The Research Ethics Committee of the Faculty of Veterinary Medicine, Universitas Gadjah Mada (Approval No. 00108/EC-FKH/Eks./2021). This research is a quasi-laboratory experimental study with 12 male Wistar (Rattus novergitus) rats based on calculations using the resource of equation method with the minimum sample calculation formula in research with ANOVA design. Sample calculation: Minimum n= 10/kr +1 =10/(2×2) +1 = 3,5. Maximum n= 20/kr +1 = 20/(2×2) +1 = 6 (k = number of treatments, r = number of repeated measurements). The conclusion is the use of 6 rats meets the sample size requirements. They were randomly divided into four groups of euthanasia day by simple randomisation. Random numbers were generated using the standard = RAND() function in Microsoft Excel. That is, on the 3rd and 6th day after being given treatment, 6 subjects each. Subjects were taken with inclusion criteria including: males, three months old, weight ± 250 grams, looked healthy, physically active, and no anatomical defects. Exclusion criteria included: postoperative pain and infection, death before the euthanasia day and unstable body weight (weight loss <20% in a week). The rats were first adapted to the laboratory environment with temperature and humidity that had been adjusted to laboratory standards for one week, given standard feeding and drinking, and placed in individual cages.\n\nRats were anesthetized by injection of Ketamine 10% (80-100 mg/kg body weight) and Xylazine (10-12.5 mg/kg body weight) intra peritoneal, then marking the back area to be shaved with a size of 3×3 cm with guidelines covering the area to be shaved in the excision that was 0.5 cm right and left of the vertebral column and 2.5 cm from the ears. The hair in the area was shaved and then a re-marking of the area to be excised was made. The skin was excised with a round punch biopsy with a diameter of 4 mm. The biopsy punch was pressed against the skin and then rotated while continuing to be pressed until the tool touched the fascia. The punch biopsy was pulled up along with the excised tissue. The tissue that had been cut by a punch biopsy was removed using tweezers and cut with surgical scissors so that a circular wound was obtained with the base of the wound being fascia. The blood that came out was cleaned with a cotton swab that had been dipped in saline solution (0.9% NaCl).\n\nThe post-excision wound of the rat's back was then covered with a film dressing from the cocoons of the silkworm (Bombyx mori) in the treatment group and covered with sterile gauze moistened with saline in the control group (Figure 2). The entire edge of the film dressing was then covered with a Tegaderm film to provide stability to the film dressing so that it could last for the desired length of treatment. All rats were given analgesics in the form of Paracetamol 50 mg/kg body weight ad libitum orally after excision and the wound dressing was changed every day.\n\nThe wound tissue sampling from the rats’ back skin of was with a subcutaneous depth of 3×3 cm around the punch biopsy wound area, then attached to cardboard using staples to prevent the tissue from curling before being stored in 10% formalin phosphate buffer solution. Rats were sacrificed by injection of Ketamine 150 mg/kg body weight and Xylazine 30 mg/kg body weight intra peritoneal after tissue sampling, then incinerated according to the standards of the Experimental Animal Laboratory of PSPG UGM.\n\nSamples that had been soaked in formalin were taken to the Anatomical Pathology Laboratory of the Faculty of Medicine, Universitas Gadjah Mada to make preparations. The following parameters were assessed: IHC staining was carried out to see COX-2 expression and HE staining to see the number of neutrophils. COX-2 expression was brown in the cytoplasm in the wound margin area per 6 fields of view with 400x magnification. The calculation results for each field of view on each slide were added up and then divided by 6 to obtain the mean number of COX-2 expression in inflammatory cells. Neutrophils were observed by counting the number of neutrophil cells in the wound margin area using a 400× magnification light microscope, observed in 6 fields of view. The calculation results of each field of view on each slide were added up and then divided by six to obtain the mean number of neutrophils.\n\nThe data obtained from the observations were tested for normality of the data with the Shapiro-Wilk test and homogeneity test with Levene's test. The results of the normality test showed that the data was not normally distributed, so data transformation was carried out. The homogeneity test showed that the data was homogeneous, then parametric analysis was carried out with the Two-way ANOVA test to determine the significant difference between the treatment groups and the time of observation. Statistical calculations were performed using statistical package for the social sciences (IBM SPSS Statistics 25) software at a confidence level of 95% (α < 0.05). Independent t-test was used to compare the significance between the control and treatment groups in one observation time.\n\n\nResults\n\nThe calculation of the amount of COX-2 expression in each group was carried out by observing it under a microscope with 400× magnification in 6 fields of view after IHC staining on the 3rd day and the 6th day of observations. The expression of COX-2 was indicated by the presence of brown color expression in the cytoplasm of inflammatory cells in the wound margin area. Figure 3 shows a microscopic picture of COX-2 expression on inflammatory cells, the cytoplasm of cells that absorbs brown color (red arrow) with IHC staining at 400× magnification shows that on the 3rd day of observation time more cells express COX-2 in the group. The control group (Figure 3A) is compared to the treatment group (Figure 3B), as well as on the 6th day, at 400× magnification, the cytoplasm of the inflammatory cells painted brown in the control group (Figure 3C) is more than that of the treatment group (Figure 3D).\n\nThe observations results of the number of COX-2 expressions in each treatment group at each observation time were calculated on the average and presented in Table 1.\n\nTable 1 shows that the average number of COX-2 expressions on the 3rd day (39.4133) and the 6th day (20.4417) after excision in the control group is more than the treatment group on the 3rd day (19.4050) and 6th day (4.8050).\n\nAn illustration of the number of COX-2 expressions is presented in Figure 4.\n\nData analysis using Two-way ANOVA showed a significant difference between the number of COX-2 expressions between the observation times on the 3rd and the 6th day (p=0.001), as well as the comparison of the number of COX-2 expressions between the control and treatment groups (p=0.000), while between the time of observation and the treatment group p=0.614, which meant there was no interaction between the time of observation and the treatment group. The data analysis results of the difference in the number of COX-2 expressions can be seen in Table 2.\n\nIndependent t-test was to compare the mean number of COX-2 expression between treatment groups at each observation time. The results of the t-test showed a significant difference (p<0.05) between the control and treatment groups on both the 3rd day (p=0.024) and 6th day (0.003).\n\nThe calculation of the number of neutrophils in each group was carried out by observing them under a microscope with 400× magnification in 6 fields of view after HE staining on the 3rd day and the 6th day of observations. Figure 5 shows a microscopic picture of the number of neutrophils, the nucleus of neutrophil cells that absorbs purple color and is oval in shape (black arrow) with HE staining at 400× magnification, that appears on the 3rd day of observation time have more neutrophils in the control group (Figure 5A) compared to the treatment group (Figure 5B), as well as on the 6th day, at 400× magnification, the number of neutrophils in the control group (Figure 5C) is more than that of the treatment group (Figure 5D).\n\nThe mean calculation of the observation results of the neutrophils number in each treatment group at each observation time is presented in Table 3.\n\nThe mean number of neutrophils on the 3rd day obtained in the control group (65.5517) was more than the treatment group (30.1917). The mean number of neutrophils on the 6th day post-excision in the control group (39.1267) was also higher than the treatment group (8.4333) (Figure 6).\n\nHomogeneity test results obtained homogeneous data results (p=0.117). The results of the analysis using Two-way ANOVA showed that there was a significant difference in the number of neutrophils (p<0.05) both between the days of observation and the treatment group, while between the time of observation and the treatment group was p>0.05, which meant that there was no interaction between the time of observation and the treatment group.\n\nTable 4 shows that the number of neutrophils between the time of observation (the 3rd day and the 6th day) differs significantly (p=0.014), similarly the comparison of the number of neutrophils between the control and treatment groups is significantly different (p=0.001), while between the time of observation and the treatment group is p=0.797, which means that there is no interaction between the time of observation and the treatment group.\n\nIndependent t-test was to compare the mean number of neutrophils between treatment groups at each observation time. The results of the t-test showed a significant difference (p<0.05) between the control and treatment groups on both the 3rd day (p= 0.036) and the 6th day (0.014).\n\n\nDiscussion\n\nThe excision wound was chosen because the excision wound represents a secondary healing condition, has a greater risk of impaired healing, and has a large area of wound that requires dressing application. The excision wound model can be used in research for the healing process of skin wounds.10\n\nThe calculation of the number of rat samples and the actions taken in this study were in accordance with the principle of reduction in the 3Rs (replacement, reduction, refinement).11 During the study, all Wistar rats were in healthy condition, stable body weight (did not experience weight loss), no postoperative infection, actively moving with the back area still covered with dressing, so that no rats were excluded in this study. The age of the rats in this study ranged from 3-4 months old. Rats aged 3-6 months can be an ideal comparison of tissues in the human body of young adults. Rats that are too young or too old will have a reduced ability to cope with environmental stress, which can lead to increased comorbidities and reduced skin blood flow.12\n\nThe excision wound in this study was made on the back of the rats using a round punch biopsy with a diameter of 4 mm. The wound size of 4 mm was chosen because this size is sufficient to represent a secondary wound that can be covered by dressings easily and is still within the wound size limits that can be tolerated by rats, both with 1 and 2 wounds. Wound size that is too large can increase physical and metabolic stress in rats. Physical and metabolic stress can occur in large wounds relative to the total body surface area (TBSA) so that it can affect the results of wound healing studies. In order to prevent the effects of physical and metabolic stress, a wound size of less than 15 mm × 15 mm should be used in rats weighing 200 to 350 grams. Skin excision in rats can be done on any parts of the body because almost all parts of the rat's body are movable skin, but generally it is done on the back of rats so that observations can be done more easily.10\n\nThe wound healing optimization can be done by following several basic principles, including (1) wound moisture, (2) adequate blood supply, and (3) infection minimization. These principles can be facilitated by the use of an ideal wound dressing. The ideal wound dressing requirement is to use a basic material that can protect and cover the wound, maintain moisture, is permeable to air so that the tissue gets an adequate oxygen supply, and is able to inhibit the growth of pathogens without inhibiting tissue growth. The ability of wound dressings to trap moisture in the wound area has proven that epithelial growth is twice as fast as wounds that are not treated with wound dressings. This happens because moisture will prevent the superficial dermis drying. Drying of the superficial dermis causes impaired cell migration and proliferation.13 Moist gauze soaked in NaCl selected as a control group in this study was also based on the principles of ideal wound dressing, so that it could be used as a comparison equivalent to silkworm cocoon wound dressing which also has certain humidity.\n\nThe use of silkworm cocoons in its history has been recognized as a pioneer of biopolymer materials in medical applications. Silkworm cocoons, since their discovery until now, have been used as a biocompatible suture material. There have been many studies showing that the main proteins that make up the cocoon structure of silkworms, namely fibroin and sericin, are highly biocompatible materials and have fine regenerating abilities for human body tissues.6,9 This study used silkworm cocoons which were degummed for 90 minutes to be used as the base material for wound dressings used in excision wounds of Wistar rats’ skin.\n\nThe time of observation in this study was carried out on the 3rd day and the 6th day after skin excision. The timing of the observation was on the 3rd day because it was the peak of the inflammatory phase as neutrophils reached the highest number in the wound area, while the 6th day was the time when the inflammatory phase had entered its final period.14 Another study on the back skin of rats that were injured using a 6 mm diameter punch biopsy without using a wound dressing showed that the number of neutrophils after a skin wound increased within 12 hours and reached a maximum value on the 2nd day, tending to level off until the 3rd day, then it will decrease drastically by 50% starting on the 5th day. On the 2nd day post-injury, many neutrophils were found in the dermis of the rats’ skin and on the 6th day only a few neutrophils and monocytes or macrophages in the tissue indicating the inflammatory phase were almost complete.15\n\nThe stimulus given in this study was an excision wound made using a punch biopsy. In the injured tissue there would be a wound healing process that began with the formation of blood clots and was then followed by an inflammatory phase. The wound healing process will not occur if there is no inflammation and it will be a source of pain. The inflammatory process causes an increase in inflammatory mediators, one of which is prostaglandin which is the result of biosynthesis of arachidonic acid through the cyclooxygenase pathway. Increased prostaglandins will stimulate pain nerves and increase the inflammatory response. The inflammatory response must be controlled because a continuous and long-lasting inflammatory response will cause tissue damage to get worse. Inhibition of the cyclooxygenase pathway is useful to reduce or eliminate inflammatory symptoms.16 The microscopic image of COX-2 expression in the treatment group that was given the silkworm cocoon wound dressing application showed that the inflammatory cells that expressed COX-2 were significantly decreased compared to the control group. Likewise, the microscopic image of the number of neutrophils in the treatment group was seen to decrease significantly compared to the control group on both the 3rd day and the 6th day observations.\n\nThe decrease in the amount of COX-2 expression in the treatment group could mean that the silkworm cocoons had the effect of inhibiting COX-2 expression and could be said to have anti-inflammatory effect. Silkworm cocoon wound dressing can inhibit COX-2 expression by the following mechanism: fibroin and sericin contained in silkworm cocoons have the ability to inhibit the activation of NFkB thereby inhibiting the synthesis of IL-1 and TnFα. Inhibition of IL-1 and TnFα synthesis causes reduced stimulation of cell membrane phospholipids, so that arachidonic acid is not released from cell membrane phospholipids by phospholipase activation. This situation causes reduced COX-2 protein synthesis and reduced prostaglandin biosynthesis so that the inflammatory response is reduced.16 The fibroin content in silkworm cocoons has an anti-inflammatory effect by inhibiting the signaling pathway associated with nuclear transcription factor (NF)-κB. Nuclear transcription factor (NF)-κB plays a role in transcription of a number of genes involved in the inflammatory pathway, cellular stress response, and tissue remodeling, including COX-2.15\n\nThe results also showed that the mean number of neutrophils in the treatment group given the application of silkworm cocoon wound dressing showed a significant decrease compared to the control group which was only covered with gauze moistened with NaCl, both on the 3rd day and the 6th day observations. The number of neutrophils in the skin of normal rats without wounds was also observed and the result was no neutrophils were found. The significant difference between the number of neutrophils in the treatment and control groups at each observation time was due to the silkworm cocoons having anti-bacterial and anti-inflammatory effects. Silkworm cocoon wound dressings contain sericin which has an antibacterial effect, especially against Streptococcus aureus and Escherichia coli, so it can prevent infections that can interfere the wound healing process, while gauze dressings do not have anti-bacterial abilities.9 The sericin protein in silkworm cocoons can be degraded and carried into the wound through exudate, skin absorption, and water vapor molecules generated by moisture in the wound area and the sweating process. The mechanism of decreasing the number of neutrophils in the treatment group could also occur due to the influence of the active substance fibroin contained in the silkworm cocoons which has an anti-inflammatory effect that is able to inhibit the activation of NFkB thereby inhibiting the synthesis of IL-1 and TnFα. Inhibition of IL-1 and TnFα synthesis causes vasodilation of blood vessels and increases capillary permeability so that there is no activation of complement factor C5a, and inhibits neutrophil adhesion to blood vessel walls. The adhesion of neutrophils to the vessel wall is the beginning of the movement of neutrophils into the tissue. Inhibition of neutrophil adhesion to blood vessel walls causes the infiltration of neutrophils into the tissue to decrease so that inflammation will decrease.15\n\n\nConclusion\n\nThe application of silkworm cocoon wound dressing can reduce COX-2 expression (p=0.000) and reduce the number of neutrophils significantly (p=0.001) after skin excision.\n\n\nData availability\n\nFigshare: Figure 1. Silkworm cocoon dressing process.\n\nhttps://doi.org/10.6084/m9.figshare.19365596.v4\n\nThis project contains the following underlying data:\n\n- JPG file showing the making of wound dressings from silkworm cocoons was carried out by following the guidelines made by Yu, et al.6 The cocoons used were oval in shape, then they were cut at both ends so that they became tubular and cut back on one side of the tube to form a rectangular sheet measuring 4×1.5cm. The silkworm cocoons that had been cut were then immersed in a beaker containing a solution of CaCl2-ethanol- H2O with a molar mass ratio of 1:2:8. The beaker containing the cocoon sheets was then placed in a water bath at 58oC for 90 minutes. The silkworm cocoons were then rinsed with sterile distilled water at room temperature 4 times and dried with silica gel desiccant for 24 hours. Sheets of silkworm cocoons that had been processed were formed into pieces of transparent film measuring 4×1.5 cm with a thickness of 0.7 mm and were ready to be used as wound dressings on wounds. The wound dressing was then sterilized using a sterilization pack and ethylene oxide gas (EOG) at 36°C for 7 hours.\n\nFigshare: Figure 2. Making an excision wound. https://doi.org/10.6084/m9.figshare.19373192.v1\n\nThis project contains the following data:\n\n- JPG file showing the wound excision on the skin of the rat's back with a punch biopsy and closed with a silkworm cocoon wound dressing on the right back and sterile gauze moistened with NaCl on the left back.\n\nFigshare: Figure 3. Histology of excision wounds COX-2 expression. https://doi.org/10.6084/m9.figshare.19373168.v1\n\n- JPG file showing microscopic photo of the histology of COX-2 expression on the healing of excision wounds on the back of Wistar rats with a magnification of 400x.\n\nFigshare. Figure 2A. wound excision design. https://doi.org/10.6084/m9.figshare.19374851.v1\n\nFigshare. Figure 2B. excision wound on the skin of the rat's back with a punch biopsy. https://doi.org/10.6084/m9.figshare.19374863.v2\n\nFigshare. Figure 2C. close the excision wound with a silkworm cocoon wound dressing on the right back and sterile gauze moistened with NaCl on the left back. https://doi.org/10.6084/m9.figshare.19374866.v1\n\nFigshare. Figure 3A. Microscopic photo of the histology of COX-2 expression on the healing of excision wounds control group on 3rd day. https://doi.org/10.6084/m9.figshare.19374893.v1\n\nFigshare. Figure 3B. Microscopic photo of the histology of COX-2 expression on the healing of excision wounds treatment group on 3rd day.https://doi.org/10.6084/m9.figshare.19374893.v1\n\nFigshare. Figure 3C. Microscopic photo of the histology of COX-2 expression on the healing of excision wounds control group on 6th day. https://doi.org/10.6084/m9.figshare.19374893.v1\n\nFigshare. Figure 3D. Microscopic photo of the histology of COX-2 expression on the healing of excision wounds treatment group on 6th day. https://doi.org/10.6084/m9.figshare.19374896.v2\n\nFigshare. Figure 5A. Microscopic photo of histology of neutrophils on excision wounds control group on 3rd day. https://doi.org/10.6084/m9.figshare.19374899.v1\n\nFigshare. Figure 5B. Microscopic photo of histology of neutrophils on excision wounds treatment group on 3rd day. https://doi.org/10.6084/m9.figshare.19374908.v1\n\nFigshare. Figure 5C. Microscopic photo of histology of neutrophils on excision wounds control group on 6th day. https://doi.org/10.6084/m9.figshare.19374914.v1\n\nFigshare. Figure 5D. Microscopic photo of histology of neutrophils on excision wounds treatment group on 6th day. https://doi.org/10.6084/m9.figshare.19374923.v1\n\nFigshare. Raw data of Cox-2 expression on treatment group 3rd day. https://doi.org/10.6084/m9.figshare.19376048\n\nFigshare. Raw data of Cox-2 expression on control group 3rd day. https://doi.org/10.6084/m9.figshare.19376063\n\nFigshare. Raw data of Cox-2 expression on treatment group 6th day. https://doi.org/10.6084/m9.figshare.19376066\n\nFigshare. Raw data of Cox-2 expression on control group 6th day. https://doi.org/10.6084/m9.figshare.19376069\n\nFigshare. Raw data of Neutrophil counts on treatment group 3rd day. https://doi.org/10.6084/m9.figshare.19376075\n\nFigshare. Raw data of Neutrophil counts on control group 3rd day. https://doi.org/10.6084/m9.figshare.19376078\n\nFigshare. Raw data of Neutrophil counts on treatment group 6th day. https://doi.org/10.6084/m9.figshare.19376081\n\nFigshare. Raw data of Neutrophil counts on control group 6th day. https://doi.org/10.6084/m9.figshare.19376084\n\nFigshare. Recapitulation data of Cox-2 expression and Neutrophil counts on treatment and control group 3rd and 6th day. https://doi.org/10.6084/m9.figshare.19376093\n\n\nExtended data\n\nFigshare: Table 1. The mean and standard deviation (SD) of COX-2 expression in each treatment group based on the time of observation. https://doi.org/10.6084/m9.figshare.19373978.v1\n\n- Table 1. Shows that the average number of COX-2 expressions on the 3rd day (39.4133) and the 6th day (20.4417) after excision in the control group is more than the treatment group on the 3rd day (19.4050) and 6th day (4.8050).\n\nFigshare: Figure 4. Mean number of COX-2 expressions based on observation time. https://doi.org/10.6084/m9.figshare.19373894.v1\n\n- JPG file showing diagram illustration of COX-2 as described in Figure 3 and Table 1.\n\nFigshare: Table 2. Statistical analysis. https://doi.org/10.6084/m9.figshare.19373990.v1\n\n- Table 2. Shows statistical analysis using Two-way ANOVA of differences in the amount of COX-2 expression.\n\nFigshare: Figure 5. Microscopic photo of histology of neutrophils on wound healing. https://doi.org/10.6084/m9.figshare.19373933.v2\n\n- JPG file shows microscopic photo of histology of neutrophils on wound healing of Wistar rat back skin excision with 400x magnification.\n\nFigshare: Table 3. Mean number of neutrophils in each treatment group based on observation time. https://doi.org/10.6084/m9.figshare.19374122.v1\n\n- Table 3 shows the mean number of neutrophils on the 3rd day obtained in the control group (65.5517) was more than the treatment group (30.1917). The mean number of neutrophils on the 6th day post-excision in the control group (39.1267) was also higher than the treatment group (8.4333).\n\nFigshare: Figure 6. Mean number of neutrophils based on the observation time. https://doi.org/10.6084/m9.figshare.19373960.v1\n\n- JPG file diagram illustration of number of neutrophils as described in Figure 5 and Table 3.\n\nFigshare: Table 4. Two-way ANOVA statistical analysis of differences in neutrophil counts. https://doi.org/10.6084/m9.figshare.19374185.v1\n\n- Table 4 shows that the number of neutrophils between the time of observation (the 3rd day and the 6th day) differs significantly (p=0.014), similarly the comparison of the number of neutrophils between the control and treatment groups is significantly different (p=0.001), while between the time of observation and the treatment group is p=0.797, which means that there is no interaction between the time of observation and the treatment group.\n\n\nReporting guidelines\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nIn vivo animal studies follow the ARRIVE reporting guideline.\n\nhttps://doi.org/10.6084/m9.figshare.19396481",
"appendix": "Acknowledgments\n\nWe thank our colleagues for providing their insights and expertise to this research.\n\n\nReferences\n\nGonzalez AC, de Oliveira T , Zilton FC, et al.: Wound Healing-A Literature Review. An. Bras. Dermatol. 2016; 91(5): 614–620. PubMed Abstract | Publisher Full Text\n\nVishwakarma RK, Negi DS: The Development of Cox-1 and Cox-2 Inhibitors: A Review. International Journal of Pharmaceutical Sciences and Research (IJPSR). 2020; 11(8): 3544–3555. Publisher Full Text\n\nKumar V, Abbas A, Aster J: Robbins Basic Pathology. 9th ed.W.B. Saunders Company; 2012; 26–40.\n\nRizani N: Modern Wound Dressing For Wound Infection: An Overview. Indonesian Journal of Tropical and Infectious Disease. 2012; 3(1): 39–59. Publisher Full Text\n\nDhivya S, Padma VV, Santhini E: Wound dressings – a review. Biomedicine. 2015; 5(4): 22. PubMed Abstract | Publisher Full Text\n\nYu K, Lu F, Li Q, et al.: Accelerated wound-healing capabilities of dressing fabricated from silkworm cocoon. Int. J. Biol. Macr. 2017; 102: 901–913. PubMed Abstract | Publisher Full Text\n\nBorda LJ, Macquhae FE, Kirsner RS: Wound Dressings: A Comprehensive Review. Curr. Dermatol. Rep. 2016; 5(4): 287–297. Publisher Full Text\n\nOliveira HG, Barud HS, Cavicchioli M: Preparation and Characterization of a Bacterial Cellulose/Silk Fibroin Sponge Scaffold for Tissue Regeneration. Carbohydr. Polym. 2015; 128: 41–51. PubMed Abstract | Publisher Full Text\n\nKamalathevan P, Peng SO, Yew LL: Silk-Based Biomaterials in Cutaneous Wound Healing: Wound Care Journal. Adv. Skin Wound Care. 2018; 31(12): 565–573. PubMed Abstract | Publisher Full Text\n\nBrubaker AL, Carter SR, Kovacs EJ: Experimental Approaches to Tissue Injury and Repair in Advanced Age. Methods Mol. Biol. 2015; 1343: 35–51. PubMed Abstract | Publisher Full Text\n\nKendall LV, Owiny JR, Dohm ED, et al.: Replacement, Refinement, and Reduction in Animal Studies With Biohazardous Agents. ILAR J. 2018; 59(2): 177–194. PubMed Abstract | Publisher Full Text\n\nSengupta P: The Laboratory Rat: Relating Its Age with Human’s. Int. J. Prev. Med. 2013; 4(6): 624–630. PubMed Abstract\n\nGantwerker EA, Hom DB: Skin: Histology and Physiologyof Wound Healing. Facial Plast. Surg. Clin. North Am. 2011 Aug; 19(3): 441–453. Publisher Full Text\n\nSabol F, Dancakova L, Gal P, et al.: Immunohistological Changes in Skin Wounds During the Early Periods of Healing in Rat Model. Vet. Med. 2012; 57(2): 77–82. Publisher Full Text\n\nKim YI: Bombyx Mori Hemocyte Extract Has Anti-Inflammatory Effects on Human Phorbol Myristate Acetate-Differentiated THP-1 Cells via TLR4-Mediated Suppression of The NF-Κb Signaling Pathway. Mol. Med. Rep. 2017; 16: 4001–4007. Publisher Full Text\n\nLandén NX, Li D, Ståhle M: Transition from inflammation to proliferation: a critical step during wound healing. Cell. Mol. Life Sci. 2016; 73: 3861–3885. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "138286",
"date": "08 Jun 2022",
"name": "Huawei He",
"expertise": [
"Reviewer Expertise Silkworm",
"silk-based biomaterials",
"insect biochemistry and molecular biology",
"insect development"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSilk is a natural polymeric biomaterial with excellent biological properties. In the manuscript entitled “The effects of silkworm cocoon (Bombyx mori) wound dressing applications to the COX-2 expression and the number of neutrophils after skin excision wounds (in vivo research on Wistar rats)”, the authors Efron et al. study the effects of the wound dressing prepared by silkworm cocoons toward COX-2 expression and neutrophils number in the inflammatory phase after skin excision. The topic is of interest. However, the conclusions drawn could not be adequately supported by the results in this study, and the study design is not appropriate to better support the results and the conclusion. Hence, I recommend that the editor rejects this manuscript for indexing.\nMy comments are as follows:\nIn the abstract, twelve male Wistar rats were randomly divided into 4 groups, each group of 6. Please double check whether the number is correct. The experiment needs to be repeated at least three times.\n\nAccording to the authors, the silkworm cocoons were immersed in CaCl2-ethanol-H2O with a molar mass ratio of 1:2:8, and then placed in a water bath at 58oC for 90 minutes. Please check whether sericin protein was completely removed from fibroin. The wound dressing only contained fibroin, or both fibroin and sericin. This is very important, as the authors discuss the mechanism in the discussion “Silkworm cocoon wound dressing can inhibit COX-2 expression by the following mechanism: fibroin and sericin contained in silkworm cocoons have the ability to inhibit the activation of NFkB thereby inhibiting the synthesis of IL-1 and TnFα”.\n\nIt is recommended to supplement qRT-PCR with western blotting to better analyze the expression of COX-2.\n\nMore evidence should be provided to better support the conclusion.\n\nThe mechanism by which the cocoon dressing works should be carefully investigated such as the signaling pathway associated with nuclear transcription factor (NF)-κB, and the synthesis of IL-1 and TNFα.\n\nThe figures should be well revised to improve the quality and visibility.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "151056",
"date": "03 Oct 2022",
"name": "Gianluca Tettamanti",
"expertise": [
"Reviewer Expertise Silkworm biology",
"silk proteins",
"wound healing"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this manuscript by Tarigan et al. the authors investigate the effects of wound dressing prepared from silkworm cocoon on skin excision wounds. Their results demonstrate that the application of silk protein on wounds reduces the expression on COX-2 and the number of infiltrating neutrophils in the damaged area.\nThe topic investigated herein is potentially interesting, as well as the use of silk products to cure skin lesions represents an application that deserves attention. However, the study presents weaknesses:\n1. The experimental evidence collected by the authors is limited and, not only definitely supports the reduction of COX-2 expression, but does not allow to go deeper into the mechanisms that lead to this effect. I think that additional experiments are necessary, on both sides, to have a stronger and convincing manuscript.\n2. The presentation of data needs to be reconsidered. In particular, the different sections of the paper are not presented in a balanced manner: some of them provide too many details, while other aspects are completely overlooked. Moreover, more criticism is needed in the Discussion. A language revision is necessary, too.\n3. Abstract. The final sentence of Methods is not clear. The first sentence of Results must be moved to Methods.\n4. Introduction (see “protection mechanism”). It is not clear which are the protective functions of cocoons.\n5. Methods:\nI think that all cocoons are oval in shape, so I do not understand this detail.\n\nOnce removed the pupa inside, were the cocoons sterilized?\n\nIt is not clear the purpose of the treatment with CaCl2 on the cocoon.\n\nThe sentence “The wound tissue sampling from…..wound area” must be rephrased.\n\nIHC and HE must be detailed.\n\nDetails on sample embedding and immunostaining procedure must be provided.\n\nWhich was the area considered for counting neutrophils?\n6. Figure 1. Please modify as “Bombyx mori”.\n7. Results:\nThe sentence “The control group (Figure 3A)….(Figure 3D)” must be rephrased.\n8. Figure 3 and Figure 5. Scale bars are necessary. Moreover, I suggest reducing the dimension of the letters (A-D).\n9. Figure 4 and Figure 6. Images at higher resolution must be provided.\n10. Discussion:\nThe sentence “The calculation of the number...refinement) is superfluous in this context.\n\nThe sentence “The microscopic image of COX-2...observation” is not clear.\n\nThe last paragraph “The decrease in the amount…will decrease” contains hypotheses that are not supported by experimental data, thus it is highly speculative.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-521
|
https://f1000research.com/articles/10-486/v1
|
18 Jun 21
|
{
"type": "Case Report",
"title": "Case Report: Delayed treatment of tuberculosis of the elbow joint",
"authors": [
"Desdiani Desdiani",
"Hidayat Rizal",
"Anindita Basuki",
"Fadilah Fadilah",
"Hidayat Rizal",
"Anindita Basuki",
"Fadilah Fadilah"
],
"abstract": "Extrapulmonary tuberculosis (TB) is known to occur in the musculoskeletal system, including the elbow joints. These cases are rarely found because the signs and symptoms are not specific to extrapulmonary TB or other diseases. We report a case of a 24-year-old male, who complained about pain in his left elbow and noticed swelling. Initially, he complained about pain all over his left arm, after several reflexology massages to alleviate his toothache. However, instead of seeking medical treatment, he visited a traditional massage therapist every week without improvement in his left arm pain for almost one year. Examination showed skin perforation with discharge. He also had fever during the first few days when the elbow became swollen. Weight loss and a decreased appetite were also noticed by the patient. The patient went to the orthopedic department and underwent surgery. Radiological examination indicated bone erosion on the left humerus and radius, while posteroanterior chest X-ray did not show any abnormality. Histopathological examinations from biopsy and fluid aspiration showed granulomas and datia Langhans cells. Mycobacterium tuberculosis was found on acid-fast bacteria smear and culture. The patient was administered multidrug tuberculosis therapy, which consisted of two months of an intensive phase and seven months of a continuation phase, in accordance with the World Health Organization’s guidelines for extrapulmonary tuberculosis treatment. He has currently undergone the continuation phase of the treatment and his condition has improved. Early detection of tuberculosis of the elbow can prevent damage to joint structure and impairment of joint function.",
"keywords": [
"Elbow",
"Arthritis",
"Tuberculosis",
"Delayed treatment"
],
"content": "Abbreviations\n\nAFB: acid fast-bacteria\n\nAP: anteroposterior\n\nCKD: chronic kidney disease\n\nCT: computed tomography\n\nESR: erythrocyte sedimentation rate\n\nHIV: human immunodeficiency virus\n\nPA: posteroanterior\n\nTB: tuberculosis\n\nWHO: World Health Organization\n\n\nIntroduction\n\nExtrapulmonary tuberculosis (TB) is known to occur in joints with a percentage of approximately 1-3% of all TB cases, 2-5% of which are rare cases that occur in the elbow joints.1 TB is an endemic disease with the total number of cases approximating 845,000 in Indonesia.2 Elbow dysfunction is the result of progressive erosion and destruction of bone and joint, therefore early diagnosis and treatment are needed to prevent this outcome. Diagnosis is quite challenging and often late due to non-specific symptoms3 Joint TB is rarely detected because joint pain is not commonly considered to be a symptom of joint TB, especially if there are no respiratory complaints. Thus, diagnosis and treatment are often delayed. Here, we report a rare case of a patient with TB of the elbow joint, who received delayed treatment because he chose to undergo traditional treatment with massage therapy.\n\n\nCase report\n\nA 24-year-old Indonesian male who worked in an internet rental shop came to the orthopedic department of Bhayangkara Brimob hospital (Depok, Indonesia) with left arm pain and left elbow joint swelling. Physical examination revealed skin perforation with yellowish discharge on the left elbow. The patient experienced fever on the first few days as the left elbow became swollen, weight loss, and a decreased appetite, but no respiratory complaints.\n\nChronologically, one year prior to coming to the hospital, the patient noticed another pain in his left arm both in the upper and lower arm. He then chose to undergo regular traditional massage therapy every week for almost one year instead of seeking for medical treatments. At the first hospital visit, the elbow pain had gotten more severe and it became swollen. Within a month, discharge emerged from a small skin perforation located on the inner side of the left elbow. The patient finally went to the orthopedic department and underwent surgery. The patient had a history of undergoing reflexology massages between the fingers of his left hand to alleviate his toothache.\n\nUpon physical examination, the left elbow joint appeared swollen and discharge was exuding from the perforated skin, as depicted in Figure 1. The patient could not lift his left arm because it was painful. Flexion and extension were also difficult due to the severity of the pain. The patient’s social environment has a culture of seeking help from local traditional massage therapists who are known to be uncertified to treat various health problems, and instead of recovering, the patient showed symptoms of worsening.\n\nLaboratory examination revealed a leukocyte count of 15,000 (normal range: 5000-10,000 cells/μl), erythrocyte sedimentation rate (ESR) of 40 mm/hour (normal range: 0-10 mm/hour), eosinophils 9% (normal range: 1-3%), and monocytes 10% (normal range: 2-6%). Radiological examination by posteroanterior (PA) chest X-ray did not show any abnormality (Figure 2), anteroposterior (AP) and lateral projection of the left elbow joint radiographs showed erosion of the distal cortex of the humerus and radial bone, destruction of the distal cortex, and swelling of the soft tissue of the left elbow area (Figure 3).\n\nThe patient was subsequently diagnosed with TB of the elbow joint. He then underwent left elbow arthrotomy and synovial fluid aspiration. The surgery was performed with the patient supine under general anesthesia. Incisions were made layer by layer on the posterior region of cubiti sinistra. White granulation tissue and thick yellow intra- and extra-articular pus were evacuated. Histopathological examination was also performed. The wound was irrigated with 2 L of 0.9% NaCl and hecting was performed layer by layer subsequently. Specimens were collected and sent for microbiological and pathological analyses. Acid-fast bacteria (AFB) smear and culture showed Mycobacterium tuberculosis. Histopathological examination showed granulomatous inflammation, swollen connective tissues containing epithelioid tubercle nests with necrotization, and datia Langhans cells (Figure 4). The results were consistent with TB. Furthermore, the anti-human immunodeficiency virus (HIV) test was negative.\n\nThe patient was given a standard first-line oral regimen of extrapulmonary TB treatment; an intensive phase for two months with rifampicin 450 mg once daily, isoniazid 300 mg once daily, pyrazinamide 1000 mg once daily, and ethambutol 1000 mg once daily (2HRZE) and seven months of a continuation phase with rifampicin 450 mg once daily and isoniazid 300 mg once daily (7HR). The patient has been undergoing continuation phase of the treatment and his condition has been showing improvements, including decreased pain, increased appetite, and weight gain. However, flexion and extension are restricted. The patient reported clinical improvement and discharge was decreased. Left elbow joint radiographs showed minimal improvement (Figure 5). Computed tomography (CT) scan results showed destruction of the lateral epicondylus of the humeral bone and the processus olecranon of ulna bones, after two months of the treatment (Figure 6).\n\nPicture was edited with photoshop CS4 version 11.0 to remove specific details of dates of patient care and patient’s identity.\n\n\nDiscussion\n\nMusculoskeletal TB occurs in about 10% of all cases of extrapulmonary TB, which commonly affects weight-bearing joints such as the spine (51%), pelvis (12%), hip,femur (10%), knee and tibia (10%). Reported cases of non-weight-bearing joints such as elbow joint TB are still relatively rare, and the diagnosis often neglected.1 Diagnosis of musculoskeletal TB requires the clinician’s ability to pay attention to joint swelling and chronic pain, as well as their effects on joint function4\n\nUsually, respiratory and systemic symptoms are absent or only briefly present. In this report, only a history of fever was identified. Radiological examination of the lungs showed no abnormality. The complaints for joint TB are often non-specific, hence a late diagnosis1\n\nThe findings in this report are consistent with several previous studies. A study by Yazici et al. (2016) reported a TB of the elbow joint case in which there were no signs and symptoms of respiration. The results of chest radiographs were still within normal limits. The diagnosis was confirmed by AFB and histopathology examinations.5 Another study by Guan & Zeng (2021) reported osteoarticular TB with a picture of swelling and pain that was previously diagnosed as osteoarthritis. Although these cases are rare, they are difficult to diagnose and can cause pain and impaired function.6\n\nRadiographic changes of the joints may suggest multiple osteolytic lesions and there may be erosions of the joints and swelling of the soft tissues.7 Unfortunately, this patient did not undergo a magnetic resonance imaging examination due to the limited available facilities. Definite diagnosis required synovial fluid aspiration. Microscopic examination and culture of fluid aspiration were very helpful, followed by histopathological results showing the caseous granuloma.8 These non-specific signs and symptoms often delay the diagnosis as skeletal TB, as reported in one study that showed the time lag from the onset of complaints until the diagnosis was confirmed as approximately 4-11 months. Additionally, some cases of skeletal TB occasionally were not detected by AFB and culture.9,10\n\nClinicians should not neglect to explore the history of exposure and factors that increase the risks of TB infection, such as close contact with confirmed TB patients, immunocompromised patients (e.g. HIV infection), diabetes mellitus, and having comorbid diseases such as chronic kidney disease. Therefore, it is necessary to screen the patient for the co-infectious diseases listed above. Other risk factors are old age, poor nutrition, and receiving immunosuppressive treatments6 Regarding this case, the risk factors are not clear.\n\nIn summary, the significance of this case is the recognition of risk factors for skeletal TB and chronic symptoms, so that they can be treated properly. Early diagnosis and treatment can be achieved through careful anamnesis that does not ignore the history of close contact with confirmed cases of TB patients, risk factors for TB infection, physical/clinical, radiological, and laboratory examinations. It is important for clinicians, especially those who work in an area endemic to TB, to suspect chronic joint pain whose clinical symptoms do not improve with conventional treatment as skeletal TB in the differential diagnosis. The specific AFB smear and culture tests are still important, although they can occasionally show false negative results. Extrapulmonary TB can be deceptive because it does not always cause typical symptoms and pulmonary involvement. Prompt diagnosis and treatment are essential to prevent joint damage and impaired function.\n\n\nPatient’s perspectives\n\nLeft-arm and elbow pain, swelling, and immobility made me suffer. I knew that I had to go to the hospital for further treatment. However, I was afraid of surgery and at the suggestion of my family, I underwent traditional medicine with massage therapy for almost 1 year. I didn't expect that my illness would get worse and I had to have surgery immediately and take long-term medication. Now I feel better, my arm pain and swelling of my left elbow have decreased, even though I haven't been able to move my arm to its full potential.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and clinical images was obtained from the patient.",
"appendix": "References\n\nThimmaiah VT, Deepashree: Unusual presentation of tuberculosis of elbow joint: a case report. Res Rev: J Med Health Sci. 2013; 2(4): 17–20.\n\nWorld Health Organization: WHO. Global tuberculosis report [Internet]. Who. int . 2018 [cited 2021 Apr 1];Reference Source\n\nBroderick C, Hopkins S, Mack DJF, et al.: Delays in the diagnosis and treatment of bone and joint tuberculosis in the United Kingdom. Bone Joint J. 2018 Jan; 100-B(1): 119–24. PubMed Abstract | Publisher Full Text\n\nPigrau-Serrallach C, Rodríguez-Pardo D: Bone and joint tuberculosis. Eur Spine J. 2012 Jun 19; 22(S4): 556–66. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYazici A, Kayan G, Yaylaci S, et al.: Tuberculous arthritis of the elbow joint: A case report. Eur J Rheumatol. 2016 Sep 26; 3(3): 142–3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuan Y, Zeng Z: Elbow arthroplasty complicated by Mycobacterium tuberculosis infection. Medicine. 2021 Mar 5; 100(9): e24376. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDe Backer AI, Vanhoenacker FM, Sanghvi DA: Imaging features of extraaxial musculoskeletal tuberculosis. Indian J Radiol Imaging. 2009; 19(3): 176–86. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArathi N, Fayaz A, Huda N: Osteoarticular tuberculosis-a three years retrospective study. J Clin Diagn Res. 2013; 7(10): 2189–92. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHeld MFG, Hoppe S, Laubscher M, et al.: Epidemiology of Musculoskeletal Tuberculosis in an Area with High Disease Prevalence. Asian Spine J. 2017 Jun 30 [cited 2021 Apr 1]; 11(3): 405–11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarg RK, Somvanshi DS: Spinal tuberculosis: A review. J Spinal Cord Med. 2011 Sep [cited 2021 Apr 1]; 34(5): 440–54. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "88014",
"date": "05 Jul 2021",
"name": "Musofa Rusli",
"expertise": [
"Reviewer Expertise Infectious disease"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe background and risk factors of the case and the case’s progression are sufficiently described. In addition, there are enough details provided of the physical examination, diagnostic tests, and brief outcome of the case. Furthermore, a good discussion is included of the importance of the findings and their relevance in managing the particular case. Finally, there is an adequate presentation of the clinical management to be useful for other practitioners.\nHowever, some issues need to be taken into account. For example, it is better to use a proofreading service to correct some typographical mistakes. In the Case Report Section, the source of sample in the sentence “histopathological examination was also performed” needs to be clarified; is it from the pus or other tissue?\nBelow are some references worth considering to be included in the manuscript:\nBoodoo et al. (20201) Liao et al. (20172)\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "6915",
"date": "13 May 2022",
"name": "Desdiani Desdiani",
"role": "Author Response",
"response": "Dear Dr. Musofa Rusli, Thank you for allowing us the opportunity to submit a revised draft of the manuscript “Case Report: Delayed treatment of tuberculosis of the elbow joint” for publication in the F1000Research. We appreciate the time and effort that you dedicated to providing feedback on our manuscript and are grateful for the insightful comments and valuable improvements to our paper. We have incorporated most of the suggestions made by the reviewers. Please see below, for a point-by-point response to the reviewers’ comments and concerns: We have used a proofreading service to correct some typographical mistakes with scribendi.com The source of the sample for histopathological examination was taken from white granulation tissue on the posterior region of cubiti sinistra. We are agree that references such as Voodoo et al. (2020) and Liao et al. (2017) can be used for comparison of clinical, histopathological and radiological findings with the patients we analyzed and reported at this time. Thank you so much, Best Regards, Desdiani Desdiani"
},
{
"c_id": "8378",
"date": "15 Jun 2022",
"name": "Desdiani Desdiani",
"role": "Author Response",
"response": "Dear Musofa Rusli, Thank you for your respond and review. Best Regards, Desdiani Desdiani"
}
]
},
{
"id": "127931",
"date": "04 Apr 2022",
"name": "Yunita Arliny",
"expertise": [
"Reviewer Expertise pulmonary infection"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReflexology that is done for complaints of elbow pain or pain in other places? Because it is somewhat contrary to the statement of elbow pain and does not seem to be related to delayed therapy.\n\nOn photo session, it's better if you include a photo of the elbow before the operation.\n\nThe sentence \"The patient was subsequently diagnosed with TB of the elbow joint\" should be placed after the results of AFB and histopathological examinations are obtained. the sentence \"diagnosed with TB of the elbow joint\" should be replaced with suspected TB elbow joint.\n\nPlease complete the result of AFB examination (IULTD scale) and culture.\n\nHas the patients examined of Gene Xpert MTB/RIF from the tissue? Please mention this.\n\nPlease add an explanation of the epidemiology of bone and joint TB (age, gender) and its pathogenesis.\n\nPlease explain the sentence \"The specific AFB smear and culture tests are still important, although they can occasionally show false negative results.\n\nPlease mention the gold standard of diagnostics for bones or joint TB.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "8196",
"date": "13 May 2022",
"name": "Desdiani Desdiani",
"role": "Author Response",
"response": "Dear Dr. Yunita Arliny, Thank you for allowing us the opportunity to submit a revised draft of the manuscript “Case Report: Delayed treatment of tuberculosis of the elbow joint” for publication in the F1000Research. We appreciate the time and effort that you dedicated to providing feedback on our manuscript and are grateful for the insightful comments and valuable improvements to our paper. We have incorporated most of the suggestions made by the reviewers. Please see below, for a point-by-point response to the reviewers’ comments and concerns: Reflexology that is done for complaints of elbow pain or pain in other places? Because it is somewhat contrary to the statement of elbow pain and does not seem to be related to delayed therapy. This patient complained about pain in his left elbow and noticed swelling. Initially, he complained about pain all over his left arm, after several reflexology massages to alleviate his toothache for almost 2 months. However, instead of seeking medical treatment, he visited a traditional massage therapist every week without improvement in his left arm pain including his left elbow for almost one year. At the first hospital visit, the elbow pain had gotten more severe and it became swollen. Discharge emerged from a small skin perforation located on the inner side of the left elbow. The patient finally went to the orthopedic department and underwent surgery. On photo session, it's better if you include a photo of the elbow before the operation. Initially, this patient came to the orthopedic clinic and was treated because of severe pain and swelling in the elbow of the left arm. Unfortunately, the orthopedic specialist did not think to take a photo, he was immediately treated and underwent laboratory and radiological examinations, and then surgery was performed. The sentence \"The patient was subsequently diagnosed with TB of the elbow joint\" should be placed after the results of AFB and histopathological examinations are obtained. the sentence \"diagnosed with TB of the elbow joint\" should be replaced with suspected TB elbow joint. We agree and have updated. Please complete the result of AFB examination (IULTD scale) and culture. The result of the AFB examination is based on types of grading scale by the World Health Organization and the International Union against Tuberculosis and Lung Disease (WHO-IUATLD): 1–10 AFB per field, 2+. Tissue culture was found to be positive. Has the patients examined of Gene Xpert MTB/RIF from the tissue? Please mention this. Initially, this patient came to the orthopedic clinic and was treated because of severe pain and swelling in the elbow of the left arm. Unfortunately, the orthopedic specialist did not think to take a photo, he was immediately treated and underwent laboratory and radiological examinations, and then surgery was performed. The source of the sample for histopathological examination was taken from white granulation tissue on the posterior region of cubiti sinistra. Histopathological examination showed granulomatous inflammation, swollen connective tissues containing epithelioid tubercle nests with necrotization, and datia Langhans cells. Please add an explanation of the epidemiology of bone and joint TB (age, gender) and its pathogenesis. We agree and have updated. In Europe and the United States, bone and joint TB accounts for 2.2–4.7 percent of all TBcases and roughly 10–15 percent of EPTB cases, whereas in developing countries, particularly Asia, the incidence of EPTB rises to 15–20 percent. Males and females have identical rates of infection with Mycobacterium tuberculosis until adolescence, following which males have a greater rate. For all ages, male rates became higher than female rates. Many developing countries' current notification rates for both sexes are comparable to those of industrialized countries in the mid-twentieth century, though the sex and age pattern is similar to that of industrialized countries today, with men's disease rates exceeding women's after the age of fifteen. These data raise the potential that tuberculosis cases among women in underdeveloped countries are underreported. The average age of tuberculous vertebral osteomyelitis patients is 45–60 years old. Nonetheless, some research show a bimodal age distribution, with two peaks, one between 20 and 30 years old, linked to immigration and/or HIV infection (60 percent of cases in one study), and the other between 60 and 70 years old. Simultaneous extraspinal involvement is seen in 5–50% of cases, while concomitant lung illness is seen in 2.3–65% of cases. The development of symptoms in spinal TB is usually gradual, and the disease progresses slowly, albeit an early onset has been documented. Symptoms might last anywhere from two weeks to many years at the time of diagnosis. The typical symptom duration was at least 12 months in early studies, although more current articles report a symptom duration of 2–7 months. Pain is common (83–100%), although only a third of individuals have a fever or other constitutional symptoms. Patients with extraspinal TB and those with disseminated disease are more likely to experience these symptoms. In tuberculosis of the upper limb, the elbow joint is the most commonly implicated joint. The incidence of elbow tuberculosis has been observed to range from 2 to 5% of all skeletal sites. There are only a few important reports on TB of the elbow joint that have been published. There were no management options or classifications. Histopathology, AFB staining, and polymerase chain reaction (PCR) were all performed on the samples. Pathogenesis Reactivation of bacilli embedded in bone during the first mycobacteremia of primary infection causes tuberculous elbow and arthritis. The extensive vascular supply of the vertebra and growth plates of the long bones explains the bacillus' preference for the spine and major joints. Musculoskeletal tuberculosis develops as a result of the bacilli being seeded in the bloodstream shortly after the initial pulmonary infection. Osteoarticular tuberculosis begins as osteomyelitis in the growth plates of bones, where the blood supply is strongest, and subsequently spreads locally into joint spaces. It can also spread through the lymphatic system; however this is a less usual occurrence. The stimulation of dormant lymphatic or blood stream areas of morbidity might cause infections in joints. In the long bones, tuberculosis begins in the epiphysis and progresses to the marrow, where it causes tubercle formation and trabeculae infection. The mycobacteria cause an inflammatory response in the synovium of the joint, which is followed by the production of granulation tissue. The granulation tissue pannus then starts to erode and degrade cartilage and finally bone, resulting in demineralization. Proteolytic enzymes that damage peripheral cartilage aren't created because tuberculosis isn't a pyogenic infection. As a result, for a long period, the joint space is kept. Abscesses in the surrounding tissue may occur if the infection is allowed to proceed without treatment. Sequestration of bone is uncommon due to the absence of space-occupying exudates with substantial interruption of vascular supply. As a result, the active phase of tuberculous elbow is characterized by bone loss without sequestra and little new bone growth. Please explain the sentence \"The specific AFB smear and culture tests are still important, although they can occasionally show false negative results. A negative AFB smear indicates that there is no infection, that symptoms are caused by anything other than mycobacteria, or that mycobacteria were not present in sufficient numbers to be detected under a microscope. In order to increase the likelihood of finding the organisms, at least three samples are usually taken. However, if AFB smears are negative but a strong suspicion of a mycobacterial infection remains, more samples may be taken and analyzed on different days. Because the culture media permits tiny amounts of germs to thrive and be detected, a smear negative sample can nonetheless grow mycobacteria. AFB smears that are positive suggest a mycobacterial infection. To confirm a diagnosis, however, a culture must be taken. AFB smear results are combined with results from the nucleic acid amplification test (NAAT) for TB in persons who have signs and symptoms of an active TB infection. Though a culture is required for a conclusive diagnosis, the results of the smear and NAAT may be useful in determining what to do. Histopathology, AFB staining, and polymerase chain reaction all validated the diagnosis of elbow tuberculosis (PCR). Biopsy without affecting the bone's integrity. The histopathologic results such as epitheloid infiltration, tubercle formation, caseous necrosis, and Langhan's gaint cells confirmed the TB pattern. Please mention the gold standard of diagnostics for bones or joint TB. Bone biopsy is the gold standard for diagnosis. References : [1] Holmes CB, Hausler H, Nunn P. A review of sex differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis. 1998;2(2):96–104. [2] Dhillon M, Goel A, Prabhakar S, Aggarwal S, Bachhal V. Tuberculosis of the elbow: A clinicoradiological analysis. Indian J Orthop. 2012;46(2):200. DOI: https://doi.org/10.4103/0019-5413.93684 [3] Haider Abdul-Lateef Mousa. Bones and Joints Tuberculosis. Bahrain Med Bull . 2007;29(1):17–21. [4] Pigrau-Serrallach C, Rodríguez-Pardo D. Bone and joint tuberculosis. Eur Spine J. 2013;22 Suppl 4(Suppl 4). DOI: https://doi.org/10.1007/S00586-012-2331-Y"
}
]
}
] | 1
|
https://f1000research.com/articles/10-486
|
https://f1000research.com/articles/11-519/v1
|
13 May 22
|
{
"type": "Research Article",
"title": "Internet addiction during COVID-19 restricted movement period: A cross-sectional study from Bangladesh",
"authors": [
"Anika Tasneem Chowdhury",
"Saleka Raihana Siddiqua",
"Lamisa Rahman",
"Mosharop Hossian",
"Mohammad Hayatun Nabi",
"Anika Tasneem Chowdhury",
"Saleka Raihana Siddiqua",
"Lamisa Rahman",
"Mohammad Hayatun Nabi"
],
"abstract": "Background: The restricted movement period related to COVID-19 has presumably contributed to the deterioration of the Internet addiction crisis. Therefore, this study aimed to determine the prevalence of Internet addiction and identify the factors associated with the increase in severity of Internet addiction among the general population of Bangladesh during the COVID-19 related restricted movement period. Methods: We conducted a cross-sectional online survey in Bangladesh from September 20 to October 5, 2020, and 315 Bangladeshi adults were included in the study. We used Young’s Internet Addiction Scale to assess the prevalence of Internet addiction and identified the factors associated with the increase in severity of Internet addiction during the restricted movement period using multivariable logistic regression analysis. Results: The overall prevalence of Internet addiction was 39.7% among the general population of Bangladesh during the restricted movement period. Almost 75% of the respondents reported increased time spent on recreational use of the Internet during the period of interest, and 48.5% of the respondents reported increases in the severity of Internet addiction. In logistic regression analyses, the increase in severity of Internet addiction was found to be significantly associated with social class, occupation, sleeping hours, and increased time spent on recreational use of the internet (p < 0.05). Watching movies/series was the main activity of the respondents during the restricted movement period. Conclusion: Our study reported an increase in the prevalence of Internet addiction among the general population of Bangladesh during the restricted movement period. Social class, occupation, sleeping hours, and increased time spent on recreational use were the significant determinants of the increase in severity of Internet addiction. The policymakers should undertake tailored policies to prevent people from being victims of the consequences of psychological issues in the long run.",
"keywords": [
"Internet addiction",
"COVID-19 restricted movement period",
"Bangladesh",
"depression",
"sleep quality",
"social inequality"
],
"content": "Introduction\n\nThe Internet has become an inseparable element of daily life, providing an integrated platform for communication and access to a broad range of information. In recent decades, the number of Internet users and their use hours has risen significantly.1 As of March 2021, 65.6% of the global population were using the Internet, with 1,331.9% growth between 2000-2021.2 However, excessive or limitless use can result in Internet addiction, also known as “pathological Internet use” or “problematic Internet use”. It can cause significant distress and functional impairments in daily life and comorbid psychiatric disorders such as depression, attention deficit and hyperactivity disorder and substance abuse.3,4\n\nMark D. Griffiths was the first to publish a scientific article on Internet addiction in November 1996.5 The term ‘Internet addiction’ is often defined as a situation in which a person has lost control of their Internet usage and continues to use it excessively to the point that they encounter negative consequences that adversely influence their lives.6 It has become a severe concern for mental health in different groups of people on different parts of the world, including South Korea (20.0%), China (16.4%), Vietnam (21.2%), Bangladesh (32.6%) and the Philippines (21.0%).7–10 Its prevalence is also increasing in the Western countries.11\n\nThe COVID-19 pandemic had unprecedented social, economic, and healthcare consequences, and it caused widespread psychological issues. During the COVID-19 pandemic, relatively high rates of anxiety (6.33%-50.9%), depression (14.6%-48.3%), and posttraumatic stress disorder (7.0%-53.8%) were reported in the general population.12–15 These traumatic emotional reactions contribute to the development and relapse of addictive behaviours, including substance and behavioural addictions.16 Disasters, such as large-scale natural catastrophe and economic downturns, have boosted rates of Internet addiction.17,18 When individuals with disordered coping mechanisms are exposed to stressful or traumatic situations, they are more likely to develop internet addiction.19 Social distancing and isolation measures for pandemic containment may potentially lead to increased Internet usage, putting vulnerable groups in danger of becoming addicted to the Internet.20\n\nThe significant efforts from the Bangladesh government to deploy digital technology and transform life on a considerable level have resulted in more access to the Internet than ever before. As a consequence, there has been a substantial growth in the number of people using the Internet. By the end of January 2021, the total number of Internet customers had risen to 112.7 million and 103.2 million of them are mobile Internet users.21 Although the figure is attractive, this may also be regarded as a problem for the general population of Bangladesh as it is widely assumed that the hours spent on Internet usage increased during COVID-19 restricted movement period. Since identifying the first COVID case in Bangladesh, the government has imposed several restrictions on public transportation, businesses, schools, and all public and private offices except emergency services.22 These restrictions confined people to stay more at home and appeared to spend more time on the internet as the offline medium of accomplishing daily works and recreations was limited. This excessive usage has several adverse outcomes that are gradually becoming apparent.23\n\nConsidering the above facts, we have commenced an online survey to assess the prevalence of Internet addiction among the general population and identify the risk factors for increased severity in Internet addiction in Bangladesh during the restricted movement period.\n\n\nMethods\n\nWe obtained the ethical approval (2020/OR-NSU/IRB-No.0801) to conduct the study from the Institutional Review Board of North South University. We adequately disclosed the purpose of the research to the respondents. Participation in the study was entirely voluntary, and the respondents shared their informed consent electronically by a ticking a specific checkbox in the questionnaire before participating.\n\nWe invited general Bangladeshi people aged 18 years or above to participate in the survey by completing a self-administered questionnaire from September 20 to October 5, 2020. The invitations to participate in the survey were delivered via social media platforms like Facebook, WhatsApp and email using our personal, professional, and academic email groups. We have used a convenience sampling technique to collect data from all over Bangladesh.\n\nA single population proportion formula was employed to determine the sample size. Several prior research done on different Bangladesh based samples estimated the prevalence of internet addiction was around 24-28%.24,25 Considering 28% prevalence, the required sample size was n = 310, while the allowable error was 5%. Among the invitees, 355 individuals completed the questionnaire. By restricting each Gmail account to a single submission, we decreased the chance of the respondents to fulfil the questionnaire repeatedly. Moreover, we excluded 13 duplicate responses by cross-checking contact information and 27 questionnaires with answers that did not match the questions or seemed contradictory were discarded, leaving 315 responses to be included in the final analysis.\n\nThe respondents answered questions about socio-demographic characteristics, Internet use characteristics and degree of addiction in pre and during the restricted movement period.\n\nThe socio-demographic variables included age, gender, occupation, place of residence, and self-reported social class.\n\nWe used Young’s Internet Addiction Scale to assess the prevalence of internet addiction.26 The scale includes eight items with dichotomous responses for each item. The score ranges from 0 to 8, with the severity of addiction categorized as addiction with scores 5 to 8. We utilized the scores to assess the prevalence of Internet addictions. We also used the scale to measure changes in the severity of Internet addiction during the restricted movement period compared to the pre-COVID-19 period. Furthermore, we sought to identify the contributing factors for increased severity in Internet addiction during the restricted movement period. The Internet Addiction Scale showed a satisfactory internal consistency among the respondents of the study (During-restricted-movement period Cronbach’s alpha coefficient = 0.68). A value of Cronbach’s alpha greater than 0.6 is regarded as an acceptable index and very reliable.27,28\n\nBesides, we included questions related to the type of internet service use, monthly Internet billing and purpose of Internet use to understand the using patterns of the respondents. We have also collected information on behavioural factors like sleeping hours, physical activities.\n\nA copy of the questionnaire can be found in the Extended data.\n\nWe checked the data for consistency and completeness. STATA version 15 was used for data management and analysis. Various descriptive statistics like frequencies and percentages were calculated. The chi-square tests were used to determine the degrees of association between the response variable and predictor variables. We used multivariable logistic regression analyses to assess associated factors for increased severity in internet addiction during the restricted movement period. We adjusted the variables contained in Tables 1 and 2 using enter method (Table 3), and odds ratios were reported for each factor of the variables included in the model. Results with p < 0.05 were regarded to be statistically significant.\n\n\nResults\n\nA total of 315 respondents were included in the final analysis. We received participation from respondents of various socio-demographic backgrounds by social class and place of residence. Overall, 22.3% of the respondents (n =70) had Internet addiction prior to restricted movement period. On the other hand, 39.8% (n =125) reported having internet addiction during COVID-19 restricted movement period (Figure 1).\n\nWe included 315 valid completed questionnaires (male/female: 67.6%/32.4%) in our analysis, including 18.4% rural residents and 44.8% students. Nearly half of the participants (50.8%) were 25-34 years old, and 58.1% belonged to middle-class families. In terms of sleeping hours, nearly 40% of the respondents reported sleeping less than six hours per day during the restricted movement period. Almost 80% (77.4%) of respondents reported doing one hour or less physical exercise per day during the period of interest. Increased severity of Internet addiction during the restricted movement period was significantly associated with occupation (p = 0.001) and sleeping hours (p = 0.001) (Table 1).\n\nThe respondents mostly used the Internet to watch movies/series (43.3%) and use social media/reading news/playing games (40.4%). Nearly 70% of the respondents (69.8%) reported paying less than 1000 Bangladeshi Taka per month as an Internet bill. More than 60% of the respondents (63.8%) were satisfied with Internet speed, and 54.4% of the respondents who were not satisfied with Internet speed reported to increase in severity of Internet addiction. An increase in recreational time spent on the Internet had a significant association with increased severity of internet addiction during the restricted movement period than that of the pre-COVID-19 situation (p = 0.010) (Table 2).\n\nRisk factors for increased severity of internet addiction included lower social class (adjusted odds ratio [AOR] = 2.35, 95% confidence interval [CI] = 1.01 – 5.47), sleeping hours less than 6 hours per day (AOR = 2.21, 95% CI = 1.33 – 3.67), and increase in recreational time spent on Internet (AOR = 2.69, 95% CI = 1.46 – 4.99). Occupation housewives (OR = 0.11, 95% CI = 0.02 – 0.68) and online professionals (OR = 0.09, 95% CI = 0.02 – 0.38) were protective factors for increased severity of internet addiction compared to students.\n\n\nDiscussion\n\nThe study aimed to determine the prevalence of Internet addiction among the general population of Bangladesh during the COVID-19 restricted movement period. Furthermore, the study also sought to identify the factors associated with the increase in severity of Internet addiction.\n\nOur study provides evidence of the remarkably high prevalence of Internet addiction during the period of interest. Nearly 40% of the respondents reported suffering from Internet addiction, close to a during-pandemic Internet addiction study conducted in China.29 We also observed that the prevalence during the restricted movement period was much higher than the pre-COVID-19 period (39.7%/22.3%). One probable explanation is that more individuals spend time on the Internet during this time. The fear caused by the COVID-19 virus, as well as the implications of lockdown, stress, and anxiety have modified people’s behaviour. Nearly three-fourths of the respondents reported increasing time spent on recreational use of the Internet during the period of interest, and about half of the respondents reported increases in the severity of Internet addiction. As people had to stay more at home and the range of leisure activities (e.g., socializing, outdoor activities, etc.) became limited due to COVID, they were severely seeking an alternative source of refreshment. The recreational use of Internet filled the vacant place with a greater possession.\n\nWe found economic status of the family was a significantly associated factor with Internet addiction. Respondents from the lower social class were 2.35 times more likely to report an increase in severity of Internet addiction than respondents from higher social class. In line with our findings, studies conducted in Turkey and Greece also observed the inverse relationship between social class and Internet addiction.30,31 This might be because low-income individuals frequently prefer the Internet in this direction as a substitute for hobbies that require monetary resources to release tension, spend time, and make fun.\n\nIncreased time spent on recreational use of the Internet was revealed as a positively associated factor with increased severity of Internet addiction during restricted movement period in our multivariable logistic regression model. Several previous studies reported that individuals who spend the most time on Facebook, Instagram and other recreational platforms have a much greater risk of reporting depression than those who spend the least time.32,33 And a study conducted in India reported a significant positive relationship between depression and internet addiction.34 Recreational platforms are designed to capture people’s interest, keep them online, and keep them monitoring the screen for updates. It is how businesses generate money. But at the same time, excessive use of the platforms contributes to developing several psychological issues, including internet addiction, our study is evident.\n\nOn the other hand, being a housewife or an online professional were identified as protective factors for increased severity of internet addiction compared to students. In accordance with us, Soule et al. also stated that students are more at risk of developing internet addiction.35 The possible reason could be that during the restricted movement period, students had more free time to spend on the internet as the educational institutes were remained closed while the other professionals were struggling to maintain their professional flow. That is why it is required to develop and implement occupation-specific intervention plans to reduce excessive addiction to the internet, especially during a pandemic, and prevent long-term negative psychological consequences.\n\nWe also identified that people with shortened sleep duration were at a higher risk for increased severity in Internet addiction during the restricted movement period. Although it is well-established that Internet addiction is associated with frequent sleep disturbance, shortened sleeping hours and poor sleep quality,36,37 in our case, we can explain the relationship from the other side of the mirror. A study conducted in Greece found that anxiety levels were much higher in persons who slept for a short period.38 In link with the finding, the famous psychologist Dr Christina Gregory stated that those who are already suffering from anxiety or depression often turn to the Internet to relieve their suffering. As it is emotionally rewarding, it transforms into Internet addiction eventually.39\n\nOur target population was the general population from various regions of Bangladesh, whereas most of the previously conducted studies in Bangladesh targeted particular occupational group or a specific age group.40–42 Also, our study gathered data from multiple relevant angles related to the Internet using behaviour and regular activity from pre-COVID-19 and during the restricted movement period. Moreover, this study is one of the few studies which compared the Internet addiction level of pre-COVID-19 and during the restricted movement period.\n\nThere were several drawbacks of this research. At first, since the survey was conducted online, people who regularly use the internet and are actively involved in browsing social media websites were more likely to be participated in it, resulting in response bias. As a result, the respondents may not be representative of the whole population. Second, data on Internet use patterns prior to the COVID-19 might be skewed by recall bias. Third, rather than clinical diagnosis, we used respondents’ self-reported information from the Internet Addiction Scale to assess severity of Internet addiction. Fourth, the Young’s Internet Addiction Scale measures the possibility of Internet addiction only; it is not a confirmatory tool. Finally, we could not establish causal relationship between independent variables and increased severity of Internet addiction due to the cross-sectional nature of the data. Additional longitudinal follow-up investigation is suggested to evaluate the restricted movement period’s long-term impact on Internet use and psychological health.\n\n\nConclusion\n\nThe prevalence of Internet addiction was significantly enhanced among the general population in Bangladesh during the restricted movement period, which is in line with other studies conducted in different parts of the world. We created a detailed profile of the consequences of restricted movement on the Internet addiction in Bangladesh’s general population. We also shared our concern about the influence of the restricted movement on vulnerable communities; lack of proper recognition of the crisis may penetrate the problem in a deeper stage. Evidence-based early preventions like cognitive behavioural therapy are required for vulnerable group. The study could be a good base for policymakers to understand the severity of the problem better and undertake policies to confront long-term impact.\n\n\nData availability\n\nOSF: Internet addiction during COVID-19 restricted movement period: A study from Bangladesh. https://doi.org/10.17605/OSF.IO/FSN49.43\n\nThis project contains the following underlying data:\n\n- COVID19_Restricted_Movement_Period_Internet_Addiction_Bangladesh.dta\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nOSF: Internet addiction during COVID-19 restricted movement period: A study from Bangladesh. https://doi.org/10.17605/OSF.IO/FSN49.43\n\nThis project contains the following extended data:\n\n- A copy of the questionnaire\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nKuss D, Griffiths M, Karila L, et al.: Internet Addiction: A Systematic Review of Epidemiological Research for the Last Decade. Curr. Pharm. Des. 2014; 20: 4026–4052. PubMed Abstract | Publisher Full Text\n\nWorld Internet Users Statistics and 2021 World Population Stats.[cited 2021 Nov 14]. Reference Source\n\nPark S, Jeon HJ, Bae JN, et al.: Prevalence and Psychiatric Comorbidities of Internet Addiction in a Nationwide Sample of Korean Adults. Psychiatry Investig. 2017 [cited 2021 Nov 14]; 14: 879–882. PubMed Abstract | Publisher Full Text\n\nAdelantado-Renau M, Moliner-Urdiales D, Cavero-Redondo I, et al.: Association Between Screen Media Use and Academic Performance Among Children and Adolescents: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019 [cited 2021 Nov 14]; 173: 1058–1067. PubMed Abstract | Publisher Full Text Reference Source\n\nGriffiths M: Internet addiction: an issue for clinical psychology?.1996.\n\nYoung KS, de Abreu CN : Internet addiction: a handbook and guide to evaluation and treatment.2011 [cited 2021 Nov 14]; 289. Reference Source\n\nMak KK, Lai CM, Watanabe H, et al.: Epidemiology of Internet Behaviors and Addiction Among Adolescents in Six Asian Countries.2014 [cited 2021 Nov 14];17: 720–728. Publisher Full Text Reference Source\n\nHa JH, Yoo HJ, Cho IH, et al.: Psychiatric Comorbidity Assessed in Korean Children and Adolescents Who Screen Positive for Internet Addiction. J. Clin. Psychiatry. 2006 [cited 2021 Nov 14]; 67: 821–826. PubMed Abstract | Publisher Full Text Reference Source\n\nMamun MA, Hossain MS, Siddique AB, et al.: Problematic internet use in Bangladeshi students: The role of socio-demographic factors, depression, anxiety, and stress. Asian J. Psychiatr. 2019; 44: 48–54. PubMed Abstract | Publisher Full Text\n\nTran BX, Huong LT, Hinh ND, et al.: A study on the influence of internet addiction and online interpersonal influences on health-related quality of life in young Vietnamese. BMC Public Health. 2017 [cited 2021 Nov 14]; 17: 138–138. PubMed Abstract | Publisher Full Text\n\nMoreno MA, Eickhoff J, Zhao Q, et al.: Problematic Internet Use: A Longitudinal Study Evaluating Prevalence and Predictors. J. Pediatr X. 2019; 1: 100006. Publisher Full Text\n\nXiong J, Lipsitz O, Nasri F, et al.: Impact of COVID-19 pandemic on mental health in the general population: A systematic review. J. Affect. Disord. 2020; 277: 55–64. PubMed Abstract | Publisher Full Text\n\nLiu JJ, Bao Y, Huang X, et al.: Mental health considerations for children quarantined because of COVID-19. Lancet Child Adolesc. Heal. 2020 [cited 2021 Nov 14]; 4: 347–349. PubMed Abstract | Publisher Full Text Reference Source\n\nVasilj I, Herceg K, Covic I, et al.: Prevalence of and Risk Factors Associated With Mental Health Symptoms Among the General Population in China During the Coronavirus Disease 2019 Pandemic. JAMA Netw. Open. 2020 [cited 2021 Nov 14]; 3: e2014053–e2014053. Publisher Full Text Reference Source\n\nBao Y, Sun Y, Meng S, et al.: 2019-nCoV epidemic: address mental health care to empower society. Lancet. 2020 [cited 2021 Nov 14]; 395: e37–e38. PubMed Abstract | Publisher Full Text Reference Source\n\nSun Y, Li Y, Bao Y, et al.: Brief Report: Increased Addictive Internet and Substance Use Behavior During the COVID-19 Pandemic in China. Am. J. Addict. 2020 [cited 2021 Nov 14]; 29: 268–270. PubMed Abstract | Publisher Full Text\n\nLee JY, Kim SW, Kang HJ, et al.: Relationship between Problematic Internet Use and Post-Traumatic Stress Disorder Symptoms among Students Following the Sewol Ferry Disaster in South Korea. Psychiatry Investig. 2017 [cited 2021 Nov 14]; 14: 871–875. PubMed Abstract | Publisher Full Text\n\nSiomos K, Floros G, Makris E, et al.: Internet addiction and psychopathology in a community before and during an economic crisis. Epidemiol. Psychiatr. Sci. 2014 [cited 2021 Nov 14]; 23: 301–310. PubMed Abstract | Publisher Full Text Reference Source\n\nSchimmenti A, Passanisi A, Caretti V, et al.: Traumatic experiences, alexithymia, and Internet addiction symptoms among late adolescents: A moderated mediation analysis. Addict. Behav. 2017; 64: 314–320. PubMed Abstract | Publisher Full Text\n\nKar SK, Arafat SMY, Sharma P, et al.: COVID-19 pandemic and addiction: Current problems and future concerns. Asian J. Psychiatr. 2020; 51: 102064. PubMed Abstract | Publisher Full Text\n\nInternet Subscribers in Bangladesh January, 2021. BTRC; [cited 2021 Nov 14]. Reference Source\n\nBangladesh Post-lockdown Country Report: [cited 2021 Dec 16]. Reference Source\n\nPandya A, Lodha P: Social Connectedness, Excessive Screen Time During COVID-19 and Mental Health: A Review of Current Evidence. Front. Hum. Dyn. 2021; 3: 45. Publisher Full Text\n\nHassan T, Alam MM, Wahab A, et al.: Prevalence and associated factors of internet addiction among young adults in Bangladesh. J. Egypt. Public Health Assoc. 2020 [cited 2021 Nov 14]; 95: 3–8. PubMed Abstract | Publisher Full Text\n\nIslam MA, Hossin MZ: Prevalence and risk factors of problematic internet use and the associated psychological distress among graduate students of Bangladesh. Asian J. Gambl. Issues Public Health. 2016 61. 2016 [cited 2021 Nov 14]; 6: 11–14. PubMed Abstract | Publisher Full Text\n\nPrice HO: Internet Addiction: A New Clinical Phenomenon and Its Consequences.2016 [cited 2021 Nov 14]; 1–119. Publisher Full Text\n\nNunnally JC: Psychometric theory. 3rd ed.New York: McGraw-Hill; 1994.\n\nPallant J: SPSS Survival Manual.7th ed.2020; 2020.\n\nDong H, Yang F, Lu X, et al.: Internet Addiction and Related Psychological Factors Among Children and Adolescents in China During the Coronavirus Disease 2019 (COVID-19) Epidemic. Front. Psych. 2020; 11: 751. PubMed Abstract | Publisher Full Text\n\nPervin NB, Emre T: Examination of internet use in terms of psychological well-being. Educ. Res. Rev. 2021; 16: 296–309. Publisher Full Text\n\nAndreou E, Svoli H: The Association Between Internet User Characteristics and Dimensions of Internet Addiction Among Greek Adolescents. Int. J. Ment. Heal. Addict. 2012 112. 2012 [cited 2021 Nov 14]; 11: 139–148. Publisher Full Text\n\nLin LY, Sidani JE, Shensa A, et al.: Association Between Social Media Use and Depression Among U.S. Young Adults. Depress. Anxiety. 2016 [cited 2021 Nov 14]; 33: 323–331. PubMed Abstract | Publisher Full Text\n\nTwenge JM, Joiner TE, Rogers ML, et al.: Increases in Depressive Symptoms, Suicide-Related Outcomes, and Suicide Rates Among U.S. Adolescents After 2010 and Links to Increased New Media Screen Time.2017 [cited 2021 Nov 14]; 6: 3–17. Publisher Full Text\n\nKumar S, Kumar A, Badiyani B, et al.: Relationship of Internet Addiction with Depression and Academic Performance in Indian Dental Students. Med. Pharm. Reports. 2018 [cited 2021 Nov 14]; 91: 300–306. PubMed Abstract | Publisher Full Text Reference Source\n\nSoule LC, Shell LW, Kleen BA: Exploring Internet addiction: Demographic characteristics and stereotypes of heavy Internet users. J. Comput. Inf. Syst. 2003; 44: 64–73.\n\nKarki K, Singh DR, Maharjan D, et al.: Internet addiction and sleep quality among adolescents in a peri-urban setting in Nepal: A cross-sectional school-based survey. PLoS One. 2021 [cited 2021 Nov 14]; 16: e0246940. PubMed Abstract | Publisher Full Text\n\nJahan SM, Hossain SR, Sayeed UB, et al.: Association between internet addiction and sleep quality among students: a cross-sectional study in Bangladesh. Sleep Biol. Rhythms. 2019 173. 2019 [cited 2021 Nov 14]; 17: 323–329. Publisher Full Text\n\nSerdari A, Manolis A, Tsiptsios D, et al.: Insight into the relationship between sleep characteristics and anxiety: A cross-sectional study in indigenous and minority populations in northeastern Greece. Psychiatry Res. 2020; 292: 113361. PubMed Abstract | Publisher Full Text\n\nInternet Addiction Disorder - Signs, Symptoms, and Treatments.[cited 2021 Nov 14]. Reference Source\n\nMostafa A, Hoque R, Chakraborty R, et al.: Internet Use and Addiction: A Cross-sectional Study to ascertain Internet Utilization Level for Academic & Non-Academic Purpose among Medical and University Students of Bangladesh. Konuralp Med. J. 2019 [cited 2021 Nov 14]; 11: 404–415. Publisher Full Text Reference Source\n\nAhmed S, Seoty NR, Yasmin N, et al.: Pattern of Internet Usage and Addiction among Private Medical Colleges Students in Dhaka City, Bangladesh. Borneo J. Med. Sci. 2019 [cited 2021 Nov 14]; 13: 25–25. Publisher Full Text Reference Source\n\nSayeed A, Hassan MN, Rahman MH, et al.: Facebook addiction associated with internet activity, depression and behavioral factors among university students of Bangladesh: A cross-sectional study. Child Youth Serv. Rev. 2020; 118: 105424. Publisher Full Text\n\nHossian M, Chowdhury AT, Siddiqua SR, et al.: Internet addiction during COVID-19 restricted movement period: A study from Bangladesh.2022, January 28. Publisher Full Text"
}
|
[
{
"id": "188163",
"date": "15 Aug 2023",
"name": "Xinyan Xie",
"expertise": [
"Reviewer Expertise Mental health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study reported an increase in the prevalence of Internet addiction and identified some risk factors among the general population of Bangladesh during the restricted movement period. Some problems need to be revised.\nIs the work clearly and accurately presented and does it cite the current literature?\nIs there any more recent data available than the data in 2021 mentioned in the Introduction?\n\nWhen did the residents of Bangladesh face restricted movement? which phase of the mobility restrictions did the current study take place in?\n\nWhat is the current progress of research on Internet addiction among the Bangladesh population during the COVID-19 period? How does this study contribute to the existing research? These points need to be addressed in the Introduction.\nAre sufficient details of methods and analysis provided to allow replication by others?\nBy what criteria did the authors categorize income levels into social classes?\nIf applicable, is the statistical analysis and its interpretation appropriate?\nGiven the current sample size, does the logistic regression model support the inclusion of all 11 variables? How were the model evaluation metrics?\n\nIn the group showing an increase in addiction scores, there were only 2 individuals classified as Housewives and 3 individuals classified as Online professionals. How was the stability of the logistic regression models considered in this case?\n\nDid the authors consider dividing the population based on the presence or absence of addiction, such as transitioning from non-addiction to addiction, during the analysis process?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "180742",
"date": "22 Sep 2023",
"name": "Patrick Chin Hooi Soh",
"expertise": [
"Reviewer Expertise Internet addiction",
"Cyberloafing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall, it is a clear, concise and relevant article worthy of publication, However, a minor defect is that the researcher did not explain how the sample size of 310 was adequate.\n\nOne significant limitation of this research, which was not mentioned by the authors, is that there is no difference made between high Internet engagement and Internet addiction. Some people particularly during the pandemic may have to work online but such high engagement does not necessarily mean addiction. See https://www.sciencedirect.com/science/article/abs/pii/S074756320500049X\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "192691",
"date": "22 Sep 2023",
"name": "Shamala Ramasamy",
"expertise": [
"Reviewer Expertise Psychology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nNo research design mentioned in the manuscript.\n\nThe conclusion is far fetched, suggesting CBT etc.\n\nRQ is not available.\n\nA cross-sectional study is being used, claims the author. Increase in severity during the restricted movement period using multivariable logistic regression analysis - which is not stated as to how is the procedure of data collection. increase in severity from which point to which point, are the samples the same during the pre-Covid and MCO?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-519
|
https://f1000research.com/articles/11-518/v1
|
13 May 22
|
{
"type": "Method Article",
"title": "DeepReGraph co-clusters temporal gene expression and cis-regulatory elements through heterogeneous graph representation learning",
"authors": [
"Jesús Fernando Cevallos Moreno",
"Peyman Zarrineh",
"Aminael Sánchez-Rodríguez",
"Massimo Mecella",
"Jesús Fernando Cevallos Moreno",
"Peyman Zarrineh",
"Massimo Mecella"
],
"abstract": "This work presents DeepReGraph, a novel method for co-clustering genes and cis-regulatory elements (CREs) into candidate regulatory networks. Gene expression data, as well as data from three CRE activity markers from a publicly available dataset of mouse fetal heart tissue, were used for DeepReGraph concept proofing. In this study we used open chromatin accessibility from ATAC-seq experiments, as well as H3K27ac and H3K27me3 histone marks as CREs activity markers. However, this method can be executed with other sets of markers. We modelled all data sources as a heterogeneous graph and adapted a state-of-the-art representation learning algorithm to produce a low-dimensional and easy-to-cluster embedding of genes and CREs. Deep graph auto-encoders and an adaptive-sparsity generative model are the algorithmic core of DeepReGraph. The main contribution of our work is the design of proper combination rules for the heterogeneous gene expression and CRE activity data and the computational encoding of well-known gene expression regulatory mechanisms into a suitable objective function for graph embedding. We showed that the co-clusters of genes and CREs in the final embedding shed light on developmental regulatory mechanisms in mouse fetal-heart tissue. Such clustering could not be achieved by using only gene expression data. Function enrichment analysis proves that the genes in the co-clusters are involved in distinct biological processes. The enriched transcription factor binding sites in CREs prioritize the candidate transcript factors which drive the temporal changes in gene expression. Consequently, we conclude that DeepReGraph could foster hypothesis-driven tissue development research from high-throughput expression and epigenomic data. Full source code and data are available on the DeepReGraph GitHub project.",
"keywords": [
"Developmental Gene Regulatory Networks",
"Cis-Regulatory Elements",
"Heterogeneous Graph Representation Learning",
"Deep Graph Auto-encoders"
],
"content": "Introduction\n\nGene regulatory networks drive gene expression during cell development. Studying the regulatory networks’ effects on gene expression has become an essential topic in evolutionary developmental biology. Recently, a wide range of temporal high-throughput experiments has become available for both normal development and disease-related investigations.1–3 For example, the ENCODE consortium has provided comprehensive fetal development datasets for 12 tissues in mice from the E10.5 stage to the birth time P0.1 These datasets include both gene expression data and major transcriptional and epigenetic features. Some of the latter come from ATAC-seq experiments that measure chromatin accessibility, whole-genome shotgun bisulfite sequencing experiments measuring DNA methylation, and histone modifications.1 Similar datasets, though in lesser amount, exist to study aging (see a recent review by Pagiatakis et al.2). Cancer, instead, is among the diseases with the largest amount of available gene regulatory datasets (see a recent review by Zboril et al.3).\n\nGene expression regulation occurs via non-coding segments, also known as cis-regulatory elements (CRE).4 Associating CREs to the genes they regulate is the key to deciphering temporal dynamic changes through development. As CREs and genes are distinct entities located on different genome coordinates, a concurrent study of these has been challenging. Many methods have been developed to study genes and CREs separately through development in the last years. Infinite Gaussian Process Mixture Model5 and Convolutional Neural Networks6 are among the most successful methods to find temporal clusters of either genes or CREs. Generally, high-throughput datasets are highly clusterable, and even conventional clustering methods like K-Means clustering can also generate satisfactory results when used for a single source dataset (i.e. genes or CREs). However, combining or aligning the clusters across data sources is still a major challenge.\n\nInsights about developmental regulatory networks are typically gained by the application of Multiview learning7 to align single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq).8,9 Such methods permit the classification of different cells through the combination of various high-throughput experiments made over the same cell population.10,11 The Seurat method,12 for example, makes different reduced dimension representations of single-cell gene expression and CREs data. Such a method uses Canonical Correlation Analysis to place multiple datasets on a common latent space with reduced dimension and anchor a population of cells across different modality datasets. Other methods rely on stronger prior knowledge about cell alignment to anchor multiple modalities. This is the case of the Multi-Omics Factor Analysis v2 (MOFA+), a statistical framework for the comprehensive and scalable integration of single-cell multi-modal data.13 More recently, multi-modal dataset alignment methods have been developed based on state-of-the-art deep learning techniques.14,15 MAGAN,16 for example, successfully aligned scRNA-seq and scATAC-seq datasets using Generative Adversarial Networks (GAN). Yang et al.,17 used deep auto-encoders to map multiple data modalities of a population of cells to a common latent space. They used prior knowledge and adversarial learning to drive the correct alignment of data. Comprehensive surveys on multi-modal or multi-view learning applied to multi-omics datasets can be found in.8,18\n\nThe works mentioned above explore gene expression regulatory mechanisms by combining multiple views of the same cell population. This work investigates gene regulatory networks by clustering two diverse entity types together: We sought to group CREs with their correspondent regulated genes. In this sense, we performed a heterogeneous network clustering task. Heterogeneous data interaction was also modelled by Huang et al.19 for predicting transcription factor interactions with their target genes. Wang20 and Zhou21 instead, modelled gene-disease interactions trough a heterogenous-network model. Other recent problems solved through heterogeneous graph-based models include Gene Ontology Representation Learning,22 Gene prioritization for rare diseases23 and drug repurposing.24 The main novelty of this work is the introduction of a model for regulatory networks discovery which is based on the concept of “Heterogeneous Graphs”.25 We modelled a graph containing two classes of nodes: genes and their potential regulatory elements, now on termed as candidate-CREs (cCRE), and multiple types of relations or edges between nodes. One such relation type is the similarity between temporal gene expression profiles. Another relation type is the similarity between temporal cCREs activity patterns. Finally, we introduced a third edge type: the base-pair distance between genes and cCREs in the genome. Having defined such relations, we propose the usage of graph representation learning (graph RL) to group genes and cCREs as a function of the probability of the existence of gene regulation mechanisms between them.\n\nTo this end, we extended a state-of-the-art graph RL algorithm presented in Ref. 26 to make it capable of learning representations of heterogeneous graphs and applied it to the ENCODE heart dataset in Ref. 1. We used open chromatin regions from ATAC-seq as cCREs. Besides ATAC-seq, we used H3K27ac and H3K27me3 histone marks, well-known markers of enhancer activity, and polycomb repression. Our framework produced a relation type between genes and cCREs which is aware of both same-class pattern similarities and base-pair proximities between elements of different classes. Moreover, through the usage of the adaptive neighbors model presented in Ref. 26 we produced a “clustering-friendly” embedding where we could straightforwardly perform clustering. The resulting clusters contained both genes and cCREs and tended to identify possible regulatory mechanisms. We demonstrated this claim by evaluating such clusters’ semantic power with external expert criteria. We concluded that the proposed methodology is able to learn suitable combinations of multiple entity relations to form a unique relation under a graph that resembles a gene regulatory network. Our framework is called DeepReGraph, because it is a Deep learning-based algorithm for identification of gene expression Regulatory mechanisms through heterogeneous Graph RL. Our full code, the pre-processed datasets used, and the values used for all the parameters and hyperparameters used in our experiment are online available at our repository[1].\n\n\nMethods\n\nTo demonstrate DeepReGraph’s ability to cluster genes and cCREs simultaneously, we applied this method to a mouse heart fetal developmental dataset from the ENCODE project.1 Gene expression and cCRE activities were time-series formatted. We used three well-characterized epigenetic markers: ATAC-seq, H3K27ac, and H3K27me3 measurements as features of cCRE temporal activities. We aimed to create a low-dimensional and clustered representation of the whole dataset, where clusters represent candidate gene-expression regulatory mechanisms (GERM). In other words, we aimed to create clusters containing both genes and cCREs, with the working hypothesis that cCRES on a cluster are plausibly regulating the expression of the genes in the same cluster. Moreover, genes on the same GERM cluster should have similar gene expression profiles, and cCREs should have similar activity profiles. Lastly, the base-pair distances between genes and cCREs on the same cluster should be relatively small with respect to distances between elements in different clusters. We validated heterogeneous clusters of genes and cCRES to study how gene regulatory networks (GRN) drive changes in gene expression during mouse heart fetal development. To validate gene expression clusters, we performed enrichment analysis of biological process gene ontology terms using the ClusterProfiler bioconductor package.27 To validate the cCRE clusters, we looked for the Enriched Homer Motifs.28\n\nData pre-processing was done in two stages. Firstly, gene expression and cCRE datasets were normalized across temporal data. The second stage included filtering-out temporal profiles where the correlation across replicates or the variance across time was below some pre-defined thresholds. We explain the pre-processing stages in greater detail below.\n\nWe firstly downloaded the gene expression values, called peaks, and bam files of ATAC-seq, H3K27ac, and H3K27me3 from the ENCODE database1 (mice heart fetal tissue). We used logFPKM values of gene expression throughout this paper. To detect cCRE regions, we re-centered ATAC-seq called peaks across time points and replicates using the bioconductor DiffBind package.29 To determine chromatin accessibility in each cCRE region, we took regions of 500 nucleotides long (250 nucleotides on each side from the center of cCREs). We recorded binding intensities for each replicate of each time point separately by using the bioconductor Rsubread package.30 We counted H3K27ac and H3K27me3 marks for cCREs in the same manner, but used regions 3000 nucleotides long instead (1500 nucleotides each side from the center of cCREs). We took the median value of non-peak regions in each experiment separately to remove background counts from real intensity counts. Then, we subtracted these median values from the intensities of each experiment separately. We used logRPKM values of denoised counts across replicates and time points. Removing the background noise caused the distribution of each experiment to resemble a Gaussian distribution.\n\nAt the end of this process, we had two replicas of gene expression time-series profiles for a set of genes and two replicas of cCRE activity time-series for each activity marker over a set of cCREs. We then proceeded to filter out invalid genes and cCREs based on two criteria. The first group of filters we applied to this data were proposed in Ref. 31. For each gene, we measured the correlation of the gene expression profiles of both replicates and discarded every gene whose replicate had a negative correlation value. We did the same with the cCREs for each activity marker profile. If only one activity marker had a negative correlation between replicates, the cCRE was discarded. We also discarded every element (gene or cCRE) where two consecutive time probes had an absolute ratio greater than 2.\n\nWe also discarded low-expressed genes and low activity-characterized cCREs.32 We computed the mean gene expression value for each gene and discarded every gene whose mean expression value was under the 0.8 percentile of such mean value distribution. We did the same with cCREs: we computed the mean activity value for each activity marker and discarded every cCRE where the mean value was below a minimum percentile threshold. Such thresholds were 0.8 for ATAC-seq and 0.7 for H3K27ac and H3K27me3. Lastly, for gene expression and each activity marker dataset, we created a 3-rd degree polynomial regression to estimate the variance of each time series as a function of its mean value. We discarded all the elements where the actual variance was below the predicted variance. Our pre-processed and cleaned data consisted of 607 genes and 5239 cCREs from the mouse heart dataset. This dataset is available online on our public repository. Our objective was to shed light on regulatory mechanisms among genes and cCREs. Having cleaned our dataset, modeling it as a heterogeneous graph is the strategy we used to combine all the data and learn a new relation type between elements that gives information about gene expression regulation. We explain the graph modelling in the next paragraph.\n\nMany industrial data are represented in a graph, as multiple entities with quantifiable relationships between them. Nowadays, graph modelisation is widely used in bioinformatics.33 One strategy to extract added-value from graphs is the use of graph RL algorithms. Graph RL has been widely studied by the research community over the past few years years.25,34–36 Graph RL algorithms seek to map the information of a graph on a reduced-dimension latent space where the geometrical distances between elements in such space resemble the relations in the original graph. In other words, graph RL, also referred to as “graph embedding”, consists in finding a reduced dimensional representation of the nodes of a graph while conserving most of the semantic information of such a graph.37,38\n\nA graph can be homogeneous if it has a unique type of node and a unique type of relation defined between them, or heterogeneous, if it introduces multiple edge and node types. We argue that regulatory networks during embryonic development can also benefit from being modelled as a heterogeneous graph. Reduced-dimension representations of such a graph could contain multiple types of information that, if well combined, could semantically express regulatory mechanisms of gene expression.\n\nWe defined a heterogeneous graph and described it as G=VℰT, where V is the set of nodes, ℰ is the set of edges and T=Tℰ∪TV is the set containing all the node types and edge types. The set of node types consists of genes and cCREs, and is denoted by TV=genesccres. Each gene gi,∀i∈|Vgenes| in the dataset is characterized by a gene expression time-series profile that will be encoded in a vector denoted by gi. Note that the length of gi coincides with the number of time-points considered in the gene expression data. The vectors gi,∀i∈|Vgenes| can be concatenated as rows to form the feature matrix represented in red in panel A of Figure 1.\n\nOur framework combines multiple temporal enhancer activity markers with temporal gene expression data and base-pair distances to build a heterogeneous graph of genes and cis-regulatory elements (CRE). The proposed framework then applies an adapted version of AdaGAE26 to find a low-dimensional, easy-to-cluster embedding representation of data through an iterative optimisation process. In the final embedding produced by our method, the spatial distribution of genes and cCREs resembles candidate gene-expression regulatory Mechanisms.\n\nEvery candidate cis-regulatory element, instead, will be denoted as cj,∀j∈|Vgenes| and will be characterized by M activity time-series profiles, that will be encoded in corresponding vectors denoted as cj1,cj2,…,cjM. The time-points under which gene expression and cCRE activity values are available are the same. In this work, M=3. Specifically, we considered the ATAC-seq, H3K27ac, and H3K27me3 activity time-series profiles for each cCRE, but one could include more cCRE activity markers in the set of features. Note that the vectors cjm,∀j∈|VcCREs| can be concatenated as rows to form the matrices represented in blue in panel A of Figure 1.\n\nEach node of our graph was associated to one or multiple feature vectors that can be seen as points on a multi-dimensional feature space. The set of feature-spaces defined for the nodes in G is denoted as R=GC1C2…CM where G is the gene expression feature space and C1,C2,…CM are the feature spaces of the M cCRE activity data. Each one of these feature spaces will be referred to as original feature space, and the vectors gi,cj1,cj2,…,cjM as original feature vectors from now on. Note that such vectors correspond to the rows of the matrices in panel A of Figure 1. It is well-known that the probability of the existence of a regulatory mechanism between a gene and a cis-regulatory element is inversely proportional to the base-pair distance between them.39 For this reason, in our work, we used another data source, called the Link Matrix, that gives us information about the base-pair distance between genes and cCREs. We represented such a matrix in panel C of Figure 1. Interaction between cCREs and genes is generally possible in the range of 1 Mega base-pair.40 Consequently, we considered only distances lower than 106 base-pairs. For practical purposes, we scaled the base-pair distance values in the interval 01 to define a scaled base-pair distance function, DBP:\n\nGiven the scaled distance function, we created a base-pair proximity relationship SBP using a parametric transformation:\n\nThe interaction between CREs and the genes they regulate is complex. Some CRE markers are correlated with gene expression and some others are anti-correlated.41 This correlation or anti-correlation is governed by the mechanism that a specific marker affects the gene expression. For example, chromatin should be opened prior to the gene expression. Therefore, chromatin accessibility is commonly directly correlated with gene expression. H3K27ac is also directly correlated with gene expression, as this epigenetic modification happens in active transcription regions. On the other hand, H3K27me3 shows epigenetic modifications that happen at polycomb repressed regions, and are consequently inversely correlated with the expression of the corresponding regulated genes. We needed to capture the relevance of these and other temporal covariances between gene expression and the correspondent regulatory elements’ activity markers.\n\nTo this end, we created a joining score, JT, as a function of the temporal slopes of gene expression and cCRE activity time-series:\n\nWe computed a trend-aware score multiplying (1) and (2) for each gene-cCRE pair in our graph:\n\nWe represented the computation of Equation (3) in panel D of Figure 1. Having defined the trend-aware score, we could differentiate between any pair of genes, gj and gk, when these were equally proximal to any cCRE ci but had gene expression vectors with different temporal trends. In this case, the original base-pair proximity score in (1) assigned the same value to the association gjci and gkci. Notice that the trend-aware score in (2), instead, distinguishes the most plausible association of ci with respect to the alternatives gj and gk as a function of the temporal slopes of the gene expressions elements. In our experiment, we found the best results setting ωATAC=1,ωH3K27ac=0 and ωH3k27me3=0 in Equation (2).\n\nThe set of edge types in the graph is denoted as Tℰ=SBP|TSGSC1SC2…SCM. As explained before, SBP|T indicates the trend-aware base-pair proximity relationship explained above; SG stands for the gene expression profile similarity between genes, and SC1, SC2, …, SCM are the relationships that express the different cCRE activity time-series similarities. We aimed to combine all edge types in Tℰ to find a unique multi-semantic edge type that resembled gene expression regulation mechanisms. The process of combining edge types is represented in panel E of Figure 1 and is explained later in this section. To perform the combination of all edge types in Tℰ, we modelled the data as a heterogeneous graph and designed a graph RL algorithm capable of extracting such a dependency between elements using prior biological knowledge and the data available. We explain the graph RL algorithm we used to fulfil our objective in the next paragraph.\n\nGraph RL algorithms aim at finding a matrix: Z∈ℝ|V|×d that contains information about every feature-space in R. In our case, we used a graph RL algorithm to find a unique feature space for the nodes of G that comprises most of the information encoded by the feature spaces contained in R. The rows of Z correspond to a new set of feature vectors for each node in G. Each row of Z is called an “embedding vector” and is a reduced-dimension representation of the whole set of original feature vectors of a given node.37,34 The embedding vectors are “multi-semantic” in that they contain information from every feature space in R. The dimension of embedding vectors, d, is generally lower with respect to the dimension of the original feature spaces. The embedding matrix Z is represented in panel F of Figure 1.\n\nGraph RL is also referred to as “graph embedding”. Giving a node v∈V, and a specific edge-type τ∈Tℰ, the neighborhood of v in τ is denoted as Nτv and corresponds to the set of nodes that are connected to v by τ-type edges. We denote with Nv instead the set containing every neighborhood of v:\n\nThe heterogeneous graph embedding process can be represented by an encoding function that takes in input a node v∈V and its neighborhood set, Nv, and returns a new representation for that node:\n\nOne of the most common methodologies for implementing (4) is the encoder-decoder paradigm.25 This paradigm also models an auxiliary decoding function. Considering a homogeneous graph, i.e. a graph with a unique node feature space X, the encoder function in (4) takes as input original feature vectors of X, and outputs the corresponding embedding vectors:\n\nThe decoding function, instead, takes as input a pair of node embeddings produced by the encoder, e.g. zi and zj, and outputs a real number. Such a number is the prediction of the value of a pre-defined pair-wise relationship between xi and xj:\n\nThe encoding and decoding functions should minimize a reconstruction loss of the form:\n\nA convenient framework that implements the encoding-decoding paradigm is the deep graph auto-encoder (deep GAE).42 In this framework, (4) was implemented through a graph neural network (GNN), an artificial neural network that takes the original feature vectors and the adjacency matrix of G as input and produces the node embedding vectors. GNNs are non-linear parametric functions, and after a pre-defined initialization schema, the parameters of these functions can be optimized to minimize (6) through gradient descent.\n\nIn this work, we proposed the use of the basic GNN model presented in Ref. 25. In a homogeneous graph context, the basic GNN takes as input the node feature matrix X∈ℝ|V|×m and a pre-defined graph adjacency matrix denoted by A∈ℝ|V|×|V|, and performs non-linear parametric operations with this information to produce Z. In matrix notation, the operations made by the basic GNN model can be represented as follows:\n\nWe defined a parametric “architecture” for the encoding function using (7), but still needed to define A and X, to drive the optimization of the parameters of f to minimize (6). The initialization of these matrices can follow multiple strategies. For example, in the neural message passing framework,43 given a homogeneous graph context, one generally constructs X stacking the original feature vectors as the rows of such a matrix. However, it is not the only valid strategy. In our heterogeneous graph context, we decided to initialize X as the identity matrix because we had multiple original feature matrices. We were confident to use the identity matrix to initialize X because we carefully initialized the adjacency matrix A combining the information of every relationship type in our graph, as we will explain in the next paragraph.\n\nFinally, the similarity measure that the decoder is meant to predict needs to be specified to implement (5). In this paper, we proposed the use of the decoding similarity function proposed by Ref. 26 to converge into a clustering-friendly embedding, i.e., an embedding with dense and easily identifiable clusters. In the next paragraph, we give a brief explanation of the algorithm in,26 which performs graph RL on a single-feature space. For a more detailed exposition of the work of Xuelong et al., the reader is referred to the original paper.26\n\nIn this work, we proposed the use of AdaGAE,26 which is a state-of-the-art method for RL and clustering through graph modelling of a dataset. The whole AdaGAE algorithm is wrapped in a gray rectangle in Figure 1. This algorithm is defined in a homogeneous data context. In other words, given a unique original feature matrix X∈ℝ|V|×m, the objective was to produce a low-dimensional embedding matrix Z∈ℝ|V|×d where d≪m. Authors in26 used a deep GAE to embed high-dimensional datasets in a graph-like, low-dimensional format. Xuelong et al. generated a sparse graph as a function of the Euclidean distances between the original feature vectors using a k-nearest neighbors44 (k-NN) model.\n\nThe main novelty of AdaGAE is the adaptiveness in the sparsity parameter k. The graph auto-encoder is, in fact, iteratively optimized with respect to various objective functions like (6), and each objective function is constructed using a different sparsity parameter. With a custom decoding function, such a dynamic model leads to a sparse graph. In other words, they produce a clustering-friendly embedding of the original data.\n\nIn other words, at each iteration, l∈0,1,2…L−1, a sparse and weighted graph is generated. In this graph, the nodes correspond to the samples of the original dataset. Instead, the weights of the edges are inversely proportional to the Euclidean distances between the original feature vectors. Specifically, at iteration l, a graph is generated in which the weight of the link between nodes vi and vj is denoted as pi,jl and is a function of a sparsity parameter kl:\n\nNotice that, in (8), the parameter kl might have a different value at each iteration. Such a parameter induces the sparsity of the generated graph: for each node vi, only up to kl elements will have a non-zero weighted link with that node. Thus, at each iteration l, AdaGAE generates a kl-sparse graph. Notice also that the function (8) is a discrete probability density function (PDF):\n\nThe embedding matrix Z produced by AdaGAE was iteratively optimized. We denoted with Zl the embedding matrix after iteration l. The embedding vector of node vi after iteration l, instead, coincides with the i-th row of Zl and is denoted as zil. At each iteration, AdaGAE proposes to implement the decoding function in (5) as a function of the embeddings of the previous iteration:\n\nAt each iteration l, AdaGAE proposes to use the Kullback-Leibler divergence (KL-divergence)45 of Pl with respect to Ql to implement (6). Explicitly, the reconstruction loss that AdaGAE seeks to minimize is the following:\n\nXuelong et al. relied on the graph convolutional network (GCN) model46 to implement the encoder of their deep GAE. However, in this paper, we used a simpler GNN model, as explained in the previous paragraph. We represented the iterative computation of (8) and (9) and the iterative optimization of (10) in panel E of Figure 1.\n\nNotice that the main dynamic criterion that causes the objective functions to change is the sparsity parameter kl. However, the sparsity is not the only thing that changes from iteration to iteration: In the first iteration, the distribution family P0 is generated through (8) using the Euclidean distances between the original feature vectors. After the first iteration, instead, the distribution family Pl,∀1<l<L−1 is generated using (8) as a function of the Euclidean distances between the embedding vectors of the Zl−1 embedding matrix. By doing so, AdaGAE considers high-order neighborhoods of each node to construct the final embedding matrix. In other words, AdaGAE is said to “exploit the high-level information” present in the data.\n\nDifferent embeddings for various iterations are plotted in panel G of Figure 1. In those plots, one can see the embedding of a small set of genes and cCREs extracted from the original mouse heart dataset. Large points represent genes, while cCREs are the small points. Point colors, instead, correspond to single-modality or homogeneous cluster assignments, i.e., cluster assignments of genes and cCREs, taking into account their corresponding feature spaces separately. Note that the embedding turns more cluster-friendly at each iteration. In other words, the density and separation of clusters are increased at each iteration, and clusters can be caught visually in the final embedding in panel H of Figure 1. In AdaGAE, the sparsity parameter initialization, k0, the increment of this parameter from iteration to iteration, δk, and the number of iterations, L, regulate the number of clusters in the final embedding. In our experiment, we tested various parameter configurations and found eight significant GERM clusters with L=11, k0=350, δk=25.\n\nNotice that the original work of Xuelong et al. defined (8) as a function of the Euclidean distances over a unique feature space. We extended the AdaGAE framework to deal with multiple node feature spaces. In particular, at each iteration l, we combined the Euclidean distances of multiple node feature spaces - the gene expression and the cCRE activity time-series - to generate a unique distance function that is given to (8) to generate Pl. In the next paragraph, we explain how we combined the feature spaces to adapt AdaGAE to heterogeneous graph RL.\n\nAs explained previously, we modelled the whole set of gene expression and cCRE-activity data as a heterogeneous graph. We proposed to extend the work in Ref. 26 to heterogeneous graph RL. We ran the same process described in the previous paragraph, with some differences. The first difference was the construction of the reference distance function to feed to (8). At each iteration l, we combined the Euclidean distances defined in each one of the original feature spaces to form a unique distance function Dl that generated the sparse distribution family Pl.\n\nRecall that R=GC1C2…CM is the set of feature spaces defined, where G is the gene-expression feature space and C1,C2,…,CM are the cCRE activity feature spaces, for example ATAC-seq, H3k27ac, aH3k27me3, etc. At each iteration l, for each feature space r∈R, we computed the Euclidean distances between the original feature vectors in r, scaled these distances into the interval 01, and denoted them with di,jr,∀i,j∈|V|. Notice that the Euclidean distances between the original feature vectors were only defined between same-class elements: The Euclidean distances in the gene-expression feature space G, were defined between genes, and the distances in C1,C2,…,CM, only between cCREs. Consequently, we set the distance between different-class elements to the maximum value, i.e., 1, for each feature space. Finally, we create a custom linear combination of these distance functions to form a unique distance function D̂l:\n\nAt the beginning of the l-th iteration, the Euclidean distances between the embedding vectors of Zl−1 are denoted by DZl−1. We combined such information with D̂l defined in (11), to generate the unified distance function, Dl as follows:\n\nIn (13), αZl is the fixed parametric importance weight of the Euclidean distances in DZl−1. Notice that, in (12), D̂Zl−1 allows to exploit the high-level information in the data and D̂l helps to reduce the loss of information with respect to the original feature spaces at each iteration.\n\nAt each iteration l,∀l∈0L−1, we computed Dl using (12). This computation is represented in panel E of Figure 1. We then used Dl and the corresponding sparsity parameter kl to compute a connectivity distribution family P̂l using (8). Notice that this distribution family was generated using only the same-class relation types in Tℰ−SBP|T. In other words, we only used the node feature spaces in R to create P̂l. We needed to add the trend-aware base-pair proximity relationship SBP|T defined in (3) to compute the definitive distribution family Pl that takes into account all information we have:\n\nAfter computing P̂l, we computed Ql using (9), and optimized the embedding matrix Z, minimizing a reconstruction loss of the form (6). AdaGAE proposed the use of (10) to implement the reconstruction loss. In this paper, however, we propose to extend such a loss function to better separate elements that are distant in the original feature spaces, as explained in the next paragraph.\n\nThe minimization of (10) has the same effect of an attractive force that tends to collapse points in the embedding space, reducing the distances between zj and zj proportionally to pi,jl. When considering a single node vi, such an objective function could lead to errors in the manipulation of the position of the most distant neighbors of such node.47 Inspired by Ref. 48, in this work, we added a regularization term that acts as a repulsive force. Such a repulsive force tends to increase d̂i,jl proportionally to the inverse of pi,jl. In other words, we pushed elements away from each other proportionally to their distance Dl in (12). To create this force, we added the KL-divergence of 1−Pil with respect to 1−Qil to (10).\n\nNotice that the union of the attractive and repulsive force is equivalent to the minimization of the binary cross-entropy of Pl with respect to Ql as defined in Ref. 48. Lastly, we added parametric importance weights to the attractive and repulsive force components and constructed our final objective function:\n\nWe iteratively optimized the parameters of our GNN-based encoder. At each iteration, we minimized (15) with a different set of parameters. After running the optimization for a predefined number of iterations, we processed to a clustering-friendly embedding where the clusters reflect plausible gene regulatory networks. We then ran k-means clustering on the embedding to find plausible gene expression regulatory mechanisms. This clusterization is represented in panel H of Figure 1.\n\n\nResults\n\nDeepReGraph performs the co-clustering of genes and cCREs together. Consequentially, resulting clusters are heterogeneous in the class of elements they might contain. DeepReGraph helped us identify eight co-clusters when applied to developmental fetal mouse heart datasets. We assessed the quality of gene expression and cCREs clusters from a computational point of view. We also analyzed these clusters from a biological perspective as described below.\n\nWe employed a principle component analysis (PCA) to visualize the cCRE clusters on dimension reduced plots as shown in panel A of Figure 2. This figure highlights a clear separation of clusters on PC0, PC1, and PC2 which explains the 57% variability in the cCRE datasets. We also performed k-means clustering using k=8. Panel B of Figure 2 shows a confusion matrix that compares cCRE clusters from DeepReGraph with the uni-modal clustering produced with k-means clustering. It is clear from this confusion matrix that the result of the multi-modal clustering of DeepReGraph was highly similar to the uni-modal clustering one. This similarity indicates that DeepReGraph clustering does take into account the same-class pattern similarities when defining clusters. We also visualized the PCA plot of gene expression data in panel C of Figure 2. PC0 by itself explains 76% of the variability in gene expression. Basically, gene expression has two distinct patterns throughout mouse fetal heart tissue development: genes with increasing expression and genes with decreasing expression. Interestingly, these two major patterns have been divided into sub-patterns based on the cCRE clusters that plausibly drive their regulation.\n\nA) Principal component analysis (PCA) reduced dimension of candidate cis-regulatory elements (cCRE) profiles colored by the correspondent DeepReGraph cluster. B) Intersection between only-cCRE agglomerative clustering and cCRE extracted from DeepReGraph heterogeneous clusters. C) PCA reduced dimension of gene expression profiles colored by the corresponding DeepReGraph cluster.\n\nThe clustered patterns produced by DeepReGraph are presented in Figure 3. In this figure, the y-axis contains the mean-centered values for gene expression in the left-most column, while mean-centered CRE features are in the last three columns. The mean value reduction process mentioned was done as follows: given a time-series vector x=x0x1…xt, with a mean value x̂=∑i=0txi|x|, the mean-reduced vector is x˜=x0−x̂x1−x̂…xt−x̂. The x-axes of the plots instead correspond to the considered time-points of mouse fetal heart development. Notice that each cluster contains a set of genes and cCREs. The area between the first and 0.75 quantile is colored for each trend plot, to help visualize the trend of each cluster.\n\nThe first column of plots contains gene expression time profiles, and the rest of the columns contain enhancer activity time profiles. The space between the first and third quartile for each plot was colored to better show the trend.\n\nWe investigated the enriched function of gene expression clusters and enriched transcription factor binding site motifs of cCRE clusters to decipher the general signature of mouse fetal heart development. Figure 4 summarizes these enrichment analysis. It clearly shows that all gene expression clusters have clear functional annotation and all cCRE clusters entail clear transcription factor binding site motifs.\n\nIn general, expression of genes related to cell proliferation functions decrease during mouse fetal development, while expression of genes related to heart functions increase.4 However, if we look at the enriched terms for the detected gene expression clusters in panel A of Figure 3, and the pattern of gene expression the cCREs that drive them in Figure 3, we can observe that the story is not so simple. Two of the largest gene expression clusters are cluster2 (192 genes) which represents the heart functional genes (enriched for heart contraction function), and cluster7 (249 genes) which represents the cell proliferation genes. The smaller gene expression clusters have more specific enriched functions. Considering the other gene expression clusters down-regulated during development, cluster0 was more enriched for DNA replication, while cluster3 was enriched for non-heart developmental processes. Similarly, the smaller gene expression clusters up-regulated during development gained specific functional enrichment: cluster1 was enriched in metabolic processes to generate energy for the heart to function. Cluster4 was enriched for ventricular cardiac muscle cell membrane repolarization, and cluster6 was enriched for heart contraction. Cluster5 contained genes enriched for regulation of muscle system process. Here, co-clustering of gene expression and cCREs enabled us to derive smaller and more specific clusters. Otherwise, as it is clear from Figure 2 panel C, the smaller clusters of gene expression with more focused functions could not be deduced from gene expression alone.\n\nMulti-modal clustering can also describe how cCREs can drive gene expression during development. First, smaller gene expression clusters gained more cCREs per genes, as Figure 3 shows. Secondly, cCREs with different epigenetic patterns have been linked to similar pattern of gene expression, as can be seen also in Figure 3. For example, in the major cluster with up-regulated genes during development, i.e. cluster2, the trends of ATAC-seq and H3K27ac increased as expected. Similarly, for cluster7 which entails a large set of down-regulated genes throughout development, the trend of ATAC-seq and H3K27ac decreased. However, the H3K27me3 pattern for both cluster2 and cluster7 showed no changes in Figure 3. We can observe polycomb removal events in cluster1, cluster3, and cluster4 as H3K27me3 levels decreased in these clusters.\n\nMulti-modal clustering can further clarify how gene expression changes through development, as cCRE clusters exhibited clearly enriched motifs in panel B of Figure 4. These enriched motifs can prioritize the candidate transcription factors which drive the development. For example, the MEF2 motif was enriched in the clusters related to up-regulated genes. The only exception was cluster1, for which the AP1 motif was enriched. We can assume that a MEF2 binding transcription factor, and more probably MEF2C, was the major transcription factor which caused the increase in gene expression values. Other binding site motifs were been enriched for the clusters entailing temporally up-regulated genes in Figure 4 panel B. Interestingly, these motifs were highly cluster-specific. A similar dynamic was seen for clusters with temporally decreased gene expression. Although zinc finger motifs were enriched in these clusters, the GATA motif was only enriched in cluster0 and the basic helix-loop-helix (BHLH), nuclear receptor motifs are only enriched in cluster3.\n\n\nDiscussion\n\nThis study introduced a novel method called DeepReGraph to perform multi-modal clustering of gene expression and cCREs. DeepReGraph allows a cluster-friendly embedding, where clusters contain genes and CREs and tend to identify gene regulation mechanisms. Interestingly, the results of multi-modal clusters derived by DeepReGraph for cCRES were highly similar to the uni-modal clustering using k-means. However, DeepReGraph generated gene expression clusters that could not be derived by using gene expression data alone. Such a result might be expected if we consider cCRE and gene expression changes in a “cause and effect” manner. cCREs are part of the regulatory network and are among the driving causes of alternation in gene expression. Therefore, we can expect cCRE uni-modal clustering to be similar to co-clustering gene expression and cCREs together. However, gene expression is controlled by cCREs. In mouse fetal heart development, we have shown that similar gene expression (similar effect) can be divided into different clusters based on the controlling cCREs. This result shows the added values of the multi-modal clustering method to understand the signature of development.\n\nDevelopmental regulatory networks can be straightforwardly modelled as heterogeneous graphs. The main reason for such a claim is because they are made of two distinct classes of elements (genes and CREs) whose interaction tends to be highly correlated with multiple features like gene expression, base-pair distance, and cCRE activity. Modelling such regulatory networks as heterogeneous graphs is key to using graph RL algorithms to converge to low-dimensional embeddings for such systems. The spatial distribution of nodes in the embedding might resemble complex relationships between nodes.\n\nWe undertook the challenge of converging to an embedding where gene expression regulation mechanisms are easily identifiable. To do so, we created our own heterogeneous graph RL algorithm by carefully designing an extension of AdaGAE.26 First, we designed a dynamic combination schema of multiple node feature spaces to create a unique node feature space. This unification was a necessary step to adapt AdaGAE to a heterogeneous graph scenario. We also created a repulsive force by extending the loss function in Ref. 26. This repulsive force has proven essential to separate elements with different gene expression or activity trends. Third, we introduce a trend-aware regularization of the base-pair distance relationship between nodes. This regularization proved essential to produce more compact clusters. The resulting schema is responsible for producing a clustering-friendly embedding space that sheds light on regulatory mechanisms.\n\nIn this work, we extended the algorithm presented in Ref. 26 to produce an algorithm capable of embedding a heterogeneous graph into a low-dimensional, easy-to-cluster embedding. Other approaches to heterogeneous graph embedding that we could further investigate exist34; for example, the relational graph convolutional networks (RGCN).49 Such a model implies a greater number of parameters; various parameter-sharing approaches have been proposed, some of them making use of the attention mechanism.50,51 We could further investigate attention-based prioritization of nodes and relationships for learning embeddings.52 If we consider the production of a unified embedding of heterogeneous data as a first step, we could conceive other offline clustering algorithms. The clustering-friendly embedding we present resembles a differentiable version of agglomerative clustering. However, other algorithms like the ones in Refs. 53,54 use a differential expectation-maximization schema, where a distance-to-centroid loss is minimized to reach final embedding with compact clusters. Consequently, the use of different deep clustering approaches should be further investigated.\n\nRegulatory networks and gene regulation are dynamic processes. Therefore, temporal datasets can potentially describe them better than static ones. However, initial efforts to associate regulatory networks and chromatin states to the gene expression were made based on limited data. ChromHMM55 is the most used method to assign states of the chromatin to genes. However, with the advent of large temporal datasets like ENCODE, which we used in this paper, it is possible to move beyond a static view of regulatory networks and gene expression. This study used chromatin accessibility, H3K27ac, and H3K27me3, three well-known epigenetic markers with a well-characterized effect on gene expression. This framework can be further expanded to other epigenetic markers. Such an expansion could have two main advantages. The first advantage is the potential improvement of clustering quality. The second consists in better deciphering the combinatorial trends of epigenetic changes and their effects on gene expression dynamics.\n\nSource code, Data and Interactive Notebook available at: https://github.com/QwertyJacob/DeepReGraph. Archived source code, data and notebook at time of publication: https://doi.org/10.5281/zenodo.6416055\n\nData are available under the terms of the Apache License, Version 2.0",
"appendix": "Acknowledgements\n\nThe authors wish to thank Prof. L. Casasús and Dr. Raúl P. Caulier for their valuable insights.\n\n\nReferences\n\nGorkin DU, Barozzi I, Zhao Y, et al.: An atlas of dynamic chromatin landscapes in mouse fetal development. Nature. July 2020; 583(7818): 744–751. PubMed Abstract | Publisher Full Text\n\nPagiatakis C, Musolino E, Gornati R, et al.: Epigenetics of aging and disease: a brief overview. Aging Clin. Exp. Res. April 2021; 33(4): 737–745. PubMed Abstract | Publisher Full Text\n\nZboril E, Yoo H, Chen L, et al.: Dynamic interactions of transcription factors and enhancer reprogramming in cancer progression. Front. Oncol. September 2021; 11: 0 753051. PubMed Abstract | Publisher Full Text\n\nWittkopp PJ, Kalay G: Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nat. Rev. Genet. December 2011; 13(1): 59–69. PubMed Abstract | Publisher Full Text\n\nMcDowell IC, Manandhar D, Vockley CM, et al.: Clustering gene expression time series data using an infinite gaussian process mixture model. PLoS Comput. Biol. January 2018; 14(1): e1005896. PubMed Abstract | Publisher Full Text\n\nÖzgül OF, Bardak B, Tan M: A convolutional deep clustering framework for gene expression time series. IEEE/ACM Trans. Comput. Biol. Bioinform. November 2021; 18(6): 2198–2207. PubMed Abstract | Publisher Full Text\n\nSun S, Liang M, Dong Z, et al.: Multiview Machine Learning. Springer; January 2019.\n\nNguyen ND, Wang D: Multiview learning for understanding functional multiomics. PLoS Comput. Biol. April 2020; 16(4): e1007677. PubMed Abstract | Publisher Full Text\n\nLi Y, Fang-Xiang W, Ngom A: A review on machine learning principles for multi-view biological data integration. Brief. Bioinform. March 2018; 19(2): 325–340. PubMed Abstract | Publisher Full Text\n\nStanley JS 3rd, Gigante S, Wolf G, et al.: Harmonic alignment. Proc. SIAM Int. Conf. Data Min. 2020; 2020: 316–324. PubMed Abstract | Publisher Full Text\n\nLiu J, Huang Y, Singh R, et al.: Jointly embedding multiple single-cell omics measurements. Algorithms Bioinform. September 2019; 143.\n\nStuart T, Butler A, Hoffman P, et al.: Comprehensive integration of Single-Cell data. Cell. June 2019; 177(7): 1888–1902.e21. PubMed Abstract | Publisher Full Text\n\nArgelaguet R, Arnol D, Bredikhin D, et al.: MOFA+: a statistical framework for comprehensive integration of multi-modal single-cell data. Genome Biol. May 2020; 21(1): 111. PubMed Abstract | Publisher Full Text\n\nYuan Y, Bar-Joseph Z: Deep learning for inferring gene relationships from single-cell expression data. Proc. Natl. Acad. Sci. U. S. A. December 2019; 116: 27151–27158. PubMed Abstract | Publisher Full Text\n\nEraslan G, Avsec Ž, Gagneur J, et al.: Deep learning: new computational modelling techniques for genomics. Nat. Rev. Genet. July 2019; 20(7): 389–403. Publisher Full Text\n\nAmodio M, Krishnaswamy S: MAGAN: Aligning biological manifolds. Dy J, Krause A, editors. Proceedings of the 35th International Conference on Machine Learning, volume 80 of Proceedings of Machine Learning Research. PMLR; 2018; pages 215–223.\n\nYang KD, Belyaeva A, Venkatachalapathy S, et al.: Multi-domain translation between single-cell imaging and sequencing data using autoencoders. Nat. Commun. January 2021; 12(1): 31. Publisher Full Text\n\nXi J, Yu Z: Unsupervised Learning Models for Unlabeled Genomic, Transcriptomic & Proteomic Data. Frontiers Media SA; January 2022.\n\nHuang Y-A, Pan G-Q, Wang J, et al.: Heterogeneous graph embedding model for predicting interactions between TF and target gene. Bioinformatics. March 2022; 38: 2554–2560. PubMed Abstract | Publisher Full Text\n\nWang X, Gong Y, Yi J, et al.: Predicting gene-disease associations from the heterogeneous network using graph embedding. 2019 IEEE International Conference on Bioinformatics and Biomedicine (BIBM). November 2019; pages 504–511.\n\nZhou K, Zhang S, Wang Y, et al.: High-quality gene/disease embedding in a multi-relational heterogeneous graph after a joint matrix/tensor decomposition. J. Biomed. Inform. February 2022; 126: 103973. Publisher Full Text\n\nNourani E: GoVec: Gene ontology representation learning using weighted heterogeneous graph and Meta-Path. J. Comput. Biol. December 2021; 28(12): 1196–1207. PubMed Abstract | Publisher Full Text\n\nRao A, Vg S, Joseph T, et al.: Phenotype-driven gene prioritization for rare diseases using graph convolution on heterogeneous networks. BMC Med. Genet. July 2018; 11(1): 57. PubMed Abstract | Publisher Full Text\n\nMei X, Cai X, Yang L, et al.: Relation-aware heterogeneous graph transformer based drug repurposing. Expert Syst. Appl. March 2022; 190: 116165. Publisher Full Text\n\nHamilton WL: Graph Representation Learning. Morgan & Claypool Publishers; September 2020.\n\nLi X, Zhang H, Zhang R: Adaptive graph Auto-Encoder for general data clustering. IEEE Trans. Pattern Anal. Mach. Intell. 2021; 1–1. Publisher Full Text\n\nWu T, Hu E, Xu S, et al.: clusterprofiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (N Y). August 2021; 2(3): 100141. PubMed Abstract | Publisher Full Text\n\nHeinz S, Benner C, Spann N, et al.: Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell. May 2010; 38(4): 576–589. Publisher Full Text\n\nRoss-Innes CS, Stark R, Teschendorff AE, et al.: Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. January 2012; 481(7381): 389–393. Publisher Full Text\n\nLiao Y, Smyth GK, Shi W: The R package rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads. Nucleic Acids Res. May 2019; 47(8): e47. PubMed Abstract | Publisher Full Text\n\nErnst J, Nau GJ, Bar-Joseph Z: Clustering short time series gene expression data. Bioinformatics. June 2005; 21 Suppl 1: i159–i168. PubMed Abstract | Publisher Full Text\n\nHolmes SH, Huber W: Modern Statistics for Modern Biology. Cambridge University Press; 2018.\n\nYi B, Wang X, Li K, et al.: A comprehensive survey of network function virtualization. Comput. Netw. March 2018; 133: 212–262. Publisher Full Text\n\nShi C, Wang X, Yu PS: Heterogeneous Graph Representation Learning and Applications. Singapore: Springer; January 2022.\n\nChen F, Wang Y-C, Wang B, et al.: Graph representation learning: a survey. APSIPA Transactions on Signal and Information Processing. 2020; 9. Publisher Full Text\n\nYi H-C, You Z-H, Huang D-S, et al.: Graph representation learning in bioinformatics: trends, methods and applications. Brief. Bioinform. September 2021.\n\nXie Y, Bin Y, Lv S, et al.: A survey on heterogeneous network representation learning. Pattern Recogn. August 2021; 116: 107936. Publisher Full Text\n\nHamilton WL, Ying R, Leskovec J: Representation learning on graphs: Methods and applications.September 2017.\n\nZheng B, Sage M, Sheppeard EA, et al.: Engineering mouse chromosomes with Cre-loxP: range, efficiency, and somatic applications. Mol. Cell. Biol. January 2000; 20(2): 648–655. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMora A, Sandve GK, Gabrielsen OS, et al.: In the loop: promoter–enhancer interactions and bioinformatics. Brief. Bioinform. November 2015; 17(6): 980–995. PubMed Abstract | Publisher Full Text\n\nDong X, Weng Z: The correlation between histone modifications and gene expression. Epigenomics. April 2013; 5(2): 113–116. PubMed Abstract | Publisher Full Text\n\nBaldi P: Autoencoders, unsupervised learning, and deep architectures. Guyon I, Dror G, Lemaire V, et al., editors. Proceedings of ICML Workshop on Unsupervised and Transfer Learning, volume 27 of Proceedings of Machine Learning Research. Bellevue, Washington, USA: PMLR; July 2012; pages 37–49.\n\nGilmer J, Schoenholz SS, Riley PF, Vinyals O, et al.: Neural message passing for quantum chemistry. Precup D, Teh YW, editors. Proceedings of the 34th International Conference on Machine Learning, volume 70 of Proceedings of Machine Learning Research. PMLR; 2017; pages 1263–1272.\n\nKramer O: K-Nearest neighbors. Kramer O, editor. Dimensionality Reduction with Unsupervised Nearest Neighbors. Berlin Heidelberg, Berlin, Heidelberg: Springer; 2013; pages 13–23.\n\nKapoor R, Gupta R, Son LH, et al.: Boosting performance of power quality event identification with KL divergence measure and standard deviation. Measurement. October 2018; 126: 134–142. Publisher Full Text\n\nWu Z, Pan S, Chen F, et al.: A comprehensive survey on graph neural networks. IEEE Trans Neural Netw Learn Syst. January 2021; 32(1): 4–24. Publisher Full Text\n\nOskolkov N: How exactly umap works.Nov 2019. Reference Source\n\nMcInnes L, Healy J, Melville J: UMAP: Uniform manifold approximation and projection for dimension reduction.February 2018.\n\nSchlichtkrull M, Kipf TN, Bloem P, et al.: Modeling relational data with graph convolutional networks. The Semantic Web. Springer International Publishing; 2018; pages 593–607.\n\nMarcheggiani D, Titov I: Encoding sentences with graph convolutional networks for semantic role labeling.March 2017.\n\nSinha K, Sodhani S, Dong J, et al.: CLUTRR: A diagnostic benchmark for inductive reasoning from text.2019.\n\nZhou S, Jiajun B, Wang X, et al.: HAHE: Hierarchical attentive heterogeneous information network embedding.January 2019.\n\nYang B, Xiao F, Sidiropoulos ND, et al.: Towards k-means-friendly spaces: Simultaneous deep learning and clustering. Precup D, Teh YW, editors. Proceedings of the 34th International Conference on Machine Learning, volume 70 of Proceedings of Machine Learning Research. PMLR; 2017; pages 3861–3870.\n\nSadeghi M, Armanfard N: Deep clustering with self-supervision using pairwise data similarities.June 2021.\n\nErnst J, Kellis M: ChromHMM: automating chromatin-state discovery and characterization. Nat. Methods. February 2012; 9(3): 215–216. PubMed Abstract | Publisher Full Text\n\n\nFootnotes\n\n1 https://github.com/QwertyJacob/DeepReGraph"
}
|
[
{
"id": "160538",
"date": "02 Feb 2023",
"name": "Wanding Zhou",
"expertise": [
"Reviewer Expertise Epigenetics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe submission described a new method based on graph representation learning for co-clustering gene expression and cis-regulatory elements activity. The method seems innovative, and the code is made available in a public notebook with friendly documentation. The paper is math-heavy. Some extra details on biological intuition would make the paper more accessible to the broad biology audience. Some minor comments/questions below.\nFirst, when a gene becomes clustered with cCREs based on the method, how often is the cCRE regulating the gene? What's the edge semantics of the graph clustering? Is any proximity information used to link the genes and cCREs? Some cCRE and target links have been well established using experimental approaches such as massively parallel reporter assays. Can these data be used to validate the reported clustering?\nThe authors found that smaller gene expression clusters are associated with more cCRE per gene (Figure 3). Is it due to interactions from different cCREs in regulating gene expression and causing the expression profile to be more distinct than genes regulated by single or few cCREs?\nThe authors found that different epigenetic profiles may be associated with the same gene expression profile. But hasn't association defined those clusters in the first place? For example, clusters 1 and 4 have similar gene expression trends; why would they be associated with more different cCRE activities?\nFigure 4, clusters 2,4,5,6 all have MEF2. Should those clusters be merged into one cluster?\n\nThe author claims that MEF2 binding is driving the expression of the gene. What are the evidences/literature to support this claim?\n\nIs the rationale for developing the new method (or application) clearly explained? Partly\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Yes\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
},
{
"id": "207300",
"date": "10 Oct 2023",
"name": "Tallulah Andrews",
"expertise": [
"Reviewer Expertise Bioinformatics",
"Single-cell Expression",
"Spatial Transcriptomics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present a novel model for the integration of multimodal -omics data to generate a joint lower dimensional embedding based on potential regulatory interactions by incorporating temporal similarity in their activity levels and positional information within the genome and fed through a sparse graph autoencoder. They demonstrate their model on the ENCODE fetal heart development dataset. While the method is interesting and innovative, the authors do not present any benchmarking or comparisons to existing tools thus we’re uncertain whether the added computational complexity of their approach results in a significant improvement in predictive or interpretability of outcomes over existing approaches such as graph clustering (e.g. Louvain/Leiden, Infomap) or dimensionality reduction methods such as MOFA or NMF.\nMajor Concerns The authors do not compare their method to any other alternative methods of GRN inference or multimodal analysis : e.g. MOFA, Non-negative Matrix factorization, Leiden/Louvain clustering.\nIt’s unclear from the application to the ENCODE data whether the method manages to identify true GRN relationships or if they are false positives.\nThe manuscript lacks sufficient details of the methodology of the downstream analysis (e.g. GO enrichment - e.g. what background was used? All genes or only the 607 genes the authors included in the model?, TF motif enrichments, and the k-means clustering of the CRE-only data - how was this done on preprocessed data or after PCA?)\nIn Equation 1, what are the Beta hyper parameter values? Since base-pair distances were scaled to 0-1, I would expect the “+1” in this equation to dominate and the variance of base-pair similarities to be extremely small which is not at all representative of what actually happens in the genome where the probability of regulation rapidly declines as base pair distance increases (1/d^2) so that nearby cCREs would be much more likely to regulate a gene than distant ones. What was the author's rationale for calculating the base-pair similarities in this way?\nWhy did the authors exclude the vast majority of genes and cCREs from their analysis? They filter to only the 80th/70th percentile of most likely detected genes/cCREs, however they don’t seem to account for proximity in this filtering, so isn’t it likely that the gene(s) regulated by any particular cCRE they are considering have been filtered out of their dataset? And vice versa for the CREs that regulate any particular gene under consideration? Since the strength/probability of regulation is so strongly related to proximity in the genome, wouldn’t it make more sense to include both the most highly detected genes/CREs and their most proximal CREs/genes regardless of the latter’s detection level?\n\nCould the authors elaborate on how they determined the optimal values of wm in Equation 2 for each of their data types? H3K27me3 is a repressive transcriptional mark thus I would expect a wm = -1, while H3K27ac is an activating transcriptional mark, thus I would expect a wm=1. Does their finding that wm for methylation/acetylation is best set at 0 indicate that these datasets are far less informative of CRE relationships than ATACseq?\nIn Equation 11, why did the authors define the similarity between any gene and any CRE to be 1, while similarity between pairs of genes or pairs of CREs are always <=1. Why didn’t they use their SBP|T similarity for gene-CRE pairs? Also in this equation the authors rescale the Euclidean distances to [0,1], and then reverse them: 1-d to get similarities. Why not simply use a correlation instead? Also they call D_hat a unique distance function but it is calculated as 1-d so isn't it is a similarity function not a distance?\nMinor Concerns\nResults provided in the paper are not reproducible using the provided Ipython notebook file on the linked github page. From the ipynb: The manual_run() function in cell 4 and 5 gives an error. max_epoch and alpha_D are all unexpected keyword arguments. They are not also defined in the manual_run() function in the DeepReGraph.py file\nFig 2B. It’s hard to interpret this confusion matrix, please include a summary statistic such as ARI (Adjusted Rand Index) that is more interpretable.\nFig 4A. A) Enriched function of gene expression extracted from DeepReGraph clusters. Why is the number of genes used for gene enrichment is less than those shown in Fig3A?\nShouldn't cluster 2 and 4 be the same (in Figure 3&4)? Since they share the same enriched GO:BP (except 1 in cluster 4). How many genes/CREs are significantly different between these clusters?\nHow long does the tool take to run the tool and why was it necessary to scale it down to a such a small number of genes (607genes) and CREs?\nAre any of the regulatory relationships identified by DeepReGraph on the fetal heart dataset known regulatory relationships in the literature? Are GATA/MEF2/TBX known to be important in heart development?\n\nIs the rationale for developing the new method (or application) clearly explained? Yes\n\nIs the description of the method technically sound? Yes\n\nAre sufficient details provided to allow replication of the method development and its use by others? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-518
|
https://f1000research.com/articles/11-517/v1
|
13 May 22
|
{
"type": "Research Article",
"title": "Development and optimization of orally disintegrating tablets containing Centella asiatica solid lipid nanoparticles for supportive therapies of Parkinson's disease",
"authors": [
"Husnul Khotimah",
"Aulanni'am Aulanni'am",
"Shahdevi Nandar Kurniawan",
"Oktavia Eka Puspita",
"Oktavia Rahayu Adianingsih",
"Mardhiyah Mardhiyah",
"Andri Setiawan",
"Aulanni'am Aulanni'am",
"Shahdevi Nandar Kurniawan",
"Oktavia Eka Puspita",
"Oktavia Rahayu Adianingsih",
"Mardhiyah Mardhiyah",
"Andri Setiawan"
],
"abstract": "Background: Parkinson's disease (PD) is the most common chronic progressive neurodegenerative disorder in the older population. In this work, we have developed a formulation of orally disintegrating tablets (ODTs) containing Centella asiatica (CA) encapsulated solid lipid nanoparticles (SLNs) with rapid disintegration and dissolution, thereby providing greater convenience and ease of use to older patients with PD or dysphagia. Methods: The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of CA compounds were evaluated using QikProp module of Schrödinger. CA-SLNs were prepared using hot homogenization method. The physicochemical properties and quality control of the pre-compressed powder were characterized. The direct compression method was used to prepare ODTs, and post-compression physical properties were evaluated. Results: In silico study of ADMET properties revealed the CA compounds can follow the criteria for an orally active drug and are within the standard range in terms of \"Rule of Five\" and \"Rule of Three”. The characteristics of CA-SLNs developed in a lipid-based nanocarrier showed monodispersed particles with an average particle size of about 37.91±1.55 nm, zeta potential of -10.27±1.37 mV, encapsulation efficiency, and loading capacity of 95.07±1.14%, and 3.99±0.06%, respectively. The results obtained for the pre-compression characterization showed that the CA-SLNs powder mixture had excellent flowability properties and compressibility. Furthermore, these results affected the physical properties of CA-SLNs ODTs with a disintegration time of 14.5s, the acceptance value of content uniformity was 3.2%, and the in vitro dissolution test fulfilled the tolerance limits recommended in the United States Pharmacopeia (USP) monograph. Conclusions: Overall, these results suggest that CA-SLNs ODTs developed with lipid-based nanocarriers can be considered an alternative delivery system to protect the active compound from instability while enhancing permeability through the blood brain barrier (BBB) and can be used in the management of PD in older patients with dysphagia.",
"keywords": [
"Orally disintegrating tablets",
"Solid lipid nanoparticles",
"ADMET properties",
"Centella asiatica",
"Parkinson's disease"
],
"content": "Introduction\n\nNeurodegenerative disorders describe the progressive loss of structure or function of neurons, including neuronal cell death.1 Parkinson’s disease (PD) is the second most common chronic and progressive neurodegenerative disorder after Alzheimer’s disease (AD) that affects body movement, called progressive because the disease develops gradually and worsens over time. In addition, this disease also has a significant impact on several communities, both socially and economically for the sufferer.2 Clinical pathology and diagnosis of PD revealed loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies containing α-synuclein. The deficiency of dopaminergic neurons inhibits some motor functions, manifesting in tremor, rigidity, bradykinesia, and akinesia.3 PD therapy with a compensatory approach compensates for the effects of dopaminergic neuronal deficits targeting clinical and ongoing symptomatic treatment to manage PD, and levodopa is considered the gold standard for treating PD. In addition, alternatives are used to treat PD to slow or stop the progression of diseases monoamine oxidase-B (MAO-B)-inhibitors, Catechol-O-methyltransferase (COMT), dopamine antagonist, A2a antagonist, anticholinergics and glutamatergic.4 Current treatment strategies and recommendations in managing PD, including pharmacotherapy and supportive therapy, only relieve symptoms with serious side effects. While complementary and alternative medicine, including traditional medicine, is considered to have the ability to protect neurons and reduce side effects efficiently.5,6\n\nCentella asiatica (L.) Urb. (CA) is a herbal medicinal plant with high product value.7 This plant which is commonly known in Indonesia as Pegagan has been used in traditional medicine, its ethnopharmacology applications are wide in various cultures and countries, besides its biological effects have been proven in multiple studies.8 The main chemical component of CA responsible for pharmacological activity is triterpene, consisting mainly of asiaticoside, asiatic acid, madecassoside, and madecassic acid.9 Several pharmacokinetic studies have confirmed that the bioactive compounds of CA provide neuroactive effects that have potential for use as neurotherapy. In a recent study by Hanapi et al. (2021), asiatic acid, asiaticoside, and madecassoside have high permeability and can cross the blood brain barrier (BBB).10 Bioactive components of CA also exert cognitive effects in aging and neurodegenerative diseases,11 where bioactive CA has been shown to protect against hippocampal dysfunction and improved cognitive performance in rat models.12 Neuroprotective effects have also been found in the bioactive component of CA in several disease models; CA extract was able to protect rotenone-induced parkinsonism rats against lipid peroxidation, dopaminergic neuronal death, and locomotor deficits13; CA stimulates nuclear factor erythroid 2–related factor 2 (Nrf2)-mediated antioxidant response and reduces oxidative stress contributing to improved neurologic health in AD model mice14; in addition, the antioxidant properties of asiaticoside were shown to increase the stability of the neurotransmitter dopamine and decrease α-synuclein aggregation in rotenone-induced PD zebrafish.15 CA has been shown to have anti-inflammatory effects; in a study by Qian et al. (2018) reported that asiatic acid effectively prevents lipopolysaccharide (LPS)-induced neuroinflammation in microglial cell line by increasing Sirtuin 1 (Sirt1) expression, attenuating inducible nitric oxide synthase (iNOS) expression and reducing inflammatory cytokine expression16; asiatic acid was shown to protect BV2 cells from LPS-induced damage by suppressing NLR family pyrin domain containing 3 (NLRP3) expression and ameliorating mitochondrial dysfunction.17 It is well known that triterpenoids from CA have beneficial effects on neurological and skin diseases, confirmed through clinical studies.18,19 However, the main compounds from CA, such as asiaticoside and madecassoside, show limited water solubility and usually have low absorption, so their oral bioavailability is low.9 Therefore, in this study, we evaluated absorption, distribution, metabolism, excretion, and toxicity (ADMET) using in silico research and developed a lipid-based nanocarrier as an ideal CA delivery system for oral administration, thereby increasing its bioavailability and effectiveness for the therapy of neurodegenerative diseases.\n\nParallel with developments in nanomedicine, lipid-based nanocarriers can be categorized based on their physicochemical properties and the manufacturing process consisting of liposomes, transferosomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs).19,20 SLNs is a lipid-based nanocarrier system that is widely explored for targeted drug delivery into the brain,21 with its relatively small particle size making it efficient and causing an increase in the surface area of insoluble drug particles, which in turn results in increased absorption through monolayer cells of the gastrointestinal (GI) tract.22 In addition, SLNs are an alternative in drug delivery systems with considerable advantages; they have good physical stability, increase the solubility and bioavailability of hydrophobic drugs23; high drug loading capacity of hydrophilic or lipophilic drugs24; protects sensitive active drug, and allows controlled drug release25; they are produced from physiological, biocompatible and biodegradable lipids with less or no biotoxicity making them safe and feasible for large-scale production at low cost.26 SLNs have lipophilic properties, and their small size makes them efficient in drug delivery to the central nervous system (CNS) by prolonging their circulation time in the blood and making them more effective across the BBB.27 In addition, SLNs are used as vehicles in delivering curcumin through the BBB to the brain, which is practical and potential for treating brain diseases, particularly AD and PD.28 SLNs have lipophilic features and appropriate size, so they are colloidal drug carriers easily penetrate the CNS.29 Therefore, drugs encapsulated in SLNs, which are further formulated in capsules or tablets, can be a successful attempt to reduce erratic absorption, increase bioavailability, and enhance lymphatic uptake.30\n\nThe most common oral formulations developed in the pharmaceutical industry are tablets or capsules because of their easy administration, flexibility, and compactness in manufacture.31 However, older adults, children, and patients with symptoms of dysphagia such as PD usually experience discomfort in drinking water that causes coughing and difficulty swallowing.32 Orally disintegrating tablets (ODTs) are described as solid dosage forms that have rapid disintegration and dissolution even in the presence of less saliva in the oral cavity and provide greater convenience and ease of use to improve adherence in elderly and geriatric patients. In addition, ODTs also have advantages such as good stability, easy manufacture and administration, fast drug absorption, and increased bioavailability.33,34 Direct compression is the most straightforward and most economical method of manufacturing ODTs where the active pharmaceutical ingredients (API) are only mixed with excipients which are then compressed into tablets. Despite the simplicity of the direct compression process, the excipient must meet some additional requirements as a particular product to be marketed as a global tablet, such as adequate flowability, compressibility, and compaction ability.35 A recent study by Zhang et al. (2020) reported that direct compression technology used in levodopa or benzylhydrazine ODTs had been successfully optimized with a relatively short disintegration time and fast dissolution profile, thus providing ease of use for Parkinson’s patients.32\n\nThe fact that nanoencapsulated CA-SLNs ODTs can be rapidly disintegrated in the mouth, further enhancing their absorption and bioavailability, makes it a good prospect for oral application, so the research is essential. This study aimed to develop a formulation of ODTs containing nanoencapsulated CA-SLNs with lipid-based nanocarriers as an oral delivery system, rapid disintegration, and dissolution, thereby providing greater convenience and ease of use to PD or dysphagia patients. ADMET prediction was used to evaluate the parameters of the physicochemical properties of CA compounds. Particle size, polydispersity index, zeta potential, and encapsulation efficiency of CA-SLNs were characterized to determine the physicochemical properties of the optimized lipid-based nanocarriers, and pre-compression properties of CA-SLNs powders such as flow time, angle of repose, bulk density, tap density, Hausner ratio, compressibility index, and moisture content were analyzed. Post-compression properties such as weight variation hardness, friability, wetting time, water absorption ratio, disintegration time, and content uniformity of the manufactured CA-SLNs ODTs were evaluated to obtain good quality tablets.\n\n\nMethods\n\nThis study represents a development of CA-SLNs ODTs with several advantages that will be used as supportive therapy in Parkinson’s disease, and in this experiment did not involve live subjects (humans or animals), so the Ethical Committee, Faculty of Medicine, Universitas Brawijaya, Indonesia confirmed that no ethical approval was required. This experiment took place at the Pharmaceutical Science Laboratory, Faculty of Medicine, Universitas Brawijaya, from August 9 to December 20, 2021.\n\nTo predict the ADMET profiles of active compound CA such as asiatic acid (CID_119034), asiaticoside (CID_108062), madecassic acid (CID_73412), and madecassoside (CID_161823) were obtained from PubChem, and used the in silico method with the QikProp v6.4 module, Schrödinger, 2020-236 to determine the physicochemical parameters. In addition, several alternative open access in silico tools that can predict ADMET profiles and drug-likeness that academicians and industries most frequently use are ADMETlab, admetSAR, SwissADME, FAF-Drug, and TOPKAT.\n\nCertified CA with 0.29% asiaticoside content obtained from UPT Material Medica Batu City, East Java, Indonesia. Briefly, fresh CA leaves were made into powder by washing, cutting, drying, and crushing. Furthermore, 100 g of CA powder was extracted by maceration method for 24 hours in 900 mL of 96% v/v ethanol. The CA solvent was evaporated at 45°C at low pressure using a rotary evaporator (Büchi Rotavapor R-300 System B-301, Switzerland). Then the filtrate was evaporated and maintained at -20°C. The CA extract obtained was stored in a dark and dry place until needed.\n\nCA-SLNs were prepared by hot homogenization method. Briefly, stearic acid (50 g) was melted in a glass vial with a magnetic stirrer at 80°C. Then the CA extract was dissolved in liquid lipid and stirred until homogeneous, and formed a lipid phase. The aqueous phase consisting of tween 80 and PVP K-30 was dissolved in 200 mL of distilled water and brought to a temperature of 100°C. Keeping the respective temperatures, the lipid phase was added to the aqueous phase and homogenized with a high-performance homogenizer (Ultra-Turrax® T25, IKA, Germany) at 25,000 rpm for 5 minutes. Thus, a suspension of CA-SLNs was obtained, and the results were stored at room temperature. The CA-SLNs were then dried by adding aerosil at a ratio of 1:4 (1g CA-SLNs added 4g aerosil) and stirred to produce a powder.\n\nThe dynamic light scattering (DLS) technique by Malvern Zetasizer (Zetasizer Nano ZS-90, Version 7.01 Malvern Instruments Ltd, UK) assessed particle size distribution profiles. DLS measurements were used to determine the mean particle size, polydispersity index, and zeta potential at a fixed scattering angle of 90° at 25°C. CA-SLNs were suspended in distilled water and then vortexed. The dispersion was diluted with deionized water, and 1 mL of this sample was taken in a single-use plastic cuvette for measurement. The particle size distribution and polydispersity index were obtained from the ZetaSizer Nano software (ZetaSizer, Version 7.01, Malvern Panalytical, Malvern, UK), while the zeta potential was measured by electrophoretic light scattering. Analysis was performed in triplicate and presented as mean ± standard deviation.\n\nThe encapsulation efficiency (EE) and loading capacity (LC) were analyzed by ultrafiltration using a centrifugal ultrafiltration tube (Amicon® Ultra-4 10 kDa cut-off filter, Millipore, Billerica, MA, USA). Briefly, CA-SLNs were dissolved in sufficient quantities from phosphate buffer pH 6.8 and then filtered. An aliquot (1 mL) of CA-SLNs was placed in a centrifuge tube and centrifuged at 4000 rpm for 8 min at room temperature using a centrifuge (Centrifuge Z 327 K, Hermle Labortechnik GmbH, Wehingen, Germany). The concentration of CA-SLNs un-encapsulated in the filtrate was further determined by measuring the absorbance with ultraviolet (UV) spectrophotometry (UV-1601 spectrophotometer, Shimadzu Corporation, Kyoto, Japan) at 272.2 nm. Analysis was performed in triplicate and presented as mean ± standard deviation (SD). EE and LC are expressed in percentages calculated according to Equations 1 and 2;\n\nwhere Wtotal is the total weight of CA in SLNs, Wfree is the weight of free CA in SLNs, and Wlipid is the lipid weight in SLNs.\n\nCA-SLNs ODTs were prepared by the direct compression method. Croscarmellose is used as a superdisintegrant. The composition of the various formulations is shown in Table 1. All ingredients were sieved to produce 30 mesh separately, then weighed according to the required weight, and all except magnesium stearate were stirred homogeneously for 5 minutes. The mixture was then lubricated with magnesium stearate and mixed for 3 minutes. After that, the powder mixture was compressed into tablets using a single punch tablet machine (Tablet Press EP-1, Erweka, Heusenstamm, Germany), with a total weight of each tablet of 450 mg.37\n\nFlow times, angle of repose, and moisture content\n\n25 g of pre-compressed powder was put into Flodex Tester (Powder flowability tester Flodex™, Hanson Research, USA) to evaluate its flow times and angle of repose as well. The flow time was measured by dividing the sample mass by the time needed to flow through Flodex Tester orifice completely.37 The angle of repose was calculated using Equation 3;\n\nwhere h is the height of mass powder the flow through Flodex Tester orifice, and r is the radius formed by mass powder.\n\n25 g of pre-compressed powder was introduced into a moisture analyzer (MB23, Ohaus Corporation, Shanghai, China) to evaluate the moisture content.\n\nBulk and tap density, compressibility index, and Hausner ratios\n\n100 mL Vb of pre-compressed powder was put into a graduated cylinder which was weighed.37 After the pre-compressed powder weight m (g) is determined, the bulk density ρb (g/cm3) is calculated using Equation 4;\n\nAfter that, the pre-compressed powder was put into a 250 mL graduated cylinder, tapped gently until the powder volume stabilized, and the tapped volume Vt (mL) was recorded.37 The tap density ρt (g/cm3) was calculated using Equation 5;\n\nThe compressibility index and Hausner’s ratio were also calculated from bulk density and tap density to assess flowability using Equations (6) and (7), respectively.\n\nHardness test\n\nThe hardness test (newton, N; n=10) of randomly selected tablets from each formulation was tested using a tablet hardness tester (Tablet Hardness Tester HC6.2, Charles Ischi AG, Testing Technology, Switzerland). Results are presented as mean ± standard deviation.38\n\nWeight variation\n\nOverall, 20 individual tablets selected randomly from each formulation were weighed using an analytical balance of ±0.0002 g (Ohaus Pioneer PX224/E Analytical Balance, Ohaus Corporation, Parsippany, USA). Weight variation was evaluated by considering the standard deviation of tablet weight. Results are presented as mean ± standard deviation.39\n\nFriability test\n\nThe friability test was carried out on 20 tablets selected randomly from each formulation, then weighed accurately (Wi) and put into the friability tester (AE-1 Friability + Abrasion Tester, Charles Ischi AG, Testing Technology, Switzerland), rotated at 25 rpm for 4 minutes. The tablets were de-dusted and weighed accurately (Wf).37 Friability (%) was calculated using Equation 8:\n\nWetting time, water absorption ratio, and disintegration time\n\nThe filter paper was folded twice and placed in a 6.5 cm diameter Petri dish containing 6 mL of distilled water with methylene blue. The tablet is placed on the paper, and the time taken for wetting is recorded t(s).37 Then the wet tablets were weighed again, and the water absorption ratio R (%) was calculated using Equation 9;\n\nwhere m1 is mass of tablet before wetting (g), m2 is mass of tablet after wetting (g), and R is water absorption ratio (%).\n\nThe disintegration times tests were performed on six tablets selected at random from each formulation and determined in 750 mL distilled water at 37 ± 1°C using a disintegration tester (Erweka ZT301, Heusenstamm, Germany). The tablet was considered completely disintegrated when all the particles passed through the screen.37 The disintegration time of individual tablets was recorded, and the mean ± standard deviation was reported.\n\nDrug content uniformity\n\nThe content uniformity test was carried out on ten tablets selected at random from each formulation and weighed, then suspended in 100 mL of a mixture of methanol: ultrapure water (50:50, v/v). Each sample was filtered through a PVDF filter and analyzed in triplicate (n=3) using a UV-Vis Spectrophotometer (UV-1800, Shimadzu Corporation, Kyoto, Japan) at 291 nm. The acceptance value (VA) was calculated using Equation 10;\n\nwhere M is the label claim (%), X is the measured content of CA or CA-SLNs, k is the acceptability constant (2.4), and s is the standard deviation.39\n\nDissolution study\n\nThe in vitro dissolution test on six tablets was randomly selected using the USP dissolution apparatus II (Erweka DT 708, Heusenstamm, Germany). The tablet assay was carried out in 900 mL of phosphate buffer pH 6.8 adjusted at 37 ± 0.5°C (pH, 6.8 ± 0.05), with the paddle rotated at 50 rpm for 45 minutes. Each sample of dissolution media was taken 3 mL with predetermined time intervals (2, 5, 10, 15, 30, 45, and 60 minutes) and filtered using a PVDF filter. The samples were analyzed in triplicate (n=3) using a UV-Vis Spectrophotometer (UV-1800, Shimadzu Corporation, Kyoto, Japan) at 291 nm.40\n\nResults are presented as mean ± standard deviation (SD). The results were statistically analyzed with Mann-Whitney U test using SPSS software (SPSS, Version 21.0, IBM Inc. USA, RRID:SCR_016479). When p value was less than 0.05, the difference between the results was considered significant.\n\n\nResults\n\nTo improve the quality control of the active compound as a drug and explain its ability to reach the target protein, we predicted the ADMET of the active compound CA by in silico method. Computational approaches are beneficial in drug design to reduce costs and time and minimize failure in the clinical stage. This study used QikProp v6.4 module of Schrödinger, 2020-2 to predict ADMET and physicochemical properties of active compounds CA (asiatic acid, asiaticoside, madecasic acid, and madecasoside). Jorgensen’s “Rule of Three” and Lipinski’s “Rule of Five” predict the physical properties, relevant properties, and similar features of drugs as pharmaceutical products. The expected parameters and recommended values are summarized in Table 2, which shows that all parameters are generally within the standard range and slightly violate the abovementioned rules.41\n\n* Indicates a violation of the 95% range.\n\nThe physicochemical properties of CA compounds nanoencapsulated in SLNs using the hot homogenization method are summarized in Table 3. The prepared nanoencapsulated CA-SLNs with lipid-based nanocarriers showed a relatively uniform mean particle size distribution in the range of 37.91 ± 1.55 nm to 54.83 ± 1.40 nm with a polydispersity index ranging from between 0.14 ± 0.01 to 0.19 ± 0.01, the low polydispersity index value < 0.2 indicates that the particle size distribution is narrow and homogeneous with low variability from all formulations. Moreover, the negative zeta potential values ranged from -12.72 ± 0.69 mV to -10.27 ± 1.37 mV, indicating that the developed SLNs were stably dispersed without a tendency to aggregate. EE and LC were analyzed to evaluate whether CA can achieve high active loads and determine the amount incorporated in the lipid nanoparticles. All formulations were characterized by EE and LC ranging from 90.59 ± 1.63% to 95.07 ± 1.14%, and 3.99 ± 0.06% to 4.13 ± 0.06%, respectively. The very high EE values of all formulations indicated that functionalization did not affect the ability to incorporate CA in lipid nanoparticles efficiently. Overall, these results indicate that the CA-SLNs pre-formulation process used in this work is effective.\n\nThe physical pre-compression properties of the prepared ODTs powders (CA extracts and CA-SLNs) were evaluated to determine the bulk and tap density, powder flow (flow through an orifice, angle of repose, compressibility index, Hausner ratio), and moisture content as suggested by the Ph. Eur. 10th.37 The flowability of powders is an important property, especially in manufacturing tablets by direct compression method. As displayed in Table 4, all the optimized pre-compressed formulations of CA-SLNs and CA-extract powders showed good to excellent flow times; the results were found in the range of 4.56 ± 0.21 s and 5.05 ± 0.22 s. These results indicate good flowability properties of the powder to be formulated by direct compression method. An angle of repose analysis is carried out to evaluate the frictional force or cohesion between particles, and this test is the simplest in powder pre-compression. Analysis of the angle of repose for all formulations (CA-SLNs and CA extracts) of the optimized pre-compressed powder, the results were found in the range of 25.16 ± 1.47° and 29.16 ± 1.94°, which further supports the good flowability of all mixture. Powders with an angle of repose values in the range of 25-30° exhibit excellent flowability properties.42\n\nThe bulk density and tap density were evaluated to determine the rheological properties of the powder because the preparation, treatment, and storage processes will affect it. The data on bulk density and tap density obtained are very similar ranging from 0.53 ± 0.01 to 0.57 ± 0.01 g/cm3 and 0.65 ± 0.01 to 0.68 ± 0.01 g/cm3, respectively (Table 4). These results indicate that the pre-compressed powders have the same flowability properties. In addition, the compressibility index and the Hausner ratio method were used to predict the flowability characteristics of the powder. The compressibility index measures the stability and bridge strength of the powder, and the Hausner ratio measures the friction between particles, which is used in evaluating the flowability characteristics of the powder. The results showed that the compressibility index value ranged from 8.33 ± 1.50% to 11.83 ± 1.47%, and the Hausner ratio from 1.15 ± 0.01 to 1.17 ± 0.01 (Table 4). Based on the flowability scale in Ph. Eur. 10th, powders with a compressibility index of 1-10% and a Hausner ratio of 1.00-1.11 are considered excellent flow properties.42 This information confirms that the formulation of the optimized pre-compressed powder has excellent flow properties. Besides these values, in the manufacture of quality tablets, the moisture content must also be evaluated and controlled because the moisture content affects the flowability of the powder, when the moisture content is low, then the powder will flow better, in this study, the moisture content ranged from 2.58 ± 0.26% to 3.53 ± 0.32% which further supports good flowability properties.\n\nThe physical characteristics of powder pre-compression (CA-extracts and CA-SLNs) are presented in Table 4, indicating that the powder pre-compression has excellent flowability properties and is suitable for the direct compression method.\n\nAs displayed in Table 5, the physical characteristics of the ODTs formulation developed by direct compression method showed that the weight variation, hardness, friability, wetting time, water absorption ratio, content uniformity, and disintegration time all fulfilled the Ph. Eur. 10th specifications.37 Weight variation is one of the critical variables to ensure drug content uniformity. Table 5 shows the mean tablet weight and standard deviation for all formulations. No statistically significant differences in weight variation values for CA-extracted ODTs and CA-SLNs ODTs were noticed (Table 5, Mann-Whitney U test, p > 0.05), where CA-extract ODTs (F1 is 448.95 ± 1.93 mg), and CA-SLNs ODTs (F2, F3, and F4 are 449.35 ± 1.84 mg, 449.85 ± 1.98 mg, 449.55 ± 1.87 mg, respectively), this shows that the weight variation and standard deviation value in a tablet of less than 2.0 is acceptable with USP 43-NF 38 criteria.39 These results indicate that the obtained ODTs conform to the limits of both weight uniformity and tablet units with a very low coefficient of variation.\n\nBecause tablets prevent the risk of abrasion during packaging, handling, and transportation before use, they must possess optimal mechanical strength. The average hardness of tablet formulations developed by direct compression method is shown in Table 5. There is a significant difference between the hardness values obtained for CA-extracted ODTs and CA-SLNs ODTs (p<0.05). For CA-extracted ODTs it was found to be 24.01 ± 1.43%, and CA-SLNs ODTs (F2, F3 and F4 were 25.97 ± 1.84%, 29.17 ± 1.62 and 26.99 ± 1.54, respectively). According to USP 43-NF 38 (2021), the hardness test of the ODTs should be ≤ 30 N to maintain packaging, handling, and transportation.38 According to this information, the ODTs we developed showed a hardness value of <30 N (Table 5) and had good mechanical strength. They could withstand physical and mechanical stress conditions, also according to the properties of ODTs that rapidly disintegrate in the mouth. Another tablet property related to mechanical strength is friability. As shown in Table 5, all the prepared tablet formulations passed the Ph. Eur. 10th limit test where friability should be <1%.37 The average friability percentage of all tablet formulations (CA-extract ODTs and CA-SLNs ODTs) optimized by direct compression method ranged from 0.56 ± 0.02% to 0.89 ± 0.03%. Friability is related to tablet hardness, as shown in this study, the friability decreased, followed by increasing tablet hardness (Table 5). These results indicate that the developed ODTs formulation has stable mechanical strength during the manufacturing, packaging, and shipping processes.\n\nWetting time is strongly influenced by the composition, structure of the tablet formulation, swelling and wicking effect of the superdisintegrant. Wetting time values of all ODTs formulations are shown in Table 5; there is a significant difference between CA-extracted ODTs and CA-SLNs ODTs (Mann-Whitney U test, p > 0.05), where CA-SLNs ODTs formulations showed wetting time or methylene blue diffusion was approximately (F2, F3, and F4 were 25.66 ± 1.36s, 22.16 ± 1.94s, and 24.33 ± 1.03s, respectively) significantly lower than the CA-extracted ODTs formulations (F1was 27.66 ± 1.03s). This performance will further affect the water absorption ratios of the tablet and the drug release profile. Evaluation of the water absorption ratio found that the CA-SLNs ODTs formulation (F2, F3, and F4 were 58.50 ± 1.87s, 54.50 ± 1.37s, 56.16 ± 1.47s) were significantly lower than the CA-extracted ODTs formulations (F1 was 62.33 ± 1.21s; p < 0.05; Table 5). Wetting time and water absorption ratio are essential parameters for evaluating disintegrant expansion capacity in the presence of small amounts of water. In addition, disintegration time is a critical parameter for determining the optimal formulation of ODTs and distinguishes conventional tablets from ODTs with relatively fast disintegration time. In this experiment, we found that the disintegration time of the CA-SLNs ODTs formulation (15.66 ± 1.36s for F2, 14.50 ± 1.04s for F3, and 15.16 ± 1.16s for F4) was shorter than that of the CA-extracted ODTs formulations (17.33 ± 1.21s for F1) (Table 5). There is a significant difference between the in vitro disintegration times of CA-extracted ODTs and CA-SLNs ODTs (p<0.05). The disintegration time of ODTs set by the FDA (2008) is the 30s, whereas according to the Ph. Eur. 10th, the disintegration time is 180s longer.42,43 This confirms that the ODTs we have developed fulfil the requirements of the FDA and the Ph. Eur. 10th.\n\nThe content uniformity test is a parameter to ensure the homogeneity of the active substance of each unit of the drug dosage form and determine whether the content of each unit is within the specified limits. As shown in Table 5, the content uniformity test of ODTs formulation indicated that the AV value was < 15% for the ten individual unit criteria in the first stage, L1 (USP 43-NF 38).39 The CA-extracted ODTs formulations (F1 was 4.9%), and CA-SLNs ODTs formulation (F2, F3 and F4 were 4.1%, 3.2%, and 3.7%, respectively). In addition, the drug content for all formulations of ODTs developed were within USP 43-NF 38 limits (85-115%),39 where the label claims for CA-extracted ODTs formulations (96.45 ± 1.18% for F1) and CA-SLNs ODTs formulation (97.10 ± 1.13% for F2, 97.98 ± 1.12% for F3, and 97.44 ± 1.11% for F4).\n\nODTs are required for fast-acting dissolution, and the loaded drug must be released within a short period. In this study, phosphate buffer (pH 6.8) was used as a medium to simulate ODTs in the local environment. The in vitro dissolution profiles of the ODTs formulations are illustrated in Figure 1, They show that the percentage of CA-SLNs dissolved reaches 90% within 5 minutes in phosphate buffer of the CA-SLNs ODTs formulation. (F2, F3, and F4 which dissolved 92.36 ± 0.83%, 95.13 ± 0.35% and 94.06 ± 0.85%, respectively). Moreover, tablet dissolution efficiency was almost 100% within 10 minutes on the CA-SLNs ODTs formulations (F2, F3, and F4 which dissolved 96.03 ± 0.30%, 99.86 ± 0.20% and 98.66 ± 0.64%, respectively). These results indicate that all the prepared tablets fulfil the FDA and USP 43-NF 38 requirements for orally disintegrating tablets and allowed more than 85% of the API to be dissolved in 30 minutes.40,44\n\nIn vitro dissolution profiles of orally disintegrating tablets (ODTs) formulation containing Centella asiatica (CA)-extracts, and CA encapsulated solid lipid nanoparticles (CA-SLNs) in phosphate buffer (pH 6.8) at 37°C with a rotation speed of 50 rpm in a dissolution apparatus II. F1 is 200 mg/tablet CA-extract; F2 is 150 mg/tablet CA-SLNs; F3 is 200 mg/tablet CA-SLNs; and F4 is 250 mg/tablet CA-SLNs. Bars indicate standard deviation, n=3.\n\n\nDiscussion\n\nCA has emerged as a promising natural compound with biological properties. In this work, we are interested in its neurotherapeutic effects. However, the main compounds of CA, such as asiaticoside and madecassoside, are known to have limited water solubility and usually have low absorption.9 Several approaches have been applied to overcome this limitation, namely lipid-based nanocarriers that potentially and effectively protect active compounds from degradation in the bloodstream, enhancing oral delivery.45–47 This study was designed to develop a formulation of ODTs having rapid disintegration and dissolution, thereby providing greater convenience and ease of use to patients with PD with difficulty swallowing, nanoencapsulated CA-SLNs with lipid-based nanocarriers as an effective and potential CA delivery system through the BBB to the brain. ADMET prediction method is needed to develop active compounds as drug candidates and select potential therapies for further processing. A significant failure rate at the development stage of the active compound as a potential drug candidate was associated with ADMET deficiency; therefore, the computational method remains a reliable, cost-effective, and time-saving technique.48 The “Rule of Five” by Lipinski and the “Rule of Three” by Jorgensen were used to predict and evaluate specific molecules of compounds, such as physicochemical properties, pharmacokinetics, lipophilicity, solubility, and drug likeliness.49,50 According to the results presented in Table 2, all parameters were within the standard range, and the compound did not cause more than one violation of the “Rule of Five” (MW < 500, logP < 5, DHB ≤ 5, AHB ≤ 10, Positive PSA value) and “Rule of Three” (logS > -5.7, PCaco > 22 nm/s, PM < 7). In addition, the permeability of BBB plays a role in the early discovery of neurologic drugs due to its high-throughput.51 The log BB values, which guide compounds crossing BBB, were in the range of -5.260 to -1.325. Therefore, it can be said that the active compound CA is a potential drug candidate in the CNS because it can pass through the BBB. Most of the drugs are given orally to increase their effectiveness and pharmacokinetics, so they must be absorbed in the bloodstream through oral absorption in the gastrointestinal tract to be accessible to the brain, and Caco2 is used as a parameter in predicting intestinal permeability of drug candidates.52 Besides, the aqueous solubility (logS) is an important physicochemical property of compounds in drug discovery, and our study is still within the range of values determined. Based on the prediction findings of ADMET parameters, the active compound CA has good and promising pharmacokinetic, permeability, solubility, and toxicological properties, which may be suitable for clinical use.\n\nParticle size and polydispersity index are essential characteristics of nanoparticles used to evaluate particle distribution, stability, and preliminary prediction of biological performance. Lipid-based nanocarriers generally have diameters between 10 nm to 1000 nm, and nanocarriers with sizes less than 100 nm allow increased permeability through the BBB and absorption in the brain.53 In this study, the average particle size distribution of nanoencapsulated CA-SLNs was lower than 100 nm. In addition, the polydispersity index of the nanoencapsulated CA-SLNs is precisely less than 0.2. This polydispersity index value measures the uniformity of the particle size distribution. SLNs formulations with polydispersity index values in the range of 0.0-0.5 were described as homogeneous and monodisperse; however, SLNs with polydispersity index values greater than 0.5 were described as heterogeneous and polydispersity.54 Zeta potential is an important parameter for predicting the tendency of particles to aggregate, the size of the surface electric charge of the particles, and provides information regarding particle stability.20 SLNs can be considered stable dispersion without agglomeration when the absolute value of negative zeta potential is around -30 mV.55 This study showed that CA-SLNs encapsulated were negatively charged, with a zeta potential value between +30 mV and -30 mV, indicating that CA-SLNs have high stability and low aggregation probability.\n\nEE and LC are two important parameters to determine the potential application of SLNs as drug delivery systems that should be considered during the formulation development phase, where EE is described as the percentage of active ingredients encapsulated in nanoparticles, referring to the total active ingredient added for the preparation of SLNs (values range from 80–99%), while LC defined as the percentage of active ingredient encapsulated in nanoparticles referring to the total weight of the lipid phase (values range from 1–20%).56 Therefore, EE of CA-SLNs (95.07%) suggested that part of the hydrophobic active ingredients was lost during preparation of lipid-based nanocarriers by hot homogenization method. This minimal loss of active ingredients may be due to the organic solvent used to obtain the water-in-oil emulsion during the formulation process, which can extract the active ingredients from the lipid matrix of SLNs. In addition, the difference in the structure of the solid lipids used, where the dense lipids form fewer perfect crystals, causes an increase in the space in the dense lipid matrix to accommodate the active ingredients. The incorporation of CA into SLNs did not cause any loss of active ingredients during the formulation process, as it confirmed that CA-SLNs showed an EE value close to 100%. This evidence highlights the advantages of our lipid-based nanocarrier in obtaining high incorporation, given that CA is successfully incorporated into SLNs, with smaller particle sizes having higher EE and LC.\n\nThe direct compression method is one of the methods used to manufacture tablets without a granulation process. It requires appropriate additional ingredients, with several advantages such as being faster, simpler, lower production costs, and more accessible than other methods (wet and dry granulation), and providing integrity high mechanical properties of tablets.57 However, there are some conditions in using this method, such as the flowability properties and compressibility of the powder mixture must be suitable. Therefore, a pre-compression study was carried out to determine the flowability properties and compressibility of the powder mixture used in ODTs, which included the flow time, angle of repose, bulk density, tap density, Hausner ratio, compressibility index, and moisture content.58 As shown in Table 4, all the pre-compression parameters showed promising results to be developed in ODTs. The direct compression method was suitable for tablet preparation as suggested by the Ph. Eur. 10th 37. The angle of repose indicates friction or cohesion force between particles in powder; when angle of repose is lower than 30° for powder, they represent free-flowing behavior. The flowability properties and compressibility trend are described by Hausner’s ratio and compressibility index, respectively. Powder mixtures with compressibility index values in the range 1-10% and Hausner ratio values in the range 1.00-1.11 showed better flowability characteristics.37 So, when the value of the Hausner ratio is lower than 1.15 and the compressibility index value is less than 8.33%, the flowability properties are excellent. The compressibility index is an indirect measure of surface area, powder particle shape, bulk density, moisture content, and powder compactness.42 Since the bulk density is directly related to the particle size of the powder and tends to adhesion, it is vital in selecting packing materials and considerations of compression transport. In addition, powder flowability properties are also influenced by electrostatic interactions, moisture content, density, particle size, and shape.\n\nAll formulations developed with the direct compression method produce elegant and successful ODTs. All physical characterization tests are within the limits of the Pharmacopoeia. It is well known that individual dose unit weight variations guarantee a product’s dose uniformity. This parameter is crucial in giving the same dose of active substance during the therapeutic period to ensure the repeatable pro-health effect. As presented in Table 5; all analyzed ODTs passed the pharmacopoeial weight change test >90% of the tested tablets, and these results showed weight uniformity according to specifications (USP 43-NF 38).39 The most critical parameter of ODTs are friability, hardness, and wetting time. Those parameters directly influence the efficacy of the tablet. Tablet friability and hardness contribute to physical resistance and the ability to disintegrate in mouth. The best ODTs should have low friability and good hardness to prevent mass loss from tablet surface when being handled. On the other hand, the presence of crosscarmelose as the superdisintegrant may worsen the tablet hardness and its friability. At the same time, we need the crosscarmelose to obtain rapid disintegration within the mouth by only the presence of a minimal volume of saliva. As seen in Table 5, those critical parameters showed promising results for ODTs.\n\nDetermination of the content uniformity of active ingredients in tablet preparations is essential for quality control and is expressed as a percent on label claims. In this study, the test was carried out using a UV-Vis Spectrophotometer, which allowed the quantification of CA-SLNs and measuring their content in ODTs. USP 43-NF 38 recommends a limit of variation of 85-115%, from the content of all formulations of ODTs (CA-extracts and CA-SLNs) fulfil the criteria stated as 96.45% to 97.98% (Table 5).39 In addition, each tablet unit must have several active ingredients other than the amount stated in the content value and dosage uniformity to ensure the delivery of the correct dose of the active compound. This parameter is measured by AV calculation with a maximum value of 15%, and the results of our study showed that all formulations of ODTs (CA extracts and CA-SLNs) met these criteria (USP 43-NF 38).39 In vitro dissolution test is crucial for determining the release profile of CA-SLNs formulated in ODTs and to characterize the biopharmaceutical qualities in solid oral dosage forms, thus enabling control of the formulation quality. This test was carried out following USP 43-NF 38 conditions for tablet dissolution using apparatus II, with a dissolution medium of phosphate buffer pH 6.8. As shown in Figure 1 the release profile of CA-SLNs ODTs from different formulations. All formulations of CA-SLNs ODTs had similar dissolution profiles. Approximately 50% of CA-SLNs are released in 2 min and complete drug release is achieved in 15 min for F2, F3 and F4. Therefore, the cumulative release of the CA-SLNs ODTS prepared by direct compression method in this study is good and acceptable on the basis of the FDA and USP 43-NF 38.40,44\n\n\nConclusion\n\nThis study demonstrated that orally disintegrating tablets (ODTs) containing Centella asiatica (CA) encapsulated solid lipid nanoparticles (SLNs) were successfully developed with optimized formulations using direct compression method. ADMET study confirmed good oral bioavailability and safety of these compounds. In addition, CA-SLNs have been successfully optimized as an alternative delivery system to protect the active compound and increase its permeability through the BBB, allowing CA compounds delivery to the brain. Furthermore, CA-SLNs ODTs have been successfully developed with excellent flowability properties, relatively short disintegration time, fast dissolution profile, and fulfilled pharmacopoeial requirements. These results confirm that CA-SLNs ODTs may help manage PD, older adults, and pediatric patients with difficulty swallowing.\n\n\nData availability\n\nFigshare: Supplementary Data – Development and optimization of orally disintegrating tablets containing Centella asiatica solid lipid nanoparticles for supportive therapies of Parkinson’s disease, https://doi.org/10.6084/m9.figshare.19592935.v1.41\n\nThis project contains the following underlying data:\n\n• Supporting information predicted ADMET properties of CA compounds.docx\n\n• Raw data physicochemical characteristics of CA-SLNs.xlsx\n\n• Raw data pre-compression properties of powder.xlsx\n\n• Raw data physical properties of ODTs.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nFricker M, Tolkovsky AM, Borutaite V, et al.: Neuronal cell death. Physiol Rev. 2018; 98(2): 813–880. Publisher Full Text\n\nBloem BR, Okun MS, Klein C: Parkinson’s disease. Lancet. 2021; 397(10291): 2284–2303. Publisher Full Text\n\nKalia LV, Lang AE: Parkinson’s disease. Lancet. 2015; 386(9996): 896–912. Publisher Full Text\n\nEllis JM, Fell MJ: Current approaches to the treatment of Parkinson’s Disease. Bioorganic Med Chem Lett. 2017; 27(18): 4247–4255. Publisher Full Text\n\nCheong SL, Federico S, Spalluto G, et al.: The current status of pharmacotherapy for the treatment of Parkinson’s disease: transition from single-target to multitarget therapy. Drug Discovery Today. 2019; 24(9): 1769–1783. Publisher Full Text\n\nIslam MS, Azim F, Saju H, et al.: Pesticides and Parkinson’s disease: Current and future perspective. J Chem Neuroanat. 2021; 115(September 2020): 101966. Publisher Full Text\n\nKunjumon R, Johnson AJ, Baby S: Centella asiatica: Secondary metabolites, biological activities and biomass sources. Phytomedicine Plus. 2022; 2(1): 100176. Publisher Full Text\n\nBelwal T, Andola HC, Atanassova MS, et al.: Gotu Kola (Centella asiatica). Nonvitamin and Nonmineral Nutritional Supplements. Elsevier; 2019: 265–275. Publisher Full Text\n\nSun B, Wu L, Wu Y, et al.: Therapeutic Potential of Centella asiatica and Its Triterpenes: A Review. Front Pharmacol. 2020; 11(September): 1–24. Publisher Full Text\n\nHanapi NA, Mohamad Arshad AS, Abdullah JM, et al.: Blood-Brain Barrier Permeability of Asiaticoside, Madecassoside and Asiatic Acid in Porcine Brain Endothelial Cell Model. J Pharm Sci. 2021; 110(2): 698–706. Publisher Full Text\n\nSbrini G, Brivio P, Fumagalli M, et al.: Centella asiatica l. Phytosome improves cognitive performance by promoting bdnf expression in rat prefrontal cortex. Nutrients. 2020; 12(2) Publisher Full Text\n\nWong JH, Muthuraju S, Reza F, et al.: Differential expression of entorhinal cortex and hippocampal subfields α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors enhanced learning and memory of rats following administration of Centella asiatica. Biomed Pharmacother. 2019; 110(November 2018): 168–180. Publisher Full Text\n\nTeerapattarakan N, Benya-aphikul H, Tansawat R, et al.: Neuroprotective effect of a standardized extract of Centella asiatica ECa233 in rotenone-induced parkinsonism rats. Phytomedicine. 2018; 44(December 2017): 65–73. Publisher Full Text\n\nMatthews DG, Caruso M, Murchison CF, et al.: Centella asiatica improves memory and promotes antioxidative signaling in 5XFAD mice. Antioxidants. 2019; 8(12). Publisher Full Text\n\nKhotimah H, Ali M, Sumitro SB, et al.: Decreasing α-synuclein aggregation by methanolic extract of Centella asiatica in zebrafish Parkinson’s model. Asian Pac J Trop Biomed. 2015; 5(11): 948–954. Publisher Full Text\n\nQian Y, Xin Z, Lv Y, et al.: Asiatic acid suppresses neuroinflammation in BV2 microglia: Via modulation of the Sirt1/NF-κB signaling pathway. Food Funct. 2018; 9(2): 1048–1057. Publisher Full Text\n\nChen D, Zhang XY, Sun J, et al.: Asiatic acid protects dopaminergic neurons from neuroinflammation by suppressing mitochondrial ROS production. Biomol Ther. 2019; 27(5): 442–449. Publisher Full Text\n\nGray NE, Alcazar Magana A, Lak P, et al.: Centella asiatica: phytochemistry and mechanisms of neuroprotection and cognitive enhancement. Phytochem Rev. 2018; 17(1): 161–194. Publisher Full Text\n\nKhotimah H, Dewi Lestari Ismail D, Widasmara D, et al.: Ameliorative effect of gel combination of Centella asiatica extract transfersomes and rosemary essential oil nanoemulsion against UVB-induced skin aging in Balb/c mice. F1000Res. 2022 Mar 8; 11: 288. Publisher Full Text\n\nNsairat H, Khater D, Odeh F, et al.: Lipid nanostructures for targeting brain cancer. Heliyon. 2021; 7(9): e07994. Publisher Full Text\n\nTopal GR, Mészáros M, Porkoláb G, et al.: ApoE-targeting increases the transfer of solid lipid nanoparticles with donepezil cargo across a culture model of the blood–brain barrier. Pharmaceutics. 2021; 13(1): 1–19.\n\nSubramanian P: Lipid-based nanocarrier system for the effective delivery of nutraceuticals. Molecules. 2021; 26(18). Publisher Full Text\n\nDhiman N, Awasthi R, Sharma B, et al.: Lipid Nanoparticles as Carriers for Bioactive Delivery. Front Chem. 2021; 9(April). Publisher Full Text\n\nDolatabadi JEN, Valizadeh H, Hamishehkar H: Solid lipid nanoparticles as efficient drug and gene delivery systems: Recent breakthroughs. Adv Pharm Bull. 2015; 5(2): 151–159. Publisher Full Text\n\nMishra V, Bansal KK, Verma A, et al.: Solid lipid nanoparticles: Emerging colloidal nano drug delivery systems. Pharmaceutics. 2018; 10(4): 1–21. Publisher Full Text\n\nDuan Y, Dhar A, Patel C, et al.: A brief review on solid lipid nanoparticles: Part and parcel of contemporary drug delivery systems. RSC Advances. 2020; 10(45): 26777–26791. Publisher Full Text\n\nNeves AR, Queiroz JF, Reis S: Brain-targeted delivery of resveratrol using solid lipid nanoparticles functionalized with apolipoprotein E. J Nanobiotechnol. 2016; 14(1): 1–11. Publisher Full Text\n\nDel Prado-Audelo ML, Caballero-Florán IH, Meza-Toledo JA, et al.: Formulations of curcumin nanoparticles for brain diseases. Biomolecules. 2019; 9(2): 1–28. Publisher Full Text\n\nNaseri N, Valizadeh H, Zakeri-Milani P: Solid lipid nanoparticles and nanostructured lipid carriers: Structure preparation and application. Adv Pharm Bull. 2015; 5(3): 305–313. Publisher Full Text\n\nYuan H, Chen CY, Chai GH, et al.: Improved transport and absorption through gastrointestinal tract by pegylated solid lipid nanoparticles. Mol Pharm. 2013; 10(5): 1865–1873. Publisher Full Text\n\nKhan MS, Roberts MS: Challenges and innovations of drug delivery in older age. Adv Drug Deliv Rev. 2018; 135: 3–38. Publisher Full Text\n\nZhang Y, Li Z, Tang H, et al.: Development and optimization of levodopa and benzylhydrazine orally disintegrating tablets by direct compression and response surface methodology. Drug Dev Ind Pharm. 2020; 46(1): 42–49. Publisher Full Text\n\nVanbillemont B, De Beer T: Application of polyvinyl acetate in an innovative formulation strategy for lyophilized orally disintegrating tablets. Int J Pharm. 2020; 588(July): 119717. Publisher Full Text\n\nKadota K, Terada H, Fujimoto A, et al.: Formulation and evaluation of bitter taste-masked orally disintegrating tablets of high memantine hydrochloride loaded granules coated with polymer via layering technique. Int J Pharm. 2021; 604(March): 120725. Publisher Full Text\n\nDrašković M, Djuriš J, Ibrić S, et al.: Functionality and performance evaluation of directly compressible co-processed excipients based on dynamic compaction analysis and percolation theory. Powder Technol. 2018 Feb; 326: 292–301. Publisher Full Text\n\nKhotimah H, Setiawan A, Rita CI, et al.: In silico studies of natural compounds of Centella Asiatica as anti-aging and wound healing agents. International Conference on Life Sciences and Technology (ICoLiST 2020). 2021; p. 030031.\n\nCouncil of Europe: EDQM - European Directorate For the Quality of Medicines. European Pharmacopoeia. 10th ed.Strasbourg: 2019.\n\nUnited States Pharmacopeial Convention<1217>Tablet breaking force: States Pharmacopeia and National Formulary (USP 43-NF 38). United States Pharmacopeial Convention. USA: Rockville, MD: 2021; p. 868–70.\n\nU.S. Pharmacopoeial Convention <905> Uniformity of Dosage Units: States Pharmacopeia and National Formulary (USP 43-NF 38). United States Pharmacopeial Convention. USA: Rockville, MD: 2021; p. 4–6.\n\nU.S. Pharmacopoeial Convention <711> Dissolution: States Pharmacopeia and National Formulary (USP 43-NF 38). United States Pharmacopeial Convention. USA: Rockville, MD: 2021; p. 1–8.\n\nKhotimah H, Aulanni’am A’a, Kurniawan SN, et al.: Supplementary Data – Development and optimization of orally disintegrating tablets containing Centella asiatica solid lipid nanoparticles for supportive therapies of Parkinson’s disease. Figshare (Dataset). 2022. Publisher Full Text\n\nCouncil of Europe: EDQM. European Pharmacopeia 10.0: Powder Flow. European Directorate For the Quality of Medicine. 10th ed.Strasbourg: 2019; p. 387–90.\n\n(CDER) USD of H and HSF and DAC for DE and R: Guidance for Industry Orally Disintegrating Tablets Guidance for Industry Orally Disintegrating Tablets. Food and Drug Administration. Rockville, MD: 2008; p. 1–3.\n\nREDC/ADF: Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances Guidance for Industry. Food and Drug Administration. Rockville, MD: 2018; p. 1–8.\n\nFernandes F, Dias-Teixeira M, Delerue-Matos C, et al.: Critical review of lipid-based nanoparticles as carriers of neuroprotective drugs and extracts. Nanomaterials. 2021; 11(3): 1–51. Publisher Full Text\n\nGaranti T, Stasik A, Burrow AJ, et al.: Anti-glioma activity and the mechanism of cellular uptake of asiatic acid-loaded solid lipid nanoparticles. Int J Pharm. 2016; 500(1–2): 305–315. Publisher Full Text\n\nLakshmi Pravallika P, Krishna Mohan G, Venkateswara Rao K, et al.: Biosynthesis, characterization and acute oral toxicity studies of synthesized iron oxide nanoparticles using ethanolic extract of Centella asiatica plant. Mater Lett. 2019; 236: 256–259. Publisher Full Text\n\nWu F, Zhou Y, Li L, et al.: Computational Approaches in Preclinical Studies on Drug Discovery and Development. Front Chem. 2020; 8(September). Publisher Full Text\n\nLipinski CA, Lombardo F, Dominy BW, et al.: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001; 46(SUPPL): 3–26. Publisher Full Text\n\nJorgensen WL, Duffy EM: Prediction of drug solubility from structure. Adv Drug Deliv Rev. 2002 Mar; 54(3): 355–366. Publisher Full Text\n\nRadan M, Djikic T, Obradovic D, et al.: Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates. Eur J Pharm Sci. 2022; 168(November 2021): 106056. Publisher Full Text\n\nDahlgren D, Lennernäs H: Intestinal permeability and drug absorption: predictive experimental, computational and in vivo approaches. Pharmaceutics. 2019; 11(8) Publisher Full Text\n\nMasserini M: Nanoparticles for Brain Drug Delivery. ISRN Biochem. 2013; 2013: 1–18. Publisher Full Text\n\nZwain T, Alder JE, Sabagh B, et al.: Tailoring functional nanostructured lipid carriers for glioblastoma treatment with enhanced permeability through in-vitro 3D BBB/BBTB models. Mater Sci Eng C. 2021; 121(December 2020): 111774. Publisher Full Text\n\nMakoni PA, Kasongo KW, Walker RB: Short term stability testing of efavirenz-loaded solid lipid nanoparticle (SLN) and nanostructured lipid carrier (NLC) dispersions. Pharmaceutics. 2019; 11(8) Publisher Full Text\n\nZhu Y, Inada H, Hartschuh A, et al.: Solid Lipid Nanoparticles - SLN. Encyclopedia of Nanotechnology. Dordrecht: Springer Netherlands; 2012; p. 2471–87. Publisher Full Text\n\nGulsun T, Akdag Cayli Y, Izat N, et al.: Development and evaluation of terbutaline sulfate orally disintegrating tablets by direct compression and freeze drying methods. J Drug Deliv Sci Technol. 2018; 46(March): 251–258. Publisher Full Text\n\nKandilli B, Ugur Kaplan AB, Cetin M, et al.: Orally disintegrating tablet containing carbamazepine and levetiracetam: formulation and in vitro and in vivo characterization. Drug Dev Ind Pharm. 2021; 47(7): 1153–1165. Publisher Full Text"
}
|
[
{
"id": "200811",
"date": "29 Aug 2023",
"name": "Dharmendra Kumar Khatri",
"expertise": [
"Reviewer Expertise Neuroscience",
"Parkinson's disease",
"molecular biology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article “Development and optimization of orally disintegrating tablets containing Centella asiatica solid lipid nanoparticles for supportive therapies of Parkinson's disease. “is aimed to develop a orally disintegrating tablet containing Centella asiatica encapsulated solid lipid nanoparticles with improved ADMET properties using various in-silico, software based evaluation.\nMajor Comments:\nThis manuscript fails to convey its purpose or explain why the work was carried out. The major work was based on formulation and characterization, not the efficacy evaluation, which is utterly misleading given that the title of the work suggests otherwise. The fact that the title referenced \"therapies of Parkinson's disease\" indicates that the article does not contain a single efficacy research to validate its Parkinson therapy, either in-vitro or in-vivo (Animal study).\nTherefore, this manuscript needs to change its title, and revise accordingly.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "10881",
"date": "11 Jan 2024",
"name": "Husnul Khotimah",
"role": "Author Response",
"response": "I'm the author of this article. This article aims to develop and optimise, we didn't mention it at all for efficacy...as we know, the drug development has many steps and procedures to gain the optimum formula, dose and route of administration. We didn't conduct all of that process."
},
{
"c_id": "11760",
"date": "14 Jun 2024",
"name": "Husnul Khotimah",
"role": "Author Response",
"response": "In the title we mention explicitly that this is the Development and optimization of the tablet.. so the object is the tablet, finally we hope this tablet is effectively used to cure Parkinson's disease."
}
]
}
] | 1
|
https://f1000research.com/articles/11-517
|
https://f1000research.com/articles/11-393/v1
|
05 Apr 22
|
{
"type": "Study Protocol",
"title": "Incentives for pregnant mothers during antenatal care for better maternal and neonatal health outcomes: A systematic review protocol",
"authors": [
"Ramesh Holla",
"Bhaskaran Unnikrishnan",
"Ratheebhai Vijayamma",
"Bhumika T V",
"Anju Sinha",
"Darshan BB",
"Rekha T",
"Prasanna Mithra P",
"Nithin Kumar",
"Vaman Kulkarni",
"Ravishankar N",
"Rosemol Johnson K",
"Bhaskaran Unnikrishnan",
"Ratheebhai Vijayamma",
"Bhumika T V",
"Anju Sinha",
"Darshan BB",
"Rekha T",
"Prasanna Mithra P",
"Nithin Kumar",
"Vaman Kulkarni",
"Ravishankar N",
"Rosemol Johnson K"
],
"abstract": "Background: Universal access to maternal new-born and child healthcare services (MNCH) is detrimental for attainment of Sustainable Development Goal (SDG) three pertaining to promotion of health at all ages. Incentivization in the form of cash, vouchers, and goods have been used as part of strategies to improve maternal and neonatal health outcomes around the world. However, there exists uncertainties regarding the effectiveness of various incentive-based programmes targeted for pregnant mothers in low- and middle-income countries during their antenatal period. Methods: We will search six electronic databases, namely the Medical Literature Analysis and Retrieval System Online (Medline), Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, and Embase in addition to Google Scholar. Manual searching of the reference lists of included studies will also be done. The reporting of this protocol will follow the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) 2015 statement [29]. Only interventional studies that follow randomized, quasi randomized, and cluster randomized controlled study designs will be included. A three-stage screening process will be adopted to select articles. Risk of bias for the included studies will be assessed using the tools and criteria specified in the Cochrane handbook. In addition, the GRADE approach will be used to assess the quality of evidence for the maternal and neonatal health outcomes. Conclusion: This review of trials is essential to inform the effectiveness of incentive-based programmes targeted for pregnant women in low- and middle-income countries. It will help the policy makers to utilise the resources more effectively and to integrate the evidence based public health initiatives into the health system. This can also help build the continuum of care financial packages for all pregnant women.",
"keywords": [
"Pregnancy",
"Incentives",
"trials",
"Maternal outcomes",
"neonatal outcomes"
],
"content": "Introduction\n\nAround 86% of the maternal deaths in the world occur in South Asia and Sub-Saharan Africa. Most of these deaths occur at home owing to lack of medical attention and are largely preventable.1\n\nThe maternal mortality ratio in India as per UNICEF’s data warehouse was 145 per 100,000 live births in 2017 and 113 per 100,000 live births as per the sample registration system (SRS) 2016-2018.1,2 The neonatal mortality rate in India reduced from 38 deaths in the year 2000 to 22 deaths per 1,000 live births in 2019.3\n\nGiven the burden of maternal and neonatal deaths globally, it is essential to implement effective strategies adapted to developing economies that can help achieve the targets of the Sustainable Development Goals (SDG) pertaining to Maternal and child health (MCH).4 In the context of developing economies, many disincentives exist that act as barriers to seeking healthcare for the pregnant woman. These include cultural beliefs, social norms, lack of financial support, attitude of health workers, migration, and language barriers, etc. Customs like ‘Kuthimba’ in Malawi where the woman waits for advice from counsellors from the husband’s side of the family before starting antenatal care (ANC) are rooted in culture.5 An analysis conducted in South Asia and Sub Saharan Africa indicated that women with higher autonomy to make decisions were able to receive the elements of continuum of care compared to those who had no autonomy in decision making.6 Moreover, logistic factors like uneven roads in rural areas and long distance travel to health facilities can further widen the gap in access to health services for pregnant women based on a cross sectional study conducted in Cambodia.7\n\nFor an effective continuum of care, it is essential to strengthen the link between home, the primary health care facility and the referral centres.8\n\nVarious studies across the globe have shown that health services utilization has considerably increased owing to the Conditional Cash transfer (CCT) initiatives. The Janani Suraksha Yojana was launched in 2005 to promote institutional deliveries in India and thereby reduce neonatal and maternal deaths. As part of this scheme, pregnant women from low socio-economic background receive cash incentives subject to registration at health centres and are encouraged for institutional deliveries.9 The scheme has been instrumental in improving the utilisation of health centres below the district level by pregnant mothers.\n\nVarious other intervention studies in the past decade have assessed the impact of types of incentives among pregnant women across the globe. A trial conducted in the Democratic Republic of Congo (DRC) region has found that conditional cash transfers can help achieve retention of pregnant women in care services to prevent mother to child transmission.10 Another pilot, randomised-controlled trial study conducted in Cape Town, South Africa found that participants enrolled in the incentive-based intervention were more likely to attend the clinics delivering antenatal health care services for their first visit before five months of gestation. Also, they were more likely to go to these clinics more than four times. The intervention consisted of a package called the ‘Thula Baba Box’, that contains essential items for clothing and hygiene for babies including items for mothers like maternity pads and condoms.11\n\nThese incentive-based interventions are intended to increase uptake of antenatal care services and thereby improve health outcomes. They are also part of behaviour change interventions for smoking/tobacco cessation, improving dietary behaviour among pregnant women.\n\nA previously conducted systematic review has shown only limited evidence that incentives may improve the frequency of prenatal care. This evidence is based on five trials and participants majorly drawn only from low-income communities in Central America and North America.12\n\nIn our review, the central component will be incentives. We intend to accumulate evidence pertaining to various incentive-based intervention studies targeted for pregnant women only during the antenatal period in low- and middle-income countries (LMICs) and evaluate the effectiveness across a wide range of outcome measures.\n\nThe continuum of care approach for MCH primarily takes into consideration the time of provision of care services. Secondly, it considers the appropriate place of receiving care alongside the various approaches of caregiving services.13 The time dimension can be measured by the number of ANC care visits made by the pregnant mother and also by the components of services received. While the place dimension of the continuum of care looks into the services provided in primary and referral centres and is important to address complications of pregnancy, preterm deliveries, stillbirths and other signs of danger where specific care is required.\n\nThis review of trials is thus essential to inform the effectiveness of incentive-based programmes targeted for pregnant women in LMICs. It will help the policy makers to utilise the resources more effectively and to integrate the evidence based public health initiatives into the health system. This can also help build the continuum of care financial packages for all pregnant women.\n\nOur research questions are as follows:\n\n1. Does provision of incentives to pregnant mothers during the antenatal care period achieve better maternal and neonatal health outcomes than the absence of such services for pregnant women?\n\n1a. What are the effects of incentives (any type) on uptake of antenatal care services/utilization of antenatal health care services (frequency of antenatal care, proportion of institutional delivery etc)?\n\n1b. What are the effects of incentives (any type) on maternal and neonatal morbidity (Proportion of preterm deliveries, low birthweight (less than 2,500 g), proportion of antenatal and postnatal complications, compliance to iron-folic acid (IFA) tablets intake and tetanus (TT) injection coverage, and coverage and utilization of maternal incentive based nutritional interventions)?\n\n1c. What are the effects of incentives (any type) on maternal and neonatal mortality (neonatal deaths/maternal deaths)?\n\n\n\n• To determine if any of the incentive-based interventions had an effect on maternal outcomes (Proportion of antenatal and postnatal complications, proportion of institutional delivery, frequency of antenatal care, maternal deaths, compliance to IFA tablets intake and TT injection coverage, coverage and utilization of maternal incentive based nutritional interventions, and cessation of smoking, alcohol, tobacco, or any other unhealthy behavioural practices).\n\n• To determine if any of the incentive-based interventions had an effect on neonatal health outcomes (Proportion of preterm deliveries, low birthweight (less than 2,500 g), and perinatal and neonatal deaths).\n\nParticipants\n\nWe will include all incentive based interventional studies conducted on pregnant women in lower-middle income countries (LMICs) as per the World Bank definition.14 We will exclude studies conducted among pregnant women that belong to any of the low- and middle-income countries but reside in high income countries as immigrants during the antenatal and postnatal period. We will exclude studies that involve pregnant women living in high income countries but belonging to low-income families/communities. We will exclude studies that are focused on incentives for healthcare providers, government agencies or any other stakeholders on the supply side.\n\nIntervention\n\nWe will conduct a systematic review of all interventions that include incentives given to pregnant mothers linked to their antenatal care, which are usually not offered to pregnant mothers as a standard prenatal care. We will not place any restriction with regard to the modes of financing. These could be conditional cash transfers, vouchers, transport services, in-kind goods, mama kits, co-payments, etc. We will also include incentive-based behaviour change intervention studies conducted during the antenatal care period among pregnant women for incentive-based smoking/tobacco cessation interventions, incentivised nutrition focussed interventions for appropriate dietary behaviour during pregnancy, etc.\n\nComparators\n\nThe interventions of our interest can be compared to routine antenatal care (no incentives), no intervention or any other type of intervention that is not considered as incentives. We will not restrict the definition of usual care/routine antenatal care.\n\nOutcomes\n\nThe outcomes of interest are categorized as ‘neonatal outcomes’ and ‘maternal outcomes’. Neonatal outcomes of interest are as follows:\n\n• Proportion of preterm deliveries.\n\n• Low birthweight (less than 2,500 g).\n\n• Perinatal and neonatal deaths.\n\nMaternal outcomes of interest are as follows:\n\n• Frequency of antenatal care (number of visits and the content of care).\n\n• Proportion of antenatal and postnatal complications.\n\n• Proportion of institutional delivery.\n\n• Maternal deaths.\n\n• Compliance to IFA tablets intake and TT injection coverage.\n\n• Coverage and utilization of maternal incentive based nutritional interventions.\n\n• Cessation of smoking, alcohol, tobacco, or any other unhealthy behavioural practices.\n\nAll the above outcomes will be assessed in our review with regard to incentives targeted for pregnant women during the antenatal period only. We will exclude studies that do not measure at least one of the above outcomes.\n\nTypes of study designs\n\nWe will include studies with experimental designs such as randomised, quasi – randomised, and cluster randomised studies. Pilot randomised controlled trials (RCTs) also will be included in this review. Observational studies will be excluded in this review since the review is to determine the effectiveness of incentive-based intervention studies alone. We will restrict our studies to English language publications owing to a lack of resources for translation and nonavailability of multilingual experts. Only studies published in scientific journals will be considered for inclusion. We will exclude editorials, opinion papers, reviews, and case studies. Studies that are published as abstracts and conference proceedings will be included if we can retrieve the full texts from the authors of the trials. In addition, preprints of unpublished studies will be included.\n\n\nMethods\n\nWe have followed the 17 items listed in the PRISMA-P 2015 checklist for reporting this protocol.15 We will follow the updated PRISMA 2020 guidelines consisting of 27 listed items for reporting our systematic review.16 The conduct of the systematic review will be in adherence to the Cochrane methods as mentioned in the Cochrane Handbook for Systematic reviews on Interventions.17\n\nWe will conduct the search on the following electronic databases using a set of keywords and medical subject headings. We will take the assistance of an information specialist who works as a librarian in the University to develop and run the search strategy. We will utilise her expertise in the same manner. We have listed the search concepts and keywords in table 1 for Medline only.28 We will undertake the search in Medical Literature Analysis and Retrieval System Online (Medline), Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Web of Science, and Embase. In addition, we will undertake manual searching on the Google Scholar database using the search [“pregnancy” AND “incentive”] and will download the results shown in the first 20 pages, with each page showing 10 results.18 Reference lists of studies that we include after full text screening will be searched so that we capture more relevant articles. We will not restrict the search to the year of publication. In accordance with the guidelines in the PRISMA statement, we will use the Population, Intervention, Comparator, Outcome (PICO) acronym to inform the search strategy as mentioned in the Cochrane handbook. For study design, we will use the search strategy as specified in Cochrane methods. This strategy has been found to be highly sensitive for identifying randomised controlled trials on Medline.19 For other databases, we will customise the terms accordingly. For Embase, we will use the standardised keywords that are available under ‘Emtree’ terms. Likewise for Medline we will use, the MESH terms. We will also use appropriate field codes and Boolean operators.\n\nWe will initiate contacts with authors of published trials for clarification concerning the included studies. We will also do targeted searches with regard to the included trials to identify published protocols, pilot studies, updates, comments and corrections on the trials. We will then export the results of the search to Covidence software20 that facilitates automatic removal of duplicates. The draft search strategy for Medline has been provided in supplemental file 1.17\n\nScreening articles\n\nThe screening process also will be undertaken on Covidence software. First, two reviewers will independently do the screening of titles followed by abstract screening based on the eligibility criteria specified. Full text screening will be independently performed by two reviewers. After downloading all the full texts for the purpose of full text screening, records that are ineligible will be removed with specific reasons that will be documented in a flow chart. If there are disagreements, a third reviewer will resolve by discussion for the final decision regarding the inclusion of the particular study. The reporting will be as per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement.16 We will also provide a summary of the excluded trials along with the specific reasons for exclusion. In addition, we will also keep a record of ongoing trial protocols.\n\nData extraction\n\nTwo reviewers will independently extract data under the following headings: study ID, author details, publication year, participant details, intervention details, comparators, outcomes, funding details, and any other important details if required. We will independently pilot the data extraction form so as to ensure that all relevant details are captured and modify the data extraction form accordingly. We will initiate contact with authors of included articles for missing information in those studies. Discrepancies in the extracted data between the two reviewers will be resolved by discussion. A third author will be involved to achieve Consensus. The data will be entered into Review Manager, version 5.421 by one author and verified by another author.\n\nIn order to reduce risk associated with publication bias, we will conduct searches for trials within the previous reviews on Incentives for pregnant women.\n\nRisk of bias assessment\n\nRisk of bias will be assessed using the tools mentioned in the Cochrane Handbook for Systematic Reviews of Interventions.22 This assessment will be independently conducted by two investigators. In case of disagreements, a third investigator will be involved for resolution of the same. The current version of the ROB-2 tool (version 2019) will be used for the studies with randomised study designs. The variant of ROB 2 tool adapted for cluster randomised trials (2021 version) will be used for cluster randomised trials. We will evaluate and report the results in the ‘risk of bias’ tables. The following criteria will be used to assess the risk of bias in each of the randomized controlled studies that will be included after full text screening.\n\n• Selection bias (random sequence generation and allocation concealment)\n\n• Performance bias\n\n• Detection bias\n\n• Attrition bias\n\n• Reporting bias\n\nWe will categorize the risk of bias for each domain as ‘low’, ‘unclear’, and ‘high’ based on the adequateness of each criterion mentioned in the risk of bias tools specified in the Cochrane handbook.22\n\nThe ROBINS-I tool will be used for assessing the risk of bias for quasi randomised controlled trial studies. The tool will provide guidance to cover seven domains of bias (pre intervention, at intervention, and post intervention) and the five judgement responses (low, moderate, serious, critical risk of bias, and no information).23,24\n\nData synthesis\n\nWe will perform the statistical analysis for data analysis on Review Manager Software, version 5.4.21 as per the statistical guidelines referenced in the Cochrane Handbook.25 We will conduct a random effect meta-analysis in the case of moderate to severe heterogeneity or else we will generate fixed effect models. If a high level of heterogeneity is evident, only a narrative summary of trial findings will be provided. We will present the data in a forest plot and summary of findings tables. Results for dichotomous outcomes will be expressed as risk ratios and risk differences with 95% confidence intervals. Calculation of the number needed to treat for additional outcomes will be done in the event that the RD is statistically significant. Measures of effect will be expressed as mean differences with 95% CIs for outcomes that are reported on continuous scales. After standardisation of outcomes, standardised MD will be calculated if the data is reported on different continuous scales. While analysing the RCTs and quasi RCTs, we will check if the randomisation was done at individual or group/cluster level. If cluster-randomised studies are included, accordingly those will be adjusted for clustering. We will multiply the standard error derived from the confidence interval of the effect estimate by the square root of the design effect. We will utilize the generic inverse variance method in Review Manager 5 to perform meta-analysis using inflated variances.\n\nWe will use the T2, I2, and Chi2 statistics to assess the heterogeneity in the meta-analysis. In the Chi2 test, if the I2 shows more than 30% or the T2 was more than zero, or the P value is low (<0.10) then the heterogeneity will be considered substantial.\n\nThe need for the sensitivity analysis will be decided based on the many decision nodes that we anticipate encountering during the systematic review process. Considering the inclusion of quasi randomized studies, if required, then the sensitivity analysis will be conducted to ascertain the robustness of the results to the ROB in the included studies. The sensitivity analysis will be reported in the form of summary tables rather than individual forest plots.\n\nSubgroup analyses for the maternal and neonatal health outcomes will be conducted. The subgroups will be defined by the intervention type. The effect of the intervention will be estimated for each subgroup.\n\nWe will report the effect of the interventions on the specific outcomes mentioned in this protocol. In addition, we will also report about the certainty of these findings as high, moderate, low and very low in accordance with the GRADE levels.26 We will use the GRADE profiler software and guideline development tool to develop the summaries.27 One review author will conduct the assessments for GRADE and another author will verify the assessments. We will present the data on a table where findings will be summarized for the effects of interventions on the specific listed outcomes.\n\n\nDiscussion\n\nThe current review will systematically follow the Cochrane methodology.14–26 The results generated out of this systematic review will inform or guide in implementing public health interventions and policy with regard to incentive-based initiatives for pregnant women.\n\nNo restrictions with regard to the publication year will be followed for the search strategy.\n\nWe are including all the modes of financing that were implemented for pregnant women. There will be no restrictions on the above. The modes of financing can include vouchers, transport incentives, in-kind goods, cash transfers, etc.\n\nInclusion of studies will be restricted to English language and those published in scientific journals.\n\n\nData availability\n\nFigshare: Medline database search strategy for ‘Incentives for pregnant mother during antenatal care for better maternal and neonatal health outcomes: A Systematic Review Protocol’. https://doi.org/10.6084/m9.figshare.19161494.v328\n\nThis project contains the following underlying data:\n\n• Supplemental File 1: Search Strategy for Medline database\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nFigshare: PRISMA-P checklist for ‘Incentives for pregnant mother during antenatal care for better maternal and neonatal health outcomes: A Systematic Review Protocol’.\n\nhttps://doi.org/10.6084/m9.figshare.19161413.v3.29\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAuthors contribution\n\nRH conceived and designed the study. RH secured funding for this systematic review and is the guarantor of the systematic review. RH, RJ, BTV drafted the manuscript. RV, RH, RJ developed the search strategy, research questions and study design. NK, RT, PM, DB, VK, RJ, RH, designed the tables for data extraction, will perform data extraction, and also evaluate the quality of all included studies in the systematic review. RH, RV, RJ, BTV contributed to the introduction section and supplementary files 1 and 2. RT, PM, RN, DB will contribute to data synthesis and meta-analysis. AS, BTV and BU provided direction, mentorship and extensively revised the manuscript. All the authors are in consensus to abide by the protocol and ensure their services throughout the conduct of the review process.\n\nStudy status: This study is currently at the stage of data synthesis.",
"appendix": "References\n\nMaternal Mortality: 2019. Accessed 20 May 2021. Reference Source\n\nMaternal Mortality Ratio: 2021. Accessed 13 July 2021. Reference Source\n\nSubnational mapping of under-5 and neonatal mortality trends in India: the Global Burden of Disease Study 2000–17. Lancet. 2020; 395(10237): 1640–1658. Accessed 17 May 2021. PubMed Abstract | Publisher Full Text\n\nThe Global and National Maternal Mortality Targets for the Sustainable Development Goals: Accessed February 22, 2022. Reference Source\n\nChimatiro CS, Hajison P, Chipeta E, et al.: Understanding barriers preventing pregnant women from starting antenatal clinic in the first trimester of pregnancy in Ntcheu District-Malawi. Reprod. Health. 2018; 15(1):158. Accessed 7 April 2021. PubMed Abstract | Publisher Full Text\n\nSingh K, Story WT, Moran AC: Assessing the Continuum of Care Pathway for Maternal Health in South Asia and Sub-Saharan Africa. Matern. Child Health J. 2016; 20(2): 281–289. Accessed 5 July 2021. Publisher Full Text PubMed Abstract |\n\nYasuoka J, Nanishi K, Kikuchi K, et al.: Barriers for pregnant women living in rural, agricultural villages to accessing antenatal care in Cambodia: A community-based cross-sectional study combined with a geographic information system. PLoS One. 2018; 13(3). e0194103. Accessed 10 May 2021. PubMed Abstract | Publisher Full Text\n\nThe maternal, newborn and child health Continuum of Care: Opportunities for Africa’s newborns. Accessed 10 May 2021.Reference Source\n\nJANANI SURAKSHA YOJANA: National Health Mission. Accessed 7 June 2021. Reference Source\n\nYotebieng M, Moracco KE, Thirumurthy H, et al.: Conditional Cash Transfers Improve Retention in PMTCT Services by Mitigating the Negative Effect of Not Having Money to Come to the Clinic. J. Acquir. Immune Defic. Syndr. 2017; 74(2): 150–157. Accessed 15 May 2021. PubMed Abstract | Publisher Full Text\n\nRossouw L, Burger R, Burger R: An Incentive-Based and Community Health Worker Package Intervention to Improve Early Utilization of Antenatal Care: Evidence from a Pilot Randomised Controlled Trial. Matern. Child Health J. 2019; 23: 633–640. Accessed 12 May 2021. Publisher Full Text PubMed Abstract |\n\nTill SR, Everetts D, Haas DM: Incentives for increasing prenatal care use by women in order to improve maternal and neonatal outcomes. Cochrane Database Syst. Rev. 2015; 2015: CD009916. Accessed 10 May 2021. Publisher Full Text\n\nKerber KJ, de Graft-Johnson JE , Bhutta ZA, et al.: Continuum of care for maternal, newborn, and child health: from slogan to service delivery. Lancet. 2007; 370: 1358–69. Accessed 2 May 2021. PubMed Abstract | Publisher Full Text\n\nClassifying countries by income. Reference Source\n\nShamseer L, Moher D, Clarke M, et al.: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015; Jan 2; 349 (Jan02 1): g7647. Accessed 2 May 2021. PubMed Abstract | Publisher Full Text\n\nPage MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372:n71. Accessed 9 May 2021. PubMed Abstract | Publisher Full Text\n\nPage MJ, Higgins JPT, Sterne JAC: Chapter 13: Assessing risk of bias due to missing results in a synthesis. Higgins JPT, Thomas J, Chandler J, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane; 2021. Accessed 29 June 2021. Reference Source\n\nGoogle Scholar website. Reference Source\n\nSensitivity- and precision-maximizing version: 2008 revision. PubMed format. Accessed 12 May 2021. Reference Source\n\nCovidence software. Reference Source\n\nReview Manager (RevMan) [Computer program]. Version 5.4. The Cochrane Collaboration; 2020.\n\nRoB 2: A revised Cochrane risk-of-bias tool for randomized trials: Accessed 22 February 2022. Reference Source\n\nStern JAC, Herńan MA, Reeves BC, et al.: ROBINS-I: a tool for assessing risk of bias in non-randomised studies of intervention. BMJ. 2016; 355: 355i4919. Accessed 5 July 2021. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTool Documentation: 2016. Accessed 21 May 2021. Reference Source\n\nChapter 10: Analysing data and undertaking meta-analyses. Accessed 22 February 2022. Reference Source\n\nGrade handbook: 2013. Accessed 17 June 2021. Reference Source\n\nGRADEpro GDT: GRADE profiler and guideline development tool. Accessed February 22, 2022. Reference Source\n\nHolla R: Medline Database Search strategy for 'Incentives for pregnant mother during antenatal care for better maternal and neonatal health outcomes: A Systematic Review Protocol'. figshare. Dataset. 2022. Accessed February 24, 2022. Publisher Full Text\n\nHolla R: PRISMA-P checklist for ‘Incentives for pregnant mother during antenatal care for better maternal and neonatal health outcomes: A Systematic Review Protocol’. figshare.2022. Online resource. Accessed February 24, 2022. Publisher Full Text"
}
|
[
{
"id": "130034",
"date": "29 Apr 2022",
"name": "Praveen Kulkarni",
"expertise": [
"Reviewer Expertise Epidemiology",
"Medical Education",
"Clinical research"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe proposed systematic review protocol on incentives for pregnant mothers during antenatal care for better maternal and neonatal health outcomes is a timely and most relevant effort by authors to throw light on a very attractive intervention to improve pregnancy outcomes. The review proposes to focus on the effectiveness of commonly adapted interventions to attract pregnant women to utilize maternal new-born and child healthcare (MNCH) services in low- and middle-income countries (LMICs). Few suggestions that can be taken into consideration to further improve the review are as follows:\nAs the review is going to focus on low- and middle-income countries, it can be mentioned in title to make it more explicit.\n\nIn the inclusion criteria, authors can mention the incentive-based interventions can be both public health care system driven or initiated by NGOs or others.\n\nIn outcomes can authors define pre-term in the same way they have defined low birth weight (LBW)?\n\nPlease think of quasi experimental to be added/replaced along with quasi randomized, as most of the studies could be community-based trials, where quasi experimental may sound better than quasi randomized.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": [
{
"c_id": "8219",
"date": "13 May 2022",
"name": "Ramesh Holla",
"role": "Author Response",
"response": "Thank you for your suggestions. We appreciate your time and willingness to review the manuscript. We have incorporated the following changes in the manuscript based on your suggestions. \"As the review is going to focus on low- and middle-income countries, it can be mentioned in title to make it more explicit.\" Response: Added the words ‘low- and middle-income countries’ in the study title. \"In the inclusion criteria, authors can mention the incentive-based interventions can be both public health care system driven or initiated by NGOs or others.\" Response: In Intervention section, we added this sentence, ‘the incentive-based interventions can be both public health care system driven or initiated by NGOs or others’. \"In outcomes can authors define pre-term in the same way they have defined low birth weight (LBW)?\" Response: For preterm deliveries, we added ‘(baby born alive before 37 weeks)’. \"Please think of quasi experimental to be added/replaced along with quasi randomized, as most of the studies could be community-based trials, where quasi experimental may sound better than quasi randomized.\" Response: Thank you for your critical feedback. Owing to time constraints and scope of the current review, we have decided to limit the review to randomized trials and quasi randomized trials only."
}
]
},
{
"id": "130035",
"date": "29 Apr 2022",
"name": "Preethy D'Souza",
"expertise": [
"Reviewer Expertise Evidence synthesis",
"Public Health",
"International Development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverall well-written protocol on a relevant topic. The authors followed Systematic Review (SR) guidelines. However, the review scope is more like a systematic map rather than a synthesis. When I read the protocol, I understand that the review authors are trying to look at different types of incentives on a wide range of outcomes. This could make synthesis less useful and superficial. Hence, my suggestion is to limit the outcomes rather than looking at it very broadly - it will be helpful if the authors could provide more conceptual clarity on interventions and outcomes and how they are going to synthesize the data. It is mentioned that the subgroups will be defined by the intervention type. How about the wide range of outcomes such as mortality, care utilization, service provisions, morbidity, behavioural change etc. will they be grouped for analysis?\n\nIs the rationale for, and objectives of, the study clearly described? Partly\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "8220",
"date": "13 May 2022",
"name": "Ramesh Holla",
"role": "Author Response",
"response": "Thank you for your suggestions. We appreciate your time and willingness to review the manuscript. As per your suggestions, we have provided conceptual clarity on the outcomes and interventions. We will do subgroup analysis based on the outcomes or intervention types depending on the availability of sufficient data from existing literature sources. In outcomes section, we have added definitions beside the outcome names. For preterm deliveries, we added ‘(baby born alive before 37 weeks)’, perinatal death (death between 28 weeks of gestation to first 7 days of life) and neonatal deaths (death within first 28 days of life), maternal deaths (death during pregnancy and childbirth or within 42 days of termination of pregnancy). We have added a new reference no. 15 for institutional deliveries. In addition, for TT vaccination uptake outcome, we have added ‘(operational definition for vaccine uptake in our review is based on if the mother received any number of doses of the TT vaccine)’. We changed the word ‘TT injection coverage’ to ‘TT vaccination uptake’. Likewise, we removed the word ‘coverage’ in outcome name ‘coverage and utilization of maternal incentive based nutritional interventions’. So, the new outcome name is 'utilization of maternal incentive based nutritional interventions’. In Intervention section, we added this sentence, ‘the incentive-based interventions can be both public health care system driven or initiated by NGOs or others’. In Data synthesis section, we have added the statement, ‘we will do subgroup analysis based on the outcomes or intervention types depending on the availability of sufficient data from existing literature sources’."
}
]
}
] | 1
|
https://f1000research.com/articles/11-393
|
https://f1000research.com/articles/11-515/v1
|
12 May 22
|
{
"type": "Systematic Review",
"title": "Effectiveness of contact tracing apps for SARS-CoV-2: an updated systematic review",
"authors": [
"Kevin Jenniskens",
"Martin C.J. Bootsma",
"Johanna A.A.G. Damen",
"Mona Ghannad",
"Michiel S. Oerbekke",
"Robin W.M. Vernooij",
"René Spijker",
"Karel G.M. Moons",
"Mirjam E.E. Kretzschmar",
"Lotty Hooft",
"Martin C.J. Bootsma",
"Johanna A.A.G. Damen",
"Mona Ghannad",
"Michiel S. Oerbekke",
"Robin W.M. Vernooij",
"René Spijker",
"Karel G.M. Moons",
"Mirjam E.E. Kretzschmar",
"Lotty Hooft"
],
"abstract": "Objective – To systematically review evidence on effectiveness of contact tracing apps (CTAs) for SARS-CoV-2 on epidemiological and clinical outcomes Design – Update of a systematic review (https://doi.org/10.1136/bmjopen-2021-050519) Data sources - EMBASE (OVID), MEDLINE (PubMed), BioRxiv, and MedRxiv were searched up to June 9th 2021 Study selection – Studies, empirical or model-based, assessing effect of CTAs for SARS-CoV-2 on quarantine rate, reproduction number (R), total number of infections, hospitalization, mortality, and other epidemiologically and clinically relevant outcomes, were eligible for inclusion. Data extraction – Empirical and model-based studies were both critically appraised based on dedicated quality and risk of bias assessment checklists. Data on type of study (i.e., empirical or model-based), sample size, (simulated) time horizon, study population, CTA type (and associated interventions), comparator, and outcomes assessed, were extracted. Key findings were extracted and narratively summarized. Specifically for model-based studies, characteristics and values of important model parameters were collected. Results – 5123 studies were identified, of which 27 studies (five empirical, 22 model-based studies) were eligible and included in this review. All empirical studies were observational (non-randomized) studies and either at unclear or high risk of bias, mostly due to uncontrolled confounding. Risk of bias of model-based studies was considered high for 7 of 22 studies. Most studies demonstrated beneficial effects of CTAs on R, total number of infections, hospitalization, and mortality. Effect size was dependent on other model parameter values (e.g., proportion of asymptomatic individuals, testing delays), but in general a beneficial effect was observed at CTA adoption rates of 20% and over. Conclusions – CTAs are potentially effective at reducing SARS-CoV-2 related epidemiological and clinical outcomes, though effect size depends on other model parameter values. Methodologically sound comparative empirical studies on effectiveness of CTAs are lacking and would be desirable to confirm findings from model-based studies.",
"keywords": [
"Contact tracing apps",
"epidemiology",
"methodology",
"systematic review",
"COVID-19"
],
"content": "Introduction\n\nThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has dominated worldwide news and scientific research throughout 2020. Since the outbreak in Wuhan (People’s Republic of China) in early December 2019, reducing transmission of SARS-CoV-2 has been a worldwide priority. Digital technology could be applied for efficient contact tracing. Contact tracing applications (CTAs) are able to identify individuals who have recently been in close contact with infected individuals (and may have acquired infection as a consequence). After identification, the contact person can be instructed to go in self-quarantine, preventing further transmission and spread of the virus.\n\nA substantial amount of research on CTAs for SARS-CoV-2 has been performed since the start of the pandemic. Summarizing all evidence, including results from research that has not yet, or is currently undergoing peer-review, is warranted to provide an overview of what is known regarding CTA effectiveness. Research that has not yet undergone peer-review is often published by authors through so-called preprint databases. However, identifying these articles, extracting data, and drawing conclusions can be a challenge, as this requires knowledge on epidemiology, mathematical modelling, systematically appraising evidence, and summarizing that evidence.\n\nA few overviews of evidence on effectiveness of CTAs have been published in recent time. Anglemyer et al. provided an overview of study characteristics and quality appraisal of studies on effectiveness of CTAs and other digital contact tracing technologies.1 However, their data were based on both SARS-CoV-2 infections and other infections (e.g., Ebola), and lacked a quantitative effectiveness measure of CTAs on clinically relevant outcomes. Other systematic reviews focused only on user experience in using a CTA for SARS-CoV-2,2 barriers and challenges for implementation,3 or only studied manual as opposed to digital contact tracing.4 One systematic review did look into studies on automated and semi-automated CTAs for SARS-CoV-2, but lacked reporting on CTA effectiveness on total number of infections, and hospitalization or mortality rates.5\n\nIn this systematic review, we evaluate all (empirical and model based) studies addressing effectiveness of CTAs for SARS-CoV-2 on relevant, i.e., epidemiological and clinical, outcomes. We provide descriptive characteristics, critical appraisal, and a narrative summary of evidence of included studies. This paper is an update of the original systematic review on this topic (doi: 10.1136/bmjopen-2021-050519; published July 2021). An update is warranted, as additional empirical and model-based studies assessing the effectiveness of CTAs have been disseminated since publication of the original systematic review. In particular, empirical studies assessing effects of CTAs on quarantine rates, infections, and mortality rate, have been published in recent time, and have been included in this updated systematic review.\n\n\nMethods\n\nReporting in this paper follows guidance from the PRISMA statement. The checklist and all supplementary files are available via the Open Science Framework repository.36\n\nThe Bern COVID-19 Open Access Project (COAP) database was used for identification of relevant research. The COAP database is comprised of research from EMBASE (OVID), MEDLINE (PubMed), BioRxiv and MedRxiv databases, specifically focused on SARS-CoV-2. On June 9th 2021 the COAP database was searched for scientific literature evaluating the effectiveness of CTAs for SARS-CoV-2 on epidemiological and clinical outcomes. The complete search strategy, as well as background information on the COAP database provided by Bern University, are provided in the Extended data: Supplementary File 1.\n\nEmpirical (both observational and experimental) and model-based studies evaluating effectiveness of CTAs for SARS-CoV-2 were eligible for inclusion. Peer-reviewed publications as well as preprint papers were considered.\n\nCTAs were considered when they provided feedback about potential recent exposure to an infected individual, based on proximity measurements (e.g., Bluetooth or GPS). Feedback should be provided directly to the individual through a CTA, although other feedback mechanisms, such as personal devices (e.g., a smartwatch), were also considered. National emergency warning systems using SMS were also included, provided they used proximity data to inform individuals.\n\nAll epidemiologically or clinically relevant outcomes that were used to quantify the impact of CTAs were considered, which include but are not limited to: quarantine rate, reproduction number (R), total number of infections, hospitalization rate, and mortality rate related to SARS-CoV-2. Studies investigating other relevant outcomes, such as prevention of outbreaks, a second infection wave, or flattening the curve, were also included. Studies solely assessing (determinants affecting) adoption rate of CTAs (i.e., the proportion of citizens using, and following recommendations provided by, the CTA), temporal change in incidence SARS-CoV-2, or other non-epidemiological or clinical outcomes were excluded.\n\nStudies identified in the search were first screened independently on title and abstract by two reviewers. Relevant studies were included for full text screening, and further selection of articles was performed by two independent reviewers. Any discrepancies were discussed and resolved. When consensus was not reached, a third reviewer was consulted to provide the final judgement.\n\nRisk of bias was independently assessed by two researchers using separate checklists for empirical and model-based studies. Discrepancies between researchers were discussed and a final verdict was provided by a third reviewer if consensus was not reached. Empirical studies were appraised using a formal scoring method based on the Critical Appraisal Skills Programme (CASP) and Cochrane’s Effective Practice and Organisation of Care (EPOC) checklists6,7 (Extended data: Supplementary File 2). Risk of bias in model-based research was evaluated by assessing use of empirical input data for the model, number of scenarios analyzed, and transparency of model reporting (Extended data: Supplementary File 3). Information on competing interests and funding were also collected for both empirical and model-based studies.\n\nData extraction was performed manually by one reviewer and checked by a second reviewer. Descriptive characteristics on type of research, i.e., empirical or model-based, sample size, (simulated) time horizon, study population, CTA properties and intervention, comparator, and epidemiological and clinical outcomes studied, were extracted from all included studies.\n\nSpecifically for model-based research, model characteristics (i.e., type of model and distributions used) and values used for important model parameters were collected. Furthermore, CTA specific properties were extracted, such as the method of contact tracing used by these apps. Forward tracing CTAs can only detect the ‘offspring’, i.e., individuals the index case has infected, of an infected individual. Bidirectional tracing CTAs also detect the ‘parents’, i.e., the individual that infected the index case of an infected individual. Models were considered to use bidirectional (as opposed to forward) tracing when, after the index case is detected and registered, all contacts within a period of at least the incubation time are identified, such that the parent of the index case could be found.\n\nAnother CTA specific property included the use of 1-step-tracing or sequential tracing. When a CTA-identified individual could only notify their contacts after testing positive themselves, this was considered 1-step-contact tracing. When notified contacts could subsequently also notify their own contacts, creating a cascade, even before that individual has shown symptoms or received a positive test result for SARS-CoV-2, this was considered sequential tracing.\n\nThe most important findings regarding effectiveness of CTAs for SARS-CoV-2 on epidemiological and clinical outcomes were extracted, synthesized, and reported narratively. These outcomes were pooled quantitatively whenever it was feasible to do so.\n\n\nResults\n\nA total of 5,123 potential studies were identified by the search. After selection based on title and abstract, 4,941 articles were excluded. Full texts of the 182 remaining studies were assessed, after which 27 articles were included for critical appraisal and data extraction (Extended data: Supplementary File 4). The 155 excluded studies with their reasons for exclusion are summarized in Extended data: Supplementary File 5.\n\nA total of 27 primary studies were included, of which five were empirical observational (non-randomized) studies, and 22 were model-based studies (Tables 1 and 2).\n\nN/R = not reported, R = reproduction number, R0 = baseline reproduction number, CTA = Contact tracing app, Manual contact tracing = MCT.\n\n* Household, family, workplace, friends, children,\n\n** Household, school, work, community, church, professional sports, community sports, beaches, entertainment, cafés /restaurants, pubs/bars, public transport, national parks, public parks, large events, child care, social networks, and aged care.\n\nR = reproduction number, R0 = baseline reproduction number, CTA = Contact tracing app, MCT = MCT.\n\nTwo of the 27 studies were published preprints, meaning they had not (yet) gone through the peer review process at the time of data extraction.8,9 Included studies focused predominantly on the general population, although some analyzed the effectiveness of CTAs for specific populations such as hospital personnel, or school children.10–19 Especially in model-based studies, results were often presented graphically. Consequently, the effectiveness of CTAs on epidemiological and clinical outcomes was only partly, or not at all, reported in key numerical figures.\n\nThe model-based studies typically assessed the effectiveness of CTAs by simulating one or more scenarios based on certain baseline or input values (e.g., proportion of asymptomatic infections). Table 3 provides an overview of characteristics and the most important input parameters used in models of the 22 included studies. Ten of the 22 model-based studies evaluated forward tracing CTAs,12,13,15,16,18–23 nine studies analyzed bidirectional tracing CTA,8–11,14,24–27 and three used an alternative or unclear method.17,28,29 Ten studies used a CTA with sequential tracing.8–11,14,17,24–27 Nine of these also used bidirectional CTAs, which are more effective than forward tracing CTAs in reducing R, but require quarantining many more contact persons. This is especially the case when a significant number of infections come from asymptomatic individuals (i.e., transmission from a case who does not (yet) have symptoms), who are unaware they have SARS-CoV-2.25\n\nHyphens (-) indicate a continuous range between numbers, semicolons indicate separate distinct values. R = Reproductionnumber, N/A = not applicable, N/R = not reported, ODE = ordinary differential equations, PDE = partial differential equations, HH = household.\n\n1 For individuals with moderate to severe symptoms.\n\n2 Days between developing symptoms and quarantine of contact. Testing not explicitly modeled.\n\n3 Fraction of infections before symptoms is relevant.\n\n4 Isolation based on positive notification, not a positive test.\n\n5 Based on model by Ferretti et al.\n\n6 Initial phase epidemic, taking household structure into account.\n\n7 Changing app coverage covers imperfect isolation.\n\n8 No true tracing, fixed proportion cases will self-isolate.\n\n9 Time-dependent, maximum value reported in table.\n\nThe percentage of CTA adoption was varied in almost all studies, allowing for assessment of the impact of CTAs on epidemiological and clinical outcomes. Average incubation time, i.e., the mean time between infection and symptom onset of SARS-CoV-2, was estimated to be 5 to 6 days for SARS-CoV-2, which was used by the majority of model-based studies.9–11,13–16,19,21,22,24,25,27,29 The proportion of asymptomatic SARS-CoV-2 infections, used as input parameter in model-based studies, was estimated at 20% to 50% based on empirical data,12,13,15,22 but could vary between 18% to 86%.15 The baseline R value chosen in the model-based studies varied between 1.212 and 5.22.24\n\nFurthermore, superspreaders (i.e., individuals that infect numerous other individuals, and consequently have a high individual R) were discussed in context of the SARS-CoV-2 pandemic. Tracing these superspreaders and their contacts using CTAs was more effective compared to manual contact tracing (MCT).21 Hence, it is warranted to use bidirectional CTAs to trace these superspreaders, and advise them to immediately enter quarantine on identification.16,30\n\nRisk of bias of the five empirical studies was judged to be unclear for two,31,32 and high for three33–35 (Table 4). Confounding variables (such as smoking, work status, and income) were insufficiently taken into account for the three high risk studies, which was due to the explanatory nature of these observational empirical studies. In four out of five studies it was also unclear how missing (outcome) data were dealt with.\n\n* Adjusted for age group, sex, education and employment status.\n\n** Only adjusted for age.\n\n*** Study combines empirical data with modelling of the outcome, hence misclassification is not applicable in this case.\n\nMost model-based research was judged to have a low risk of bias (Table 5). Seven of the 22 studies had a high risk of bias due to the lack of use of empirical distributions for variables, the limited number of scenarios analyzed, and insufficient transparency regarding reporting of the model.10,11,14,17,19,28,29\n\n* Scenarios were limited only to variation in rate of adoption of the contact- and tracing app and voluntary quaranti.\n\nEvidence from empirical studies\n\nFive empirical comparative observational studies assessed the effectiveness of CTAs.31–35 Two studies used empirical data to derive downstream consequences of CTAs using model-based extensions.32,35\n\nBallouz et al. studied the time of going to quarantine for users and non-users of the SwissCovid.31 Results showed that close contacts of index cases that used a CTA went into quarantine sooner compared to non-users of the CTA [Hazard Ratio (HR) 1.5 (95% confidence interval (CI) 1.2–2.0)]. A second study looking at the SwissCovid CTA used empirical data on the number of authorization codes entered by SARS-CoV-2 positive individuals to model the downstream consequences on quarantine recommendations sent out and the increase in number of positively tested contacts.35 From their model-based assessment they found that at most 1.7-5.1% additional cases of SARS-CoV-2 could have been detected by CTA in addition to MCT.\n\nAnother study investigated the introduction and adoption of a ‘Test and Trace’ app by 34,000 individuals living on the Isle of Wight (UK) and compared the estimated value of R in that region to that in the general UK population.34 The CTA marked individuals as positive based on self-reporting of symptoms. Individuals that came in contact with an individual marked as positive were provided with social distancing advice. The study found that R reduced from 1.3 to 0.5 after implementation of the CTA. Within 2 to 3 weeks after implementation, incidence of SARS-CoV-2 diagnoses declined by around 90%.34\n\nA fourth study looked at the effectiveness of a text warning system used in 627,386 individuals who came in contact with an exposed population, and compared this cohort to the general population of Taiwan who did not use such a warning system.20 They showed a reduction in incidence of respiratory syndrome from 19.23 to 16.87 per 1000 individuals. They also showed a reduction in pneumonia incidence from 3.81 to 2.36 per 1000 individuals.20\n\nFinally, Wymant et al. studied the effect of introduction of the NHS COVID-19 CTA on number of cases averted and mortality rate.32 Usage and notification data from 16.5 million users in the UK were used to estimate downstream consequences of NHS CTA use. They used a model-based and a statistical analysis approach and found that respectively 284,000 (95% of simulations ranged between 108,000–450,000) cases, or 594,000 (95% CI 317,000–914,000) cases, could be averted through use of the NHS CTA, relating to 15% or 31% of the total number of cases. Subsequently they determined that 4,200 (95% simulation range 1,600–6,600) deaths, or 8,700 (95% CI 4,700–13,500) deaths could be prevented based on the model-based and statistical approach, respectively. This corresponds to 13% or 27% of the total number of deaths. Approximately one case was averted for each case consenting to notification of their contacts. For every percentage point increase in CTA uptake, the number of cases could be reduced by 0.8% or 2.3% based on the model-based and statistical approach respectively.\n\nEvidence from model-based studies\n\nEffect on R\n\nEffectiveness of a 1-step-contact tracing in reducing R can be approached using the following formula:\n\nHere, Rc is the reproduction number when a CTA is used, R is the reproduction number without the use of a CTA, p is the proportion of the population using the CTA, and f is the combination of other factors that affect effectiveness of notification by the CTA. Such factors include, but are not limited to, delay between CTA notification and testing, delay between testing and test result, delay between reception of test result and entry of that result in the CTA, compliance to interventions (e.g., self-quarantine), and the proportion of infections that occur pre- or asymptomatically. Note that p occurs as a quadratic term, which reflects the fact that both infector and infectee have to use the CTA for the transmission to get traced.\n\nThirteen of the 22 model-based studies assessed the effect of CTAs on reduction of R.9,12–14,16,19,21–23,25–28 CTAs were able to control an ongoing outbreak or epidemic through quicker and more efficient feedback of a positive test result, and by notifying close contacts of a positively tested individual.13,23,25 This speed and efficiency were not feasible using traditional MCT.13 New outbreaks could be controlled (i.e., Rc<1.0) by CTAs, by combining them with quarantine or self-isolation interventions, under the condition that hygiene and social distancing measures are maintained.12,16,22,28 CTAs were able to reduce R by 0.3 more than traditional MCT, provided that feedback about contact with a positively tested individual is given to all contacts of the index case of the preceding 7 days.25 Another model-based study reported that a CTA with 20% adoption rate reduces R by 17.6% compared to no contact tracing, whereas traditional MCT reduced R by 2.5% compared to no contact tracing.23 This study also demonstrated that a CTA is able to reduce the R further, even when social distancing has already reduced R to 1.2. In this situation, R can be reduced further by 30% to 0.8 when CTA adoption rate is 80%.23 Another model-based study determined that 60% adoption rate of a CTA could result in an R below 1.0.19 In one study, adoption rate of 53% resulted in a 47% reduction in R when the complete household of an individual with a positive test result is advised to be quarantined.16 The last study looking at effect of CTA on R showed that only at 60% adoption rate of the app a significant beneficial effect on R would become apparent.27 When R is high (e.g., 3.0), and a considerable proportion of individuals is asymptomatic (e.g., 40% of all infections), CTAs need to be combined with other interventions (such as social distancing and random testing) to be able to lower the R below 1.0.27 Potential for CTAs to reduce R is not only dependent on the adoption rate of the app, but also on (effectiveness of) various other factors in the downstream cascade after a positive notification. These include, but are not limited to, the delay between positive notification and testing,27 and delay between receiving a positive test result,21 and the proportion of users sharing that result through the CTA. One study found that the percentage of preventable infections by one individual strongly depends on the time delay between CTA notification and the ability to be tested.23 When there was no delay (i.e., 0 days) 79.9% of infections could be prevented, compared to 41.8% and 4.9% for 3 and 7 day delay, respectively.\n\nEffect on total number of infections\n\nTwelve of the 22 model-based studies assessed the effect of CTAs on reducing the total number of infections.8–10,15,17–20,22,24,27,29 Two studies indicated that the success of CTAs in reducing the total number of infections could only be ensured with a high adoption rate of that app.12,18 Some plateau effect at 60% adoption rate was observed by one study.24 Another study showed that with a high CTA adoption rate of 75%, there would be no more new infections occurring within three months after implementation.19 It was found that adequate hygiene and social distancing measures are needed to enable CTAs to reduce the total number of infections.12,15,20,22 Especially in areas where there is low compliance to social distancing, a sufficiently high adoption rate of a CTA is essential to maintain control of an outbreak.15\n\nThe peak number of new infections can, according to one study, be reduced by half with a 50% adoption rate of a CTA,22 whereas another study showed that this could be achieved with an adoption rate as low as 20%.29 Another study demonstrated that at 27% CTA adoption rate, a quarter of all new infections can be prevented.20 However, according to another study that used a similar adoption rate, the number of infections would stabilize, but the epidemic would be maintained by core groups in densely populated areas.22 There may be a period of time of more than two months between implementation of interventions (such as CTAs) and the effect of that implementation on the total number of SARS-CoV-2 infections.18\n\nEffect on number of hospitalizations\n\nTwo of the 22 model-based studies assessed the effect of CTAs on the number of hospitalizations due to SARS-CoV-2 infection. One study found that the peak number of hospitalizations reduced up to 46-78% for a 75% CTA adoption rate.24 Another found that peak height of number of hospitalizations could be reduced by at least 50% for a CTA adoption rate of 60% and over.9 A German study did look into the effect of a CTA on the number of days that intensive care unit (ICU) capacity was exceeded.15 They found in their simulations that – based on the German population, and assuming an ICU capacity of 24.000 beds – a CTA adoption rate of 20% would prevent exceedance of ICU capacity at any point in time. In contrast, if no contact tracing (either manual or digital) would be used, ICU capacity would be exceeded on a quarter of days.\n\nEffect on mortality rate\n\nFive of the 22 model-based studies assessed the effect of CTAs on mortality rate.9,15,22,24,29 One study demonstrated that a high adoption rate (80%) of a CTA would result in an 85% reduction in mortality rate, over a period of 500 days.15 Another study found that a low CTA adoption rate (25%) is associated with a 10% decrease in mortality rate, an average adoption rate (50%) with 25% decrease, and a high adoption rate (75%) with 40-60% decrease.22 For the latter 75% CTA adoption rate, slightly higher rates (56-67%) were observed in another study.24 Other evidence showed that at 40% adoption rate, during the peak of an outbreak, a reduction in number of deaths by 97% could be achieved.29 Ruse et al demonstrated that mortality rate could be reduced by at least 50% for CTA adoption rates of 60% and over, provided testing rates were sufficient.9\n\n\nDiscussion\n\nEmpirical evidence regarding the effectiveness of using CTAs for detection of SARS-CoV-2 is still limited. Currently, no randomized studies have been performed, and only five observational (non-randomized) studies were identified in this systematic review. Two of these assessed the effects of CTA use on the number of infections and mortality, though only through modelling based on empirically observed CTA usage data. Although, in general, benefits of using CTAs for detection of SARS-CoV-2 were observed, all studies were deemed to have a high or unclear risk of bias, due to the potential presence of uncontrolled confounding factors, unclear handling of missing data, or both.\n\nDespite these concerns for validity, the results of the empirical studies were in accordance with the (in general high quality) 22 included model-based studies assessing effectiveness of CTAs. These model-based studies showed that CTAs can be effective and a valuable addition to MCT. CTA use consistently resulted in a lower R, lower total number of infections, and lower mortality rate. These reductions were already observed at relatively low adoption rates (e.g., 20%), though higher adoption rates of CTAs clearly resulted in greater impact. Shortening delays between CTA notification and diagnostic testing may increase its effectiveness.\n\nThis systematic review assesses key features, quality, and main clinical and epidemiological outcomes of a set of studies, both empirical and model-based, on effectiveness of CTAs for SARS-CoV-2. To our knowledge, no such systematic review, assessing these specific properties, has been published. Methodological quality of empirical studies was assessed using standardized quality assessment tools. No such tool was available in literature for model-based studies, and as such a set of key features used in systematic reviews on similar topics was used. This set was validated by experts in mathematical modelling of infectious diseases.\n\nTo fully appreciate the findings from this systematic review, some considerations should be taken into account. First, the studies found through the literature search do not include studies published after the search date. Although this seems trivial, it should be noted that studies on SARS-CoV-2 are published at a rapid basis in various online repositories. Between the initial publication of this systematic review and its update on average 432 papers were published per day on SARS-CoV-2 in the COAP database. We cannot ensure that all studies on the effectiveness of CTAs for SARS-CoV-2 have been identified, however we believe that the set of included studies that we have identified is a representative sample.\n\nFurthermore, effectiveness of CTAs for SARS-CoV-2 described in model-based studies is complex. Numerous input variables used in the models interact with one another, and consequently affect effectiveness of, for example, adoption rate of CTAs on clinical or epidemiological outcomes. Summarizing these findings into the general effectiveness is difficult, and will always suffer from simplification of a system of complex interactions. Though we feel that providing (conditional) findings from these studies will help provide some general insight in the impact CTAs may have on clinical and epidemiological outcomes for SARS-CoV-2.\n\nCurrent evidence on the effectiveness of CTAs for SARS-CoV-2 is predominantly based on modelling studies, which indicate that there is potential in beneficially affecting key clinical and epidemiological outcomes. What this update of our original systematic review adds, is additional knowledge from empirical studies that use modelling to assess downstream consequences of CTAs. Although these studies are valuable, they do not provide direct empirical evidence on relevant outcomes. High quality empirical evidence, either from experimental or methodologically sound comparative observational studies, is still needed to be able to draw more robust conclusions regarding effectiveness of CTAs for SARS-CoV-2.\n\nThis paper may be further updated in the future, depending on whether additional empirical research (RCTs or observational studies) on the effectiveness of CTAs for SARS-CoV-2 is published.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nOpen Science Framework: Supplementary files for Systematic review on Effectiveness of Contact tracing apps for COVID-19, https://doi.org/10.17605/OSF.IO/J5M7D.36\n\nThis project contains the following extended data:\n\n• Supplementary file 1: Search strategy\n\n• Supplementary file 2: Method for critical appraisal of empirical studies\n\n• Supplementary file 3: Method for critical appraisal of model-based studies\n\n• Supplementary file 4: Flowchart of study selection\n\n• Supplementary file 5: Excluded studies\n\nOpen Science Framework: PRISMA checklist for ‘Effectiveness of contact tracing apps for SARS-CoV-2: an updated systematic review’, https://doi.org/10.17605/OSF.IO/J5M7D.36\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThis research was funded directly (no grant number) by the Dutch Ministry of Health, Welfare and Sport. Researchers involved in this study contributed to the study’s conception and execution independently from the funding agency, and as such it was in no way influenced by the funding agency.",
"appendix": "References\n\nAnglemyer A, Moore TH, Parker L, et al.: Digital contact tracing technologies in epidemics: a rapid review. Cochrane Database Syst. Rev. 2020; 2020: CD013699. Publisher Full Text\n\nDavalbhakta S, Advani S, Kumar S, et al.: A Systematic Review of Smartphone Applications Available for Corona Virus Disease 2019 (COVID19) and the Assessment of their Quality Using the Mobile Application Rating Scale (MARS). J. Med. Syst. 2020; 44(9): 164. PubMed Abstract | Publisher Full Text\n\nAkinbi A, Forshaw M, Blinkhorn V: Contact tracing apps for the COVID-19 pandemic: a systematic literature review of challenges and future directions for neo-liberal societies. Health Inf. Sci. Syst. 2021; 9(1): 18. PubMed Abstract | Publisher Full Text\n\nNussbaumer-Streit B, Mayr V, Dobrescu AI, et al.: Quarantine alone or in combination with other public health measures to control COVID-19: a rapid review. Cochrane Database Syst. Rev. 2020; 4: CD013574. Publisher Full Text\n\nBraithwaite I, Callender T, Bullock M, et al.: Automated and partly automated contact tracing: a systematic review to inform the control of COVID-19. Lancet Digit. Health. 2020; 2(11): e607–e621. PubMed Abstract | Publisher Full Text\n\nCASP Checklist: Critical appraisal skills programme.2018 [cited 15-10-2020]. Reference Source\n\nEPOC Resources for review authors: Cochrane Effective Practice and Organisation of Care (EPOC).2017 [cited 15-10-2020]. Reference Source\n\nGuttal V, Krishna S, Siddharthan R: Risk assessment via layered mobile contact tracing for epidemiological intervention. medRxiv. 2020:2020.04.26.20080648.\n\nRusu A, Farrahi K, Emonet R: Modelling digital and manual contact tracing for COVID-19 Are low uptakes and missed contacts deal-breakers?. medRxiv. 2021:2021.04.29.21256307.\n\nAlmagor J, Picascia S: Exploring the effectiveness of a COVID-19 contact tracing app using an agent-based model. Sci. Rep. 2020; 10(1): 22235. PubMed Abstract | Publisher Full Text\n\nBarrat A, Cattuto C, Kivela M, et al.: Effect of manual and digital contact tracing on COVID-19 outbreaks: a study on empirical contact data. J. R. Soc. Interface. 2021; 18(178): 20201000. PubMed Abstract | Publisher Full Text\n\nCencetti G, Santin G, Longa A, et al.: Digital proximity tracing on empirical contact networks for pandemic control. Nat. Commun. 2021; 12(1): 1655. PubMed Abstract | Publisher Full Text\n\nFerretti L, Wymant C, Kendall M, et al.: Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing. Science. 2020; 368(6491): eabb6936. PubMed Abstract | Publisher Full Text\n\nFyles M, Fearon E, Overton C, et al.: Using a household-structured branching process to analyse contact tracing in the SARS-CoV-2 pandemic. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2021; 376(1829): 20200267. PubMed Abstract | Publisher Full Text\n\nGrimm V, Mengel F, Schmidt M: Extensions of the SEIR model for the analysis of tailored social distancing and tracing approaches to cope with COVID-19. Sci. Rep. 2021; 11(1): 4214. PubMed Abstract | Publisher Full Text\n\nKucharski AJ, Klepac P, Conlan AJK, et al.: Effectiveness of isolation, testing, contact tracing, and physical distancing on reducing transmission of SARS-CoV-2 in different settings: a mathematical modelling study. Lancet Infect. Dis. 2020; 20(10): 1151–1160. PubMed Abstract | Publisher Full Text\n\nPandl KD, Thiebes S, Schmidt-Kraepelin M, et al.: How detection ranges and usage stops impact digital contact tracing effectiveness for COVID-19. Sci. Rep. 2021; 11(1): 9414. PubMed Abstract | Publisher Full Text\n\nScott N, Palmer A, Delport D, et al.: Modelling the impact of relaxing COVID-19 control measures during a period of low viral transmission. Med. J. Aust. 2021; 214(2): 79–83. PubMed Abstract | Publisher Full Text\n\nShamil MS, Farheen F, Ibtehaz N, et al.: An Agent-Based Modeling of COVID-19: Validation, Analysis, and Recommendations. Cognit Comput. 2021; 1–12. Publisher Full Text\n\nCurrie DJ, Peng CQ, Lyle DM, et al.: Stemming the flow: how much can the Australian smartphone app help to control COVID-19?. Public Health Res. Pract. 2020; 30(2). PubMed Abstract | Publisher Full Text\n\nElmokashfi A, Sundnes J, Kvalbein A, et al.: Nationwide rollout reveals efficacy of epidemic control through digital contact tracing. Nat. Commun. 2021; 12(1): 5918. PubMed Abstract | Publisher Full Text\n\nFerrari A, Santus E, Cirillo D, et al.: Simulating SARS-CoV-2 epidemics by region-specific variables and modeling contact tracing app containment. NPJ Digit. Med. 2021; 4(1): 9. PubMed Abstract | Publisher Full Text\n\nKretzschmar ME, Rozhnova G, Bootsma MCJ, et al.: Impact of delays on effectiveness of contact tracing strategies for COVID-19: a modelling study. Lancet Public Health. 2020; 5(8): e452–e459. PubMed Abstract | Publisher Full Text\n\nAbueg M, Hinch R, Wu N, et al.: Modeling the effect of exposure notification and non-pharmaceutical interventions on COVID-19 transmission in Washington state. NPJ Digit. Med. 2021; 4(1): 49. PubMed Abstract | Publisher Full Text\n\nBradshaw WJ, Alley EC, Huggins JH, et al.: Bidirectional contact tracing could dramatically improve COVID-19 control. Nat. Commun. 2021; 12(1): 232. PubMed Abstract | Publisher Full Text\n\nBulchandani VB, Shivam S, Moudgalya S, et al.: Digital herd immunity and COVID-19. Phys. Biol. 2021; 18(4): 045004. PubMed Abstract | Publisher Full Text\n\nPollmann TR, Schonert S, Muller J, et al.: The impact of digital contact tracing on the SARS-CoV-2 pandemic-a comprehensive modelling study. EPJ Data Sci. 2021; 10(1): 37. PubMed Abstract | Publisher Full Text\n\nKurita J, Sugawara T, Ohkusa Y: Estimated effectiveness of school closure and voluntary event cancellation as COVID-19 countermeasures in Japan. J. Infect. Chemother. 2021; 27(1): 62–64. PubMed Abstract | Publisher Full Text\n\nNuzzo A, Tan CO, Raskar R, et al.: Universal Shelter-in-Place Versus Advanced Automated Contact Tracing and Targeted Isolation: A Case for 21st-Century Technologies for SARS-CoV-2 and Future Pandemics. Mayo Clin. Proc. 2020; 95(9): 1898–1905. PubMed Abstract | Publisher Full Text\n\nEndo A, Leclerc QJ, Knight GM, et al.: Implication of backward contact tracing in the presence of overdispersed transmission in COVID-19 outbreak. medRxiv. 2020:2020.08.01.20166595.\n\nBallouz T, Menges D, Aschmann HE, et al.: Adherence and Association of Digital Proximity Tracing App Notifications With Earlier Time to Quarantine: Results From the Zurich SARS-CoV-2 Cohort Study. Int. J. Public Health. 2021; 66: 1603992. PubMed Abstract | Publisher Full Text\n\nWymant C, Ferretti L, Tsallis D, et al.: The epidemiological impact of the NHS COVID-19 app. Nature. 2021; 594(7863): 408–412. PubMed Abstract | Publisher Full Text\n\nChen CM, Jyan HW, Chien SC, et al.: Containing COVID-19 Among 627,386 Persons in Contact With the Diamond Princess Cruise Ship Passengers Who Disembarked in Taiwan: Big Data Analytics. J. Med. Internet Res. 2020; 22(5): e19540. PubMed Abstract | Publisher Full Text\n\nKendall M, Milsom L, Abeler-Dorner L, et al.: Epidemiological changes on the Isle of Wight after the launch of the NHS Test and Trace programme: a preliminary analysis. Lancet Digit Health. 2020; 2(12): e658–e666. PubMed Abstract | Publisher Full Text\n\nMenges D, Aschmann HE, Moser A, et al.: A Data-Driven Simulation of the Exposure Notification Cascade for Digital Contact Tracing of SARS-CoV-2 in Zurich, Switzerland. JAMA Netw. Open. 2021; 4(4): e218184. PubMed Abstract | Publisher Full Text\n\nJenniskens K: Supplementary files for Systematic review on Effectiveness of Contact tracing apps for COVID-19.2022, April 13. Publisher Full Text"
}
|
[
{
"id": "181006",
"date": "03 Aug 2023",
"name": "Joren Raymenants",
"expertise": [
"Reviewer Expertise Clinical infectious diseases",
"epidemiology (focus on contact tracing in COVID-19)"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI want to thank the authors for their article and work, which collates some of the literature on digital contact tracing during COVID-19. The article and tables could be a good starting point for colleagues for further reading.\nThe article doesn’t however provide much critical evaluation of the possible reasons for the large discrepancies between estimates for DPT effectiveness between studies, and more specifically, the reasons why empirical evaluations of DPT were so much less favourable than many of the modelling studies. For example, Menges et al 2021 (cited in the text) estimated that DPT could increase the number of detected cases only by a few percentages even with decent uptake. I don’t however think this is absolutely required for this work to be of use to the scientific community, and do support publication in f1000 research with some minor revisions.\nSome specific comments in sections in the text that could be of interest to the authors to have another look at:\n“Research that has not yet undergone peer-review is often published by authors through so-called preprint databases. However, identifying these articles, extracting data, and drawing conclusions can be a challenge, as this requires knowledge on epidemiology, mathematical modelling, systematically appraising evidence, and summarizing that evidence.” While I agree that some or all of this background is required for critical appraisal, this applies to peer-reviewed research as well as other data sources, so I’d leave out the specific reference to preprint manuscripts.\n\n“Forward tracing CTAs can only detect the ‘offspring’, i.e., individuals the index case has infected, of an infected individual. Bidirectional tracing CTAs also detect the ‘parents’, i.e., the individual that infected the index case of an infected individual. Models were considered to use bidirectional (as opposed to forward) tracing when, after the index case is detected and registered, all contacts within a period of at least the incubation time are identified, such that the parent of the index case could be found.” I would advise to specify that forward contact tracing to detect the offspring, while bidirectional contact tracing to also identify the parent (and subsequently sibling) cases, as the direction of transmission is not known during contact tracing.\n\n“Within 8 months, cumulative incidence of SARS-CoV-2 can be reduced to 13-24% at CTA adoption of 27%, 17-35% at CTA adoption of 40%, 36-59% at CTA adoption of 61%, and 47-76% at CTA adoption of 80%.” I think you mean “can be reduced ”?\n\n“1 in 10.9 persons who uploaded a code in the CTA tested positive for SARS-CoV-2”. Actually, Menges et al report that “For every 10.9 (95% SI, 7.6-15.6) upload authorization codes entered in the app, 1 contact had positive test results for SARS-CoV-2 after app notification.” While the first statement seems to point at test positivity rate, which cannot be correct because only infected individuals can upload a code, the second states that for every 10.9 individuals, a single infected contact is detected (which is not a lot in the context of COVID-19’s R0).\n\n“and f is the combination of other factors that affect effectiveness of notification by the CTA. Such factors include, but are not limited to, delay between CTA notification and testing, delay between testing and test result, delay between reception of test result and entry of that result in the CTA, compliance to interventions (e.g.,self quarantine), and the proportion of infections that occur pre-or asymptomatically.” I realise that this is not an exhaustive list, and thus leave it to the authors to consider my suggestion, but I’d advise to either evaluate in these studies, or at least discuss the limitations of the accuracy with which these apps are able to detect exposure events using BLE SSRI. But again I leave it to the authors to integrate this point or not.\nExamples of studies that looked at this:\nBallouz, T. et al. Individual-Level Evaluation of the Exposure Notification Cascade in the SwissCovid Digital Proximity Tracing App: Observational Study. JMIR Public Health Surveill 8, (2022);\nVogt, F., Haire, B., Selvey, L., Katelaris, A. L. & Kaldor, J. Effectiveness evaluation of digital contact tracing for COVID-19 in New South Wales, Australia. Lancet Public Health 7, e250–e258 (2022).;\nLeith, D. J. & Farrell, S. Measurement-based evaluation of Google/Apple Exposure Notification API for proximity detection in a light-rail tram. PLoS One 15, e0239943 (2020).\n\n“the results of the empirical studies were in accordance with the (in general high quality) included model-based studies assessing effectiveness of CTAs.” Actually, I think empirical studies (especially the individual bases studies from Zurich: https://publichealth.jmir.org/2021/12/e30004, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779376, https://smw.ch/index.php/smw/article/view/2931/4822, but also https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(22)00010-X/fulltext) are not in accordance with the generally very positive evaluations in modelling studies.\n\n“Although this seems trivial’. While it is understandable to set a cutoff for study inclusion, I would leave out the trivial comment, since including more recent literature could have provided a more complete picture.\nI would like to thank the authors again for the work that went into this article, and the editors for inviting me to review.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": []
},
{
"id": "180981",
"date": "04 Aug 2023",
"name": "Diane Woei-Quan Chong",
"expertise": [
"Reviewer Expertise Public health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nHere are the key recommendations:\n1. Incorporation and impact of new studies. This updated systematic review offers vital new insights into the effectiveness of CTAs. However, it would add value if the authors specifically indicated the number of additional studies included compared to the original review. Describing how these new inclusions have enriched the review in terms of the breadth and depth of analysis would substantiate the significance of this updated review.\n\n2. Explanation of inclusion methods for new studies. For enhanced clarity, I recommend a more comprehensive description of the methods employed for the inclusion of newer studies, e.g., if the search criteria were extended or other relevant modifications.\n\n3. Outcome variables in data extraction. In the phrase 'effectiveness of CTAs for SARS-CoV-2 on epidemiological and clinical outcomes,' there's a need to specify the outcomes evaluated. The use of 'most important' may seem subjective and can be further clarified to maintain objectivity.\n\n4. Impact of new studies on review results. Kindly discuss how the inclusion of new studies might have impacted the results compared to the previous review. This could entail highlighting (if any) shifts in key findings, emergence of new trends, or reinforcement of previous conclusions.\n5. Timeline and contextual factors. Given the rapidly evolving epidemiological trajectory of COVID-19, it's crucial to provide a timeline or chronological context of when each study was conducted and when the CTAs were implemented. This would offer a more robust understanding of the CTAs' effectiveness over time and across different epidemiological scenarios.\n6. Supplementary Files Accessibility. It’s essential to ensure the provided link for supplementary materials is working and accessible.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-515
|
https://f1000research.com/articles/8-1835/v1
|
31 Oct 19
|
{
"type": "Opinion Article",
"title": "Time to initiate randomized controlled clinical trials with methadone in cancer patients",
"authors": [
"Hans-Joachim Kremer"
],
"abstract": "Public media coverage has fueled a demand for methadone as potential cure for cancer itself. Because patients have asked for respective prescriptions, clinical societies issued statements warning against the use of methadone as long as preclinical findings have not been supported by clinical evidence. In fact, not all preclinical data clearly support relevant effects. However, strong epidemiologic data suggest beneficial effects of methadone on cancer. Alternative explanations, namely better safety of methadone or hidden selection bias, seem less likely. This uncertainty can only be resolved by randomized controlled clinical trials. This review discusses all relevant data pertinent to methadone and cancer, uncovers supportive epidemiologic data, and suggests possible study designs.",
"keywords": [
"Methadone",
"doxorubicin",
"cancer",
"randomized controlled clinical trials"
],
"content": "List of abbreviations\n\nAIDS Acquired immunodeficiency syndrome\n\nART Antiretroviral therapy\n\nCI Confidence interval\n\nCNS Central nervous system\n\nHIV Human immunodeficiency virus\n\nHR Hazard ratio\n\nMGMT O6-methylguanin-DNA-methyltransferase\n\nMMT Methadone maintenance therapy\n\nOR Opioid rotation\n\nSD Standard deviation\n\nVA Veterans Affairs\n\n\nBackground\n\nSince 2017, public media have suggested methadone as a potential cure of cancer. As a result, patients are demanding a prescription of methadone when cancer has been diagnosed or has progressed, perhaps with pain as an excuse. An unrepresentative online survey among German oncologists, conducted in summer 2017, indicated that 83% of 473 responding physicians had experience with patients who “frequently or very frequently” asked for methadone therapy1. There are indications that an increase in the demand for methadone has spread from Germany to Austria and Switzerland, and beyond2,3.\n\nIt is certainly not in the interest of medical sciences and not of future patients, if today’s patients continue demanding methadone for an unproven therapy. Not surprisingly, several clinical societies have published warning statements on the use of methadone as a cancer therapy4–7. While all of these societies called for controlled clinical data, they did not evaluate encouraging data on methadone and did not propose designs for a clinical trial. Sometimes, they warned on use of methadone with questionable arguments on its safety. Whether associated to this skepticism or not, no clinical trial evaluating methadone for cancer has yet been initiated, although 152 and 47 trials with methadone as an intervention, but other uses, have been posted on clinicaltrials.gov and in the EU Clinical Trials register, respectively, since 20138. Therefore, this article reviews the all data that could provide a rationale for evaluating methadone as an anticancer agent.\n\nGeneral pharmacological properties of methadone are not discussed here. These properties were discussed in a review proposing methadone as a “tumor theralgesic”. However, it did this without thoroughly discussing the clinical and epidemiologic evidence9. It should be stressed that methadone is a racemate and should be understood as such unless therwise indicated. The levo- or (–) form is considered to be active at the µ-opioid receptor, the dextro or (+) form is considered inactive there; other opioid receptors appear to be largely unaffected by both forms10. In the USA, methadone is licensed for the treatment of moderate to severe pain not responsive to non-narcotic analgesics, for detoxification treatment of opioid addiction, and for maintenance treatment of opioid addiction11. In many European countries, methadone is only approved for the treatment of opioid drug addiction12. In some European countries, levomethadone is available for the treatment of severe pain and treatment of opioid drug addiction13. Dextromethadone has not been approved anywhere, but is currently undergoing a clinical research program major depressive disorder14.\n\n\nPreclinical findings\n\nPreclinical data, rather than clinical observations, have triggered research on the use of methadone in cancer. Already in the 1980s, studies on neuroblastoma indicated delayed tumor growth after opioids of the morphine-type and their antagonism by naltrexone15–17. Similar findings were reported for morphine and naloxone in lung cancer cells, although in concentrations far above the therapeutic range18. That group then investigated methadone in human lung cancer cells19. Some effects were observed already at concentrations of 1 nM and strong effects at 10 nM; 10 nM correspond to about 3 ng/mL, i.e. rather below therapeutic plasma levels (see below). They also found similar effects with dextromethadone alone, which was slightly more active than levomethadone in some cell lines. These data prompted further studies by this group confirming the effects of methadone20–23. Apparently, these findings were not challenged by other groups.\n\nRather high concentrations of methadone, but not morphine, hydromorphone, or naloxone, increased the accumulation of vinblastine in multidrug resistant cells24.\n\nInterest in the antineoplastic potential of methadone was revived about 10 years later when a German group around Claudia Friesen took up these data25. Her group found that methadone inhibited proliferation of HL-60 myeloid leukemia cells and activated apoptosis pathways. In particular, methadone was able to overcome chemo- and apoptosis resistance, especially but not only resistance to doxorubicin (HL-60 cells were resistant to doxorubicin at a concentration of 100 ng/mL). Methadone alone showed some effects at 15 µM (5000 ng/mL) and was fully effective at 30 µM. Note, however, that peak concentrations of methadone after oral administration in humans were found between 124 to 1255 ng/mL, and steady state levels between 65 to 630 ng/mL11. Hence, the effects in these cell lines might be insufficient for claiming antineoplastic effects of methadone alone under therapeutic conditions.\n\nThen a Spanish group found that methadone was able to induce a necrotic-like cell death in SH-SY5Y cells, i.e. a cell line commonly used in basic research on neuronal functions and cancer26. Although this group admitted to having observed these effects in supratherapeutic doses, they concluded that their finding could explain the toxic effects on various cell lines including cancer and leukemia cells. A Canadian group found methadone to induce apoptosis in pediatric acute lymphoblastic leukemia cells27. They determined high levels for IC50 for all but only one pro-B-cell leukemia cell line that exhibited an IC50 of “only” 9400 ng/mL, i.e. still clearly above the therapeutic range.\n\nIn 2008, the German group filed a patent application that claimed, among others things, that methadone (1000 ng/mL) could enhance the apoptotic effects of doxorubicin (100 ng/mL) in glioblastoma cells28. Corresponding details were published 2013 showing that methadone at a concentration as low as 100 ng/mL was able to enhance the apoptotic effects of doxorubicin in concentrations between 10 and 60 ng/mL in acute lymphoblastic leukemia cells29. Peak plasma concentrations of doxorubicin average 4100 ng/mL (SD 220) after a modest 10 mg/m2 dose30. Thus, this apoptosis-enhancing combinatorial effect might occur in the therapeutic range of both substances. The authors explained the interaction by increased cellular uptake of doxorubicin by methadone, which in turn might be explained by a down-regulation of cAMP by the opioid29. This group then investigated this interaction in glioblastoma cell lines and confirmed previous findings on apoptosis and doxorubicin enhancement31. In this setting methadone exhibited significant effects at 1000 ng/mL or higher.\n\nThereafter, public interest grew, fueled by public media; the above-mentioned critical statements from oncologic societies were published, and methadone was investigated by other groups. Levomethadone was found to be ineffective in glioblastoma cells; however, data on the racemate were not reported by that group32. Instead of doxorubicin they used temozolomide, an alkylating agent that is recommended for glioblastoma, in contrast to doxorubicin, which is unable to cross the blood-brain barrier, and therefore not recommended for glioblastoma30. In fact, no controlled clinical trial of doxorubicin in glioma has ever been published. Conversely, it is unclear whether temozolomide as such is useful in vitro, as it is active only after conversion to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC)33. Another group also found no interaction of methadone and temozolomide in glioblastoma cell lines and methadone being active in only one cell line at a high concentration of 15 000 ng/mL34.\n\nWhile methadone alone was inactive in melanoma cell lines from a biobank, its combination with cisplatin decreased viability in a cell line displaying a high expression of OPRM1, a main receptor for methadone35. However, cell lines expressing OPRM1 were rather rare in this biobank of melanoma cells.\n\nA very recent report again denied in vitro interaction between methadone and temozolomide in glioblastoma cells, but reported decreased viability of fibroblasts after 1 µM methadone, i.e. about 300 ng/mL36.\n\nA more detailed review on preclinical research findings on antineoplastic effects of methadone was published end of 20183.\n\n\nEpidemiological data\n\nFrom the plethora of epidemiologic studies with methadone, those with data on mortality were selected.\n\nA thorough analysis of the Veterans Affairs (VA) database compared mortality after treatment with long-acting morphine and methadone37. The aim was to compare the safety as some authors had suggested disadvantages of methadone.\n\nThe authors identified patients who had received a new prescription for either methadone or long-acting morphine. The time frame was 2000 through 2007. They analyzed 98,068 patients in the primary analysis cohort. It should be stressed that they specifically excluded patients diagnosed with metastatic cancer and those in palliative care, and patients receiving methadone for opioid addiction (because morphine is not used for this indication and would therefore be an inappropriate control). The analyzed population was composed of patients who mainly used the drugs for a non-cancer pain indication and some who used them for non-metastatic cancer pain; less than 2% had HIV/AIDS (Table 1).\n\nP·Y: Person-years37.\n\nRatio Me/Mo indicates the ratio of the P·Y values, methadone by long-acting (LA) morphine per quintile.\n\nThe background data were derived from the supplementary appendix37. The upper 2 lines (age, any malign.) show two variables that presumably triggered the advantage for methadone over LA morphine concerning survival.\n\nThe middle 4 lines (MI, CHF, HIV/AIDS, Tobacco) show otherwise important variables related to survival without obviously relevant differences between the groups. Back pain and joint limb pain are shown as main explanation for the indication and the almost turned Me/Mo ratio in Quintile 5.\n\nAn HR below 1 indicates a lower mortality after methadone compared with LA morphine, the lower the better. The HR of 0.36 could be translated e.g. into 100/1000 LA morphine patients died but only 36/1000 methadone patients in the same time interval.\n\nMI: Myocardial infarction. CHF: Congestive heart failure.\n\nNote that the paper did not provide data on the body mass index.\n\nTo control for selection bias, they calculated propensity scores based on several demographic and medical data and split the set into five demographically more homogenous quintiles. The Kaplan-Meier survival function calculated for these quintiles found clearly improved survival (i.e. low hazard ratios, HR, cf. Table 1) in Quintile 1 favoring methadone over long-acting morphine. Quintiles 2 to 4 also indicated an advantage of methadone, but less clearly. The last quintile indicated no difference in survival. The actual survival curves indicated that Quintile 1 was at greatest risk, while Quintiles 4 and 5 were at lowest risks. A closer look at the data including the appendix of this article37 suggests that “any malignancy” was the most important dichotomic factor and that age was the most important continuous factor yielding low propensity scores and lower quintile numbers.\n\nTo test the robustness of their findings, the authors also analyzed the data after exclusion of patients “with any cancer diagnostic code”; note that this term led to numbers different from those pertinent to “any malignancy”. The authors found that the difference in survival in this subcohort “noncancer” was reduced as compared to the primary analysis set (Table 2). These data allow a recalculation of the HR of the alternative subcohort “cancer”, which was even more favorable for methadone (Table 2).\n\nHR: Hazard ratio of survival estimates. Values below 1 indicate lower mortality after methadone (compared with long-acting morphine)37.\n\na HR and CI were not reported in that paper. However, the HR can be estimated from the data given. For the CI of this subcohort a CI width between the other 2 cohorts was assumed. Note that this is a very conservative strategy given the much higher sample size in the subcohort “cancer”.\n\nHence, this powerful epidemiologic study indicates:\n\nMethadone appears to have a survival advantage (HR 0.56) compared with long-acting morphine in patients which are non-metastatic, non-HIV, and non-addicts.\n\nThe advantage is reduced or even abolished in patients without malignancy and in younger patients.\n\nThe advantage is even more pronounced in patients with a malignant history. This holds true overall (subcohort “cancer”: HR 0.51) and especially for those with highest prevalence of malignancies (Quintile 1: HR 0.36).\n\nThe authors concluded, conservatively, that they found no evidence of excess all-cause mortality after methadone compared with long-acting morphine. They did not emphasize a possibly protective or beneficial effect with respect to cancer, nor did they provide any rationale for the significant difference in the primary cohort. The vast database makes a chance finding unlikely, although hidden selection bias still cannot be ruled out. The propensity scoring controlled for selection bias to the extent possible, as did other analyses of that group38.\n\nAn earlier retrospective cohort study investigated the safety of newly prescribed methadone, extended-release oxycodone, extended-release morphine, and transdermal fentanyl from a US Medicaid database39. This study received less attention than the article discussed above, presumably due to the smaller sample size (5,684, divided into four treatment cohorts) and the lack of consistent differences. Abstracted from p-values and focused on estimates, this study can be considered in line with the VA study discussed above. Among cancer pain patients, mortality rates were lower after methadone than after morphine, while the difference was less pronounced in noncancer pain patients (Table 3), i.e. a pattern similar to that of the VA study (Table 2). The authors also found a trend towards fewer emergency department visits or hospitalizations for methadone compared with morphine (Table 3), although, in all, methadone caused more frequent overdose symptoms. Methadone was also numerically better than oxycodone and fentanyl in cancer pain patients, suggesting unique properties of methadone.\n\nTranscribed from Tables 3, 4, and 5 of reference39.\n\nEstimates from Cox Proportional Hazard Models. HR: Hazard Ratio. TD: Transdermal (patch)\n\nA retrospective cohort study analyzed data obtained between 1997 and 2009 from the Tennessee Medicaid40. The authors included 32,742 sustained-release morphine recipients and 6,014 methadone recipients, and excluded patients with evidence of cancer or HIV infection. They counted only “out-of-hospital mortality given that opioid-related deaths typically occur outside the hospital”. This resulted in the rule that “patients in the hospital could not enter the cohort until 30 days after discharge”, i.e. early mortality was disregarded. With this dataset they found an HR for mortality of 1.46 (95% CI: 1.17–1.83), indicating an increased risk of death after methadone. The authors concluded that the increased risk of death observed for users of methadone, even for low doses, supports recommendations that it should not be a drug of first choice for non-cancer pain. The data seem to contradict the VA study regarding the risk in the subcohort “non-cancer”. This difference can be explained by the discounting of early deaths in the Tennessee study. Exploratory analyses showed that overdose was the most frequent cause of unbalanced mortality. It should be remembered that methadone is often used in liquid form which facilitates overdose.\n\nSeveral studies and one meta-analysis41 have provided comparative mortality data on methadone maintenance therapy (MMT) in HIV patients receiving antiretroviral therapy (ART). The meta-analysis found significant heterogeneity among the studies analyzed. Two Chinese cohort studies were most powerful, one42 was included in the above mentioned meta-analysis, the other43 is more recent. Both studies indicated that an MMT program is better than withholding methadone; the latter study indicated that stopping opioid use entirely leads to the lowest mortality rates. The proportion of virological suppression showed only a weakly inverse correlation with mortality43. Patients with HIV infection are still at risk for the development of AIDS, and often die from various cancers, including Kaposi's sarcoma, non-Hodgkin lymphoma, Burkitt's lymphoma, primary central nervous system lymphoma, and cervical cancer. Interestingly, doxorubicin is first-line treatment for Kaposi's sarcoma and second-line for some forms of leukemia. Although it may be speculative to conclude anticancer efficacy of methadone from these data, they are at least compatible with beneficial effects of methadone alone or in combination with doxorubicin. Further epidemiological research should address a potential interaction.\n\nLiterature search for mortality, methadone, and Kaposi sarcoma or lymphoma did not yield meaningful data. The same holds true for searches for Kaposi sarcoma or lymphoma, and vinblastine or doxorubicin, and methadone.\n\n\nData from clinical trials\n\nCochrane reviews on methadone in noncancer pain44 and cancer pain45 are available. Both meta-analyses were hampered by low to very low quality of the source studies. The review in noncancer pain assessed the quantity and quality of evidence as too poor to draw conclusions on efficacy or safety between methadone, placebo, other opioids, or other treatments44. The more recent review in cancer pain concluded that methadone has similar analgesic benefits when compared with morphine, is cheaper in many countries, but might be more difficult to handle than morphine or transdermal fentanyl45. They found no differences in safety or mortality. A recent overview on several Cochrane reviews confirmed these statements46.\n\n\nTargeted investigations\n\nThe following articles explicitly referred to one of Friesen’s articles25,29,31.\n\nFriesen and clinicians from Berlin, Germany, published a retrospective study on a rather poorly defined set of glioma patients: In total, 27 patients were exposed to methadone at different stages of therapy; 13 were exposed soon after diagnosis and 12 of these 13 were classified as evaluable for efficacy47.\n\nThese 12 patients had been diagnosed with a primary glioblastoma multiforme and all initially received surgical therapy, most with gross total resection. After surgery, all received temozolomide and methadone. Of the 12, five were MGMT negative, i.e. at high risk. Of these five, four achieved progression-free survival for 6 months, which according to the authors could be compared with a published survival rate of 40%. The remaining seven patients were MGMT positive, i.e. at low to moderate risk. All seven MGMT-positive patients achieved progression-free survival for 6 months, which compared favorably with a rate of 79% observed in that centre before methadone was used. These data would be compatible with some beneficial effects, but even negative effects cannot be ruled out due to the small sample size.\n\nThe authors also presented safety, progression, and survival data of all 27 patients exposed to methadone. These data cannot be interpreted for efficacy due to heterogeneous baselines and therapies. The authors concluded that methadone can be safely combined with standard glioma chemotherapy. No patient was treated with doxorubicin.\n\nA US group analyzed the data of consecutive supportive care outpatients of a tertiary cancer center48. They identified patients who underwent opioid rotation (OR), and defined two cohorts: OR to methadone (76 patients) and OR to any other opioid (88 patients). They found median survival after OR to methadone of 3.75 months (95% CI: 2.3–6.46) and after OR to other opioids of 2.62 months (95% CI: 1.74–4.33). The difference was not statistically significant, however, the small sample sizes should be considered. Given the short survival times the difference, if true, appears to be substantial.\n\nThe authors also provided data on patients with a follow-up visit. However, these data cannot be interpreted reasonably due to attrition bias, namely early deaths after rotation to other opioids.\n\nSocial media are referring to many cases. These are ignored here as long as not published in scientific journals.\n\nThere were five isolated case reports recently discussed in an opinion article from an Austrian group that is skeptical on methadone for cancer2. Only one of these cases (counted as number 5) may have been relevant, as it was on concomitant use of chemotherapeutics and methadone; unfortunately, the outcome of this case was not reported. The other four cases may be, if any, of little relevance to the efficacy of methadone, as it was administered without concomitant chemotherapy. All these cases, however, illustrate the dilemma for physicians confronted with a patient’s last hopes, as methadone was always prescribed on patient’s demand.\n\n\nDiscussion of evidence\n\nThe preclinical data suggests that racemic methadone itself can inhibit the growth of human lung cancer cells19, increase the uptake of doxorubicin into leukemia cells29, and reduce viability of fibroblasts36 at concentrations that could be achieved with normal doses. There is little rationale to consider glioma or other CNS cancers as useful indication of methadone or add-on treatment with doxorubicin.\n\nEpidemiological data are encouraging, most of all the VA study37. The four-cohort study39 numerically supports the findings of the VA study, as well as the opioid rotation study48. The study investigating out-of-hospital mortality40 should not be considered contradictory due to selective counting of deaths and the focus on noncancer pain. The positive outcomes of HIV studies42,43 might be explained by both the beneficial effects on cancer and a diminished use of illicit drugs. However, use of illicit drugs had no relevant quantity in the other studies.\n\nThe two targeted investigations were too small, but were also compatible with beneficial effects47,48.\n\nAll in all, epidemiologic and clinical data consistently indicate that patients treated with methadone had a better prognosis than those treated with morphine, and that this difference was larger the higher the proportion of patients with cancer diagnosis was.\n\nWhat could alternative explanations be? Is methadone simply safer than long-acting morphine? Other evidence49, guidelines50,51, and market data52 on opioids do currently not support this assumption. Furthermore, there is no pharmacologic or physiologic rationale explaining why such safety advantage could be confined to unselected cancer patients.\n\nOr was there a hidden selection bias? In fact, the VA study37 did not control for socioeconomic status. However, it would be counterintuitive to assume that the “cheaper” methadone would be more often prescribed to the “rich” and the “more natural” morphine rather to the “poor”.\n\nA reasonable explanation is that methadone yields protective or beneficial effects in cancer. And this effect cannot be explained by an effect of methadone in glioma or other central nervous cancers, as these cancers have too low a prevalence.\n\n\nWhat should be done?\n\nIf methadone is beneficial, whether alone or with doxorubicin, these effects may not be so overwhelming that historically controlled or other cohort studies would be sufficient to demonstrate efficacy. Any uncontrolled distribution of methadone is certainly inappropriate and should not be encouraged. Even prospective registry studies do not appear to be reasonable solutions, as enormous sample sizes would be required given the extreme variability of indications and cancer therapies and the assumed moderate effects. Moreover, prospective registry studies could hamper recruitment into properly designed clinical trials.\n\nAs patients will continue demanding methadone for cancer, it is now time to initiate randomized controlled clinical trials with methadone in cancer patients. Doxorubicin could be used in a 2x2 design or as a factor in the analysis, calling for patients eligible for doxorubicin therapy. Instead, cancer pain should be no selection criterion. The control group could be placebo; however, a reasonable alternative could be watchful waiting for, say, 6 months. This is because most “active” patients and some investigators might correctly guess the true nature of blinded treatment. Moreover, open designs would facilitate treatment of breakthrough pain, maybe with other opioids. Anyhow, the focus should be on opioid-naïve patients.\n\nThe dosage of methadone could be based on the paper by Onken et al.47. A dose or concentration controlled design could be considered53. To investigate opioid-experienced patients, a randomized withdrawal design54 might be an option, initially switching all patients to methadone and then withdrawing (or not) it in a blinded manner after, say, 2 weeks. Under such circumstances, it would be unwise to administer any chemotherapy before the end of the withdrawal phase.\n\nUnder these prerequisites, methadone appears to be sufficiently safe for initiating a large trial. It should be stressed that it is unclear as to whether methadone would “win” against control. However, almost any outcome would relevantly expand medical knowledge and provide appropriate arguments for answering patients’ hopes, whether justified or not.\n\n\nConclusions\n\nCancer patients are asking for a methadone therapy, although such therapy is not yet supported by clinical evidence.\n\nThere are nonclinical data supporting its usefulness against certain types of cancer or as enhancer of doxorubicin.\n\nStrong epidemiologic data support its usefulness for cancer, while alternative explanations rather appear unlikely.\n\nIt is time to initiate randomized controlled clinical trials to test the efficacy of methadone as a therapy for cancer patients.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "Author contribution\n\nDr. Hans-Joachim Kremer searched and analyzed literature, and outlined, wrote, and edited the whole manuscript.\n\n\nAcknowledgement\n\nI thank Dr. Herbert Sindermann for thorough review and fruitful discussions.\n\n\nReferences\n\nGerman Society for Hematological and Medicinal Oncology: Results of the online-survey “Methadon in der Krebstherapie”. (in German). Reference Source\n\nKreye G, Masel EK, Hackner K, et al.: Methadone as anticancer treatment: hype, hope, or hazard? : A series of case reports and a short review of the current literature and recommendations of the societies. Wien Med Wochenschr. 2018; 168(7–8): 159–167. PubMed Abstract | Publisher Full Text\n\nTheile D, Mikus G: Methadone against cancer: Lost in translation. Int J Cancer. 2018; 143(8): 1840–1848. PubMed Abstract | Publisher Full Text\n\nGerman Society for Neurology. 2015; Accessed 28 October 2019. Reference Source\n\nHofbauer H, Schenk M, Kieselbach K, et al.: [Use of methadone for support of oncological treatment? : Statement of the working group on tumor pain of the German Pain Society]. Schmerz. 2017; 31(1): 2–4. PubMed Abstract | Publisher Full Text\n\nGerman Cancer Society. 2017; Accessed 28 October 2019. Reference Source\n\nAustrian Society for Hematology and Medicinal Oncology. 2017; Accessed 28 October 2019. Reference Source\n\nSearch at www.clinicaltrials.gov: and separate https://www.clinicaltrialsregister.eu/ctr-search/ on “methadone” as intervention; posted after 1 January 2013 for clinicaltrials.gov; no time restriction applied for the EU register. Lastly searched on 28 October 2019.\n\nMichalska M, Katzenwadel A, Wolf P: Methadone as a “Tumor Theralgesic” against Cancer. Front Pharmacol. 2017; 8: 733. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWikipedia: English. Methadone. Accessed August 2019.\n\nDrugs@FDA: FDA Approved Drug Products: Methadone. Accessed August 2019. Reference Source\n\nElectronic Medicines Compendium: Methadone 1 mg/ml oral solution. Accessed August 2019. Reference Source\n\nL-Polamidon® Tropfen. Accessed August 2019. Reference Source\n\nRelmada Inc. Accessed August 2019. Reference Source\n\nZagon IS, McLaughlin PJ: Heroin prolongs survival time and retards tumor growth in mice with neuroblastoma. Brain Res Bull. 1981; 7(1): 25–32. PubMed Abstract | Publisher Full Text\n\nZagon IS, McLaughlin PJ: Naltrexone modulates tumor response in mice with neuroblastoma. Science. 1983; 221(4611): 671–3. PubMed Abstract | Publisher Full Text\n\nZagon IS, McLaughlin PJ: Duration of opiate receptor blockade determines tumorigenic response in mice with neuroblastoma: a role for endogenous opioid systems in cancer. Life Sci. 1984; 35(4): 409–16. PubMed Abstract | Publisher Full Text\n\nManeckjee R, Minna JD: Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines. Proc Natl Acad Sci U S A. 1990; 87(9): 3294–8. PubMed Abstract | Free Full Text\n\nManeckjee R, Minna JD: Nonconventional opioid binding sites mediate growth inhibitory effects of methadone on human lung cancer cells. Proc Natl Acad Sci U S A. 1992; 89(4): 1169–73. PubMed Abstract | Publisher Full Text | Free Full Text\n\nManeckjee R, Minna JD: Biologically active MK-801 and SKF-10,047 binding sites distinct from those in rat brain are expressed on human lung cancer cells. Mol Biol Cell. 1992; 3(6): 613–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nManeckjee R, Minna JD: Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. Cell Growth Differ. 1994; 5(10): 1033–40. PubMed Abstract\n\nManeckjee R, Minna JD: Characterization of methadone receptor subtypes present in human brain and lung tissues. Life Sci. 1997; 61(22): PL 333–8. PubMed Abstract | Publisher Full Text\n\nHeusch WL, Maneckjee R: Effects of bombesin on methadone-induced apoptosis of human lung cancer cells. Cancer Lett. 1999; 136(2): 177–85. PubMed Abstract | Publisher Full Text\n\nCallaghan R, Riordan JR: Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J Biol Chem. 1993; 268(21): 16059–64. PubMed Abstract\n\nFriesen C, Roscher M, Alt A, et al.: Methadone, commonly used as maintenance medication for outpatient treatment of opioid dependence, kills leukemia cells and overcomes chemoresistance. Cancer Res. 2008; 68(15): 6059–64. PubMed Abstract | Publisher Full Text\n\nPerez-Alvarez S, Cuenca-Lopez MD, de Mera RM, et al.: Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis. Biochim Biophys Acta. 2010; 1802(11): 1036–47. PubMed Abstract | Publisher Full Text\n\nSingh A, Jayanthan A, Farran A, et al.: Induction of apoptosis in pediatric acute lymphoblastic leukemia (ALL) cells by the therapeutic opioid methadone and effective synergy with Bcl-2 inhibition. Leuk Res. 2011; 35(12): 1649–57. PubMed Abstract | Publisher Full Text\n\nMillner E, Friesen C, Alt A: Use of opioids or opioid mimetics for the treatment of resistant cancer patients. EP 2 149 372 A1. Date of filing: 31 July 2008. Reference Source\n\nFriesen C, Roscher M, Hormann I, et al.: Cell death sensitization of leukemia cells by opioid receptor activation. Oncotarget. 2013; 4(5): 677–90. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDrugs@FDA: FDA Approved Drug Products: Doxorubicin hydrochloride of injection. Checked in August 2019.\n\nFriesen C, Hormann I, Roscher M, et al.: Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma. Cell Cycle. 2014; 13(10): 1560–70. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLatzer P, Kessler T, Sahm F, et al.: Methadone does not increase toxicity of temozolomide in glioblastoma cells. Poster 33 Deutscher Krebskongress, 21–24. Februar 2018, Berlin; Oncol Res Treat. 2018; 41(suppl 1): 1–221.\n\nTemodar®: Prescribing Information. Accessed 2018-12-31. Reference Source\n\nBrawanski K, Brockhoff G, Hau P, et al.: Efficacy of D,L-methadone in the treatment of glioblastoma in vitro. CNS Oncol. 2018; 7(3): CNS18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrüggen MC, Mangana J, Irmisch A, et al.: Methadone-Not a magic bullet in melanoma therapy. Exp Dermatol. 2018; 27(6): 694–696. PubMed Abstract | Publisher Full Text\n\nOppermann H, Matusova M, Glasow A, et al.: D,L-Methadone does not improve radio- and chemotherapy in glioblastoma in vitro. Cancer Chemother Pharmacol. 2019; 83(6): 1017–1024. PubMed Abstract | Publisher Full Text\n\nKrebs EE, Becker WC, Zerzan J, et al.: Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain. Pain. 2011; 152(8): 1789–95. PubMed Abstract | Publisher Full Text\n\nChou R, Deyo R, Devine B, et al.: The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain. Evidence Report/Technology Assessment No. 218. AHRQ Publication No. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality; September 2014. www.effectivehealthcare.ahrq.gov/reports/final.cfm. Publisher Full Text\n\nHartung DM, Middleton L, Haxby DG, et al.: Rates of adverse events of long-acting opioids in a state Medicaid program. Ann Pharmacother. 2007; 41(6): 921–8. PubMed Abstract | Publisher Full Text\n\nRay WA, Chung CP, Murray KT, et al.: Out-of-hospital mortality among patients receiving methadone for noncancer pain. JAMA Intern Med. 2015; 175(3): 420–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLow AJ, Mburu G, Welton NJ, et al.: Impact of Opioid Substitution Therapy on Antiretroviral Therapy Outcomes: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2016; 63(8): 1094–1104. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhao Y, Shi CX, McGoogan JM, et al.: Methadone maintenance treatment and mortality in HIV-positive people who inject opioids in China. Bull World Health Organ. 2013; 91(2): 93–101. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhao Y, Zhang M, Shi CX, et al.: Mortality and virological failure among HIV-infected people who inject drugs on antiretroviral treatment in China: An observational cohort study. Drug Alcohol Depend. 2017; 170: 189–197. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHaroutiunian S, McNicol ED, Lipman AG: Methadone for chronic non-cancer pain in adults. Cochrane Database Syst Rev. 2012; 11: CD008025. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNicholson AB, Watson GR, Derry S, et al.: Methadone for cancer pain. Cochrane Database Syst Rev. 2017; 2: CD003971. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEls C, Jackson TD, Kunyk D, et al.: Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017; 10: CD012509. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOnken J, Friesen C, Vajkoczy P, et al.: Safety and Tolerance of D,L-Methadone in Combination with Chemotherapy in Patients with Glioma. Anticancer Res. 2017; 37(3): 1227–1235. PubMed Abstract | Publisher Full Text\n\nReddy A, Schuler US, de la Cruz M, et al.: Overall Survival among Cancer Patients Undergoing Opioid Rotation to Methadone Compared to Other Opioids. J Palliat Med. 2017; 20(6): 656–661. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLauche R, Klose P, Radbruch L, et al.: [Opioids in chronic noncancer pain-are opioids different? A systematic review and meta-analysis of efficacy, tolerability and safety in randomized head-to-head comparisons of opioids of at least four week's duration]. Schmerz. 2015; 29(1): 73–84. PubMed Abstract | Publisher Full Text\n\nAgency Medical Director’s Group (AMDG): Interagency Guideline on Prescribing Opioids for Pain. 3rd Edition, 2015. Reference Source\n\nGerman Pain Society: <Recommendations of the S3 Guideline Long-term opioid use in non-tumour-related pain – “LONTS”>. AWMF Register No 145/003. Lastly corrected 13 January 2015.\n\nDrewes AM, Jensen RD, Nielsen LM, et al.: Differences between opioids: pharmacological, experimental, clinical and economical perspectives. Br J Clin Pharmacol. 2013; 75(1): 60–78. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSanathanan LP, Peck CC: The randomized concentration-controlled trial: an evaluation of its sample size efficiency. Control Clin Trials. 1991; 12(6): 780–94. PubMed Abstract | Publisher Full Text\n\nHale M, Khan A, Kutch M, et al.: Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain. Curr Med Res Opin. 2010; 26(6): 1505–18. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "66075",
"date": "10 Aug 2020",
"name": "Mary Lynn McPherson",
"expertise": [
"Reviewer Expertise Palliative care",
"medication management",
"opioid conversion calculations",
"methadone dosing"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI think this is an excellent paper that offers a substantiated proposal that it is indeed time to initiate a randomized controlled clinical trial in cancer patients to determine if methadone therapy improves outcomes or mortality data. The public has become increasingly well-informed (thank you Dr. Google) and the idea that methadone may improve longevity in cancer is too titillating to ignore. However, the data is often controversial and by no means conclusive. Kremer does an excellent job reviewing what we do know to date on this topic and affirms that we are not in a position to support the uncontrolled distribution of methadone for this purpose. He does, however, suggest the time has come to “initiate randomized controlled clinical trials with methadone in cancer patients.”\n\nAdditional comments: In more detail, Kremer provides the background on how the general public has become aware of the potential for methadone possibly improving outcomes in cancer patients. This has resulted in patients demanding methadone therapy when diagnosed with cancer, regardless of the presence of pain. A chronological history of preclinical findings (predating clinical observations) follows, dating back to the 1980s. Interestingly, high concentrations of methadone (but not other opioids) boosted the effect of vinblastine in multidrug resistant cells. Research groups from Germany, Spain, and Canada found that methadone induced apoptosis in cancer cells and was able to overcome chemotherapy resistance. Survival benefit was explored in several studies. The largest included almost 100,000 patients in the Veterans Affairs system. A hazard ratio of 0.56 was seen for survival benefit with methadone-treated patients vs. long-acting morphine in a cohort with non-metastatic cancer, non-HIV, and non-addicts. Several other studies also showed positive outcomes with methadone, although a retrospective cohort study from a Tennessee Medicaid database showed increased mortality with methadone. Two targeted investigations also showed beneficial effects with methadone, although they were small in size. Kremer concludes by asking more questions than he answers? Is methadone safer or provides benefits in cancer over other opioids? Going on the assumption that there may be something to the protective or beneficial effects of methadone in certain cancers, and possibly as an enhancer of doxorubicin. I agree with Dr. Kremer that it is “time to initiate randomized controlled clinical trials to test the efficacy of methadone as a therapy for cancer patients.”\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": [
{
"c_id": "8215",
"date": "19 May 2022",
"name": "Hans-Joachim Kremer",
"role": "Author Response",
"response": "Thank you very much for your review and the positive opinion."
}
]
},
{
"id": "136917",
"date": "10 May 2022",
"name": "Harald Köfeler",
"expertise": [
"Reviewer Expertise Biochemistry"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe opinion article titled ‚Time to initiate randomized controlled clinical trials with methadone in cancer patients‘ by HJ Kremer is a timely topic with high relevance in the field of cancer therapy. The existing literature about methadone use in cancer therapy is comprehensively evaluated ranging from preclinical findings to epidemiological studies. While the data are not conclusive at this stage, there is reasonable hope that better study designs could provide conclusive data. In fact, many studies are either too small in size or do not have an appropriate study design to be useful. In this sense, the author provides valuable ideas for the design of future clinical trials judging the use of methadone in cancer therapy. At least the reviewed data at hand as of today are encouraging to further pursue this anti-cancer strategy because if future findings are negative there is not much lost, but if they are positive it could be a significant step forward. In summary, this manuscript could be an incentive for the scientific community to pick up an important topic in cancer therapy, which has so far been severely neglected.\nMinor comments:\nPage 2, paragraph 2, line 14: ‘…all the…’ instead of ‘…the all’.\n\nPage 2, paragraph 3, line 6: ‘…unless otherwise…’\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": [
{
"c_id": "8214",
"date": "19 May 2022",
"name": "Hans-Joachim Kremer",
"role": "Author Response",
"response": "Thank you very much for your review and the positive opinion."
}
]
}
] | 1
|
https://f1000research.com/articles/8-1835
|
https://f1000research.com/articles/10-267/v1
|
01 Apr 21
|
{
"type": "Case Report",
"title": "Case Report: Successful primary percutaneous coronary intervention in octogenarian with acute-on-chronic kidney disease and total atrioventricular block after acute myocardial infarction",
"authors": [
"Andrianto Andrianto",
"Ni Putu Anggun Laksmi",
"Rio Herdyanto",
"Andrianto Andrianto",
"Rio Herdyanto"
],
"abstract": "Myocardial infarction (MI) is frequently complicated by the worsening of renal function. Undergoing primary percutaneous coronary intervention (PCI) becomes crucial to a patient with ST-segment elevation myocardial infarction (STEMI). With appropriate management of MI, acute-on-chronic kidney disease (ACKD) requiring dialysis post-MI remains an important clinical predictor of elevated in-hospital mortality among patients with MI.\n\nIn this study, we reported an octogenarian patient suffering from STEMI with ACKD and total atrioventricular block (TAVB). She underwent insertion of a temporary pacemaker and primary PCI. Renal function was improved after dialysis by decreasing the amount of serum creatinine from 8.1 mg/dL at admission to 1.05 mg/dL after primary PCI and dialysis. Primary PCI should still be considered for patients with acute MI, even though these patients have kidney disease, to save the heart muscle and even indirectly improve the kidney function itself.",
"keywords": [
"primary PCI",
"dialysis",
"acute myocardial infarction",
"STEMI",
"acute-on-chronic kidney disease"
],
"content": "Introduction\n\nThe incidence of acute-on-chronic kidney disease (ACKD) varies among patients with ST-segment elevation myocardial infarction (STEMI), ranging from 5% to 30%. The structural and functional changes in the kidneys leading to chronic kidney disease (CKD) is most likely to be caused by different pathological mechanisms, including renal hypoperfusion, ischemia, and nephrotoxicity. Despite the proper treatment of myocardial infarction, ACKD still leads to a higher risk of morbidity and mortality, particularly when dialysis is required.1\n\nOctogenarian patients were rarely included in clinical investigations. Patients of advanced age possess the dilemma of revascularization therapy. Many clinicians fear that the risk-benefit ratio of doing the primary PCI is not worth it on elderly patients.2 Fox et al. states the risk of death in patient with ACS is increasing with age, but elderly patients may get an equal or greater benefit from primary PCI.3\n\n\nCase presentation\n\nAn 80-year-old Asian woman, with no history of smoking and unremarkable medical history, was referred to the emergency room department with a complaint of typical chest pain. The pain began four hours before hospitalization. It further radiated to the back and was accompanied by cold sweats. In this regard, the patient had a history of hypertension. Blood pressure was 116/53 mmHg, pulse rate was 39 ×/min, respiration rate was 23 ×/min, body temperature was 36.7°C, and oxygen saturation was 96% with O2 nasal cannula 3 l/min. Her extremities were warm, with vesicular pulmonary arteries and with no crackles or wheezing.\n\nThe electrocardiogram (ECG) of the patient showed TAVB with a junctional escape rhythm of 39 times per minute and inferior STEMI (Figure 1). The laboratory results of the initial visit were within normal limits, except that the blood urea nitrogen (BUN) 138 mg/dL (normal range: 7 – 18 mg/dL), creatinine serum 8.1 mg/dL (normal range: 0.6 – 1.3 mg/dL), and troponin I increased to 30.6 ng/mL (normal range: ≤ 0.04 ng/mL).\n\nFrom these data, we provided this patient with a diagnosis of inferior STEMI with total AV block and ACKD. She was administered with aspilet 300 mg and clopidogrel 75 mg per oral. Subsequently, a temporary pacemaker (TPM) was installed using local anesthesia with the heart rate at 70 ×/min, the sensitivity at 3 mV and the output at 3 V, and diagnostic coronary angiography (DCA) was performed.\n\nAccording to the DCA, the total occlusion was at the proximal right coronary artery (RCA) (Figure 2). There was insignificant stenosis in the proximal-mid left anterior descending artery. Besides, there were no stenosis on the left circumflex artery and the left main coronary artery. Primary PCI at the RCA was conducted using drug eluting stent (DES) promus and then thrombolysis in myocardial infarction (TIMI) grade 3 flow was shown at the RCA (Figure 3). Electrocardiography was also conducted after the installation of the pacemaker (Figure 4).\n\nThe patient was given therapy with dual antiplatelet aspirin 1 × 100 mg per oral and clopidogrel 1 × 75 mg per oral, atorvastatin 1 × 20 mg per oral, fluimucyl 3 × 200 mg per oral, packed red cell (PRC) transfusion of one bag per day, and TPM. On the third day of the treatment, electrocardiographic imaging indicated that the atrial fibrillation rhythm had a rapid ventricular response of 95–120 times per minute (Figure 5). As a consequence, the patient was given additional treatment with digoxin 0.5 mg through intravenous infusion. Additionally, she was considered by the internist for haemodialysis (HD) to do contrast clearing. This consideration was made based on the amount of BUN 138 mg/dL (normal range: 7 – 18 mg/dL) and serum creatinine 8.1 mg/dL (normal range: 0.6 – 1.3 mg/dL) from the earlier laboratory results. The internist ultimately decided to administer HD using ultrafiltration 2000 ml to this patient on the fourth day of treatment. The patient did not complain about chest pain on the next (fifth) day. The post-HD laboratory results showed that BUN reduced to 34 mg/dL, serum creatinine to 1.05 mg/dL (eGFR 50 mL/min/1.73 m2). Afterwards, removal of the TPM was attempted on the ninth day (Figure 6). In this case, the patient was given additional therapy of salbutamol 2 mg per oral three times a day. Later, the patient was discharged from the hospital on the fifteenth day.\n\nAfter three weeks of leaving the hospital, the patient was asked to undergo echocardiography. The results of this examination demonstrated that there was moderate mitral regurgitation with normal cardiac chamber dimensions. The left ventricular systolic function seemed normal with ejection fraction by Teich being 68%, as did the left ventricular diastolic function with E/A being 0.87 (Figure 7). On the other hand, the right ventricular systolic function appeared normal with tricuspid annular plane systolic excursion accounting for 1.8 cm.\n\n\nDiscussion\n\nSTEMI patients who have previously had kidney diseases or have recently suffered from kidney diseases as a result from STEMI have a worse prognosis. The renal insufficiency of patients with STEMI will increase the mortality and morbidity of cardiovascular diseases.4\n\nAtherosclerotic coronary plaque can cause coronary arterial disease (CAD) in the general population, but for patients with CKD, the pathophysiology of vascular diseases is different, due to a number of new risk factors, e.g., endothelium dysfunction, CKD-related mineral bone diseases, increased oxidative stress, and inflammation. In CKD, atherosclerosis often occurs in form of calcification of the lining of the blood vessels, which is regularly observed on peripheral vessels like the tibial and femoral arteries and on small epicardial blood vessels that contribute to microcirculation. There are many contributing factors to the incidence of chronic inflammation, such as increased oxidation and disrupted antioxidant system. These are particularly linked to hypoalbuminemia and malnutrition. Because of the deterioration of the renal function, the levels of pro-inflammatory cytokines and inflammatory mediators in the plasma will increase, thus leading to blood vessel calcification.4–6\n\nThe recent guidelines recommend that aspirin should be administered immediately after suspected acute coronary syndrome (ACS) and continued without a predetermined time, except if there is contraindication.7 Following that patients with renal insufficiency have an increased risk of bleeding, some doubt exists about the use of therapeutic antiplatelet therapy to such patients. According to the data collected, aspirin is safe and effective for ACS patients with CKD and recommended to be used in these patients to reduce mortality risk and vascular incidence.8\n\nP2Y12 inhibitors are one of the common therapies given to patients with ACS. Various studies have shown the effectiveness of prasugrel and ticagrelor in the management of ACS. Although the risk of bleeding is relatively high, these drugs have a higher potential ratio of decreasing ischemic risk in CKD patients. The lack of alternative therapies related to the interaction of renal function allows clopidogrel to be considered as a treatment in patients with decreased renal function. For patients aged over 75 years old, clopidogrel can be administered at a loading dose of 75 mg and followed with a dose of 75 mg/day for maintenance.9\n\nA number of studies suggested that statins should be used to treat ACS in order to reduce death risk or vascular incidence. American Heart Association guidelines recommend that statins should be given without seeing the initial levels of low-density lipoprotein in ACS patients without any contraindications.8\n\nThe use of lipid-lowering therapy, especially with statins, in patients with CKD remains a controversy to date. The potential of a statin-based treatment to decrease the number of vascular events will become much smaller due to a decrease in eGFR. The KDIGO guidelines propose that statins should be used in CKD patients over 50 years old, but not in dialysis patients. This recommendation is mainly based on two studies, namely 4D (Deutsche Diabetes Dialyse Studie) and AURORA (Rosuvastatin use evaluation). Nonetheless, statins still function as the foundation of the lipid management of CKD patients with CAD. In other words, giving statins to ACS patients with CKD is highly recommended.4,8,10\n\nWhether patients with the symptoms of CKD and/or end-stage renal disease should be treated with medical therapy or revascularization through either PCI or coronary artery bypass grafting is still debatable. In many cases, STEMI patients with CKD undergo the same invasive treatment as STEMI patients with no CKD. This is adherent to the fact that no specific clinical trial has been conducted of patients with CKD. Although the research appears to be more supportive of initial invasive treatment than of initial conservative treatment, there is no survival benefit from early intervention in CKD patients within a range of Grade 3a to Grade 5 (<60 ml/min/1.73 m2) in non-ST-segment-elevation randomized controlled trials of myocardial infarction.10\n\nThere is no contraindication observed in the thrombolytic therapy in this case. Nevertheless, when the worsened CKD and the in-hospital mortality rate are taken into account as a result from myocardial infarction, primary PCI should be chosen.10–12\n\nThis case presents a new successfully reperfusion therapy in octogenarian patient with kidney disease. The limitation of this case is that we did not perform further diagnostic tests to find out the underlying disease that had caused the kidney disease.\n\n\nConclusions\n\nThe prognosis of patients with decreased renal function and acute myocardial infarction is relatively poor, considering that these two conditions worsen each other. An increased rate of major adverse cardiovascular events, heart failure, and chest pain are seen in line with decreased eGFR rate. In this study, we reported the treatment of a patient of 80 years old suffering from acute myocardial infarction with ACKD and TAVB. The patient, with inferior STEMI, complicated by complete heart block, was treated with coronary angioplasty and hemodialysis. The primary PCI and dialysis post-primary PCI were performed successfully. The complaint of ischemic chest pain was resolved, and renal function was improved. In this regard, serum creatinine decreased from 8 mg/dL to 1.05 mg/dL, with eGFR being 50 mL/min/1.73 m2.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nConsent\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient.",
"appendix": "References\n\nSinkovič A, Masnik K, Mihevc M: Predictors of acute kidney injury (AKI) in high-risk st-elevation myocardial infarction (STEMI) patients: A single-center retrospective observational study. Bosn J Basic Med Sci. 2019. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMadhavan MV, Gersh BJ, Alexander KP, et al.: Coronary artery disease in patients ≥80 years of age. J Am Coll Cardiol. 2018. PubMed Abstract | Publisher Full Text\n\nFox KAA, Clayton TC, Damman P, et al.: Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome. A meta-analysis of individual patient data. J Am Coll Cardiol. 2010. PubMed Abstract | Publisher Full Text\n\nLakkas LS, Gkirdis I: Management of patients with coronary artery disease and chronic kidney disease. Contin Cardiol Educ. 2017. Publisher Full Text\n\nMallappallil M, Friedman EA, Delano BG, et al.: Chronic kidney disease in the elderly: Evaluation and management. Clin Pract. 2014. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoore PK, Hsu RK, Liu KD: Management of acute kidney injury: Core curriculum 2018. Am J Kidney Dis. 2018. PubMed Abstract | Publisher Full Text\n\nIbanez B, James S, Agewall S, et al.: ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2017: 2018. PubMed Abstract | Publisher Full Text\n\nWasham JB, Herzog CA, Beitelshees AL, et al.: Pharmacotherapy in chronic kidney disease patients presenting with acute coronary syndrome: A scientific statement from the American Heart Association. Circulation. 2015. PubMed Abstract | Publisher Full Text\n\nBonello L, Angiolillo DJ, Aradi D, et al.: P2Y12-ADP receptor blockade in chronic kidney disease patients with acute coronary syndromes review of the current evidence. Circulation. 2018. Publisher Full Text\n\nSarnak MJ, Amann K, Bangalore S, et al.: Chronic kidney disease and coronary artery disease: JACC state-of-the-art review. J Am Coll Cardiol. 2019. PubMed Abstract | Publisher Full Text\n\nKeriakos R: Kidney disease. In: Antenatal Disorders for the MRCOG and Beyond. 2016. Publisher Full Text\n\nAppleby CE, Ivanov J, Lavi S, et al.: The adverse long-term impact of renal impairment in patients undergoing percutaneous coronary intervention in the drug-eluting Stent Era. Circ Cardiovasc Interv. 2009. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "89510",
"date": "26 Jul 2021",
"name": "Mohammad Ullah Firoze",
"expertise": [
"Reviewer Expertise My area of interest is cardiovascular medicine."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a nice case report to focus on the issue of primary PCI in octogenarians and in patients with renal failure. It’s not a new method or rare event, but it will draw attention of the readers to this issue. But it needs some correction and clarifications:\nFigure 1 is showing sinus bradycardia not CHB. It should be corrected.\n\nTotal occlusion is better seen in first figure of Fig-3. So, it should be the first figure of Fig 2. And the first figure of Fig 2 should be the first figure of Fig 3. These two figures should be swapped.\n\nN-Acetylcysteine was given in the form fluimucyl. It should be mentioned as generic name.\n\nWhy was daily packed red cell transfusion given?\n\nWas the addition of anticoagulation considered during AF?\n\nWhy was digoxin used in ACS with AF with renal failure instead of beta blocker or amiodarone?\n\nThe ECG after removal of TPM there was sinus bradycardia with a rate of 52/min and QTc of 559 msec and t wave inversions. What was the rationale for using salbutamol? What was the possible cause of prolong QTc with T wave inversion? Was there any electrolyte imbalance? What was the rhythm and rate during discharge?\n\nWhat was the baseline echo during admission? What was the possible cause of moderate MR at three weeks? What was the renal function and ECG status at three weeks after hospital discharge?\n\nDiscussion- PPCI in octogenarians and management of CHB in ACS could be discussed.\n\nCIN could be discussed.\n\nJustification of hemodialysis should also be discussed. Whether it was done only because of high creatinine level? And what was the creatinine level on the fourth day before starting haemodialysis? Haemodialysis for contrast clearing is not recommended. What was the creatinine level on the day of discharge?\n\nThis is not a new reperfusion therapy- as mentioned in discussion.\n\nConclusion- It could be more concise. 4th & 5th sentence could be single sentence. 6th & 7th sentence are not necessary. Rather a recommendation from the authors could be added.\n\nEither CHB or TAVB – anyone of them should be used in the text.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? No\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": [
{
"c_id": "7735",
"date": "24 Jan 2022",
"name": "Andrianto Andrianto",
"role": "Author Response",
"response": "1. Figure 1 is showing sinus bradycardia not CHB. It should be corrected. Answer: Thank you very much for the correction. We have attached the ECG result during inferior STEMI with TAVB in this patient. 2. Total occlusion is better seen in first figure of Fig-3. So, it should be the first figure of Fig 2. And the first figure of Fig 2 should be the first figure of Fig 3. These two figures should be swapped. Answer: Thank you very much. We will revise it. 3. N-Acetylcysteine was given in the form fluimucyl. It should be mentioned as generic name. Answer: Thank you very much. We have amended it. 4. Why was daily packed red cell transfusion given? Answer: Packed red cell transfusion was administered due to anemia (Hb 8.6 g/dL). 5. Was the addition of anticoagulation considered during AF? Answer: The patient had paroxysmal atrial fibrillation, and, at that time, we did not consider adding an anticoagulant, but we considered the high risk of bleeding in the elderly. 6. Why was digoxin used in ACS with AF with renal failure instead of beta blocker or amiodarone? Answer: Because there were no intravenous beta-blockers in the hospital at that time. Thus, it was digoxin that could be considered. Patients with stage 5 chronic kidney disease (glomerular filtration rate [GFR] < 15 mL/minute), or for those on hemodialysis, alternative agents (e.g., beta-blockers or nondihydropyridine calcium channel blockers) may be preferred for heart rate control; however, it is recommended to reduce the loading dose of 3 to 5 mcg/kg (0.25 to 0.375 mg) should digoxin be used. 7. The ECG after removal of TPM there was sinus bradycardia with a rate of 52/min and QTc of 559 msec and t wave inversions. What was the rationale for using salbutamol? What was the possible cause of prolong QTc with T wave inversion? Was there any electrolyte imbalance? What was the rhythm and rate during discharge? Answer: Well, thank you very much. As a beta-agonist, Salbutamol is expected to have a positive chronotropic effect in this patient. Yes, the patient had an electrolyte imbalance, namely hypokalemia of 2.8 meq/l, which had been corrected. On discharge, the patient had asymptomatic sinus bradycardia at 55 bpm. 8. What was the baseline echo during admission? What was the possible cause of moderate MR at three weeks? What was the renal function and ECG status at three weeks after hospital discharge? Answer: We apologize for the mistake. There was mild mitral regurgitation on the patient's echocardiography, instead of moderate MR. The renal function was improved after hospital discharge. BUN was 34 mg/dL (normal range: 8–23 mg/dL), and serum creatinine was 1.05 mg/dL (normal range: 0.6–1.3 mg/dL). 9. Discussion- PPCI in octogenarians and management of CHB in ACS could be discussed. Answer: Thank you very much. We will include your suggestions in the revised article. 10. CIN could be discussed. Answer: Thank you very much for your advice. 11. Justification of hemodialysis should also be discussed. Whether it was done only because of high creatinine level? And what was the creatinine level on the fourth day before starting haemodialysis? Haemodialysis for contrast clearing is not recommended. What was the creatinine level on the day of discharge? Answer: Yes, it was done because of the high level of creatinine (8.1 mg/dL) and BUN (138 mg/dL). The creatinine level on the fourth day before starting hemodialysis was 5.8 mg/dl and BUN 109 mg/dl. On discharge, BUN was 34 mg/dL, and serum creatinine was 1.05 mg/dL. 12. This is not a new reperfusion therapy- as mentioned in discussion. Answer: We are very thankyou for the advise. 13. Conclusion- It could be more concise. 4th & 5th sentence could be single sentence. 6th & 7th sentence are not necessary. Rather a recommendation from the authors could be added. Answer: Thank you very much for your advice. 14. Either CHB or TAVB – anyone of them should be used in the text. Answer: Thank you. We use the term Total AV block."
}
]
},
{
"id": "89511",
"date": "11 Nov 2021",
"name": "Dike B Ojji",
"expertise": [
"Reviewer Expertise Preventive Cardiology",
"Hypertension",
"Hypertensive Heart Failure",
"Echocardiography"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this case report the authors report a case of an octogenarian patient suffering from STEMI with ACKD and total atrioventricular block (TAVB), who underwent insertion of a temporary pacemaker and primary PCI.\nPatient also had improved renal function after dialysis by decreasing the amount of serum creatinine from 8.1 mg/dL at admission to 1.05 mg/dL after primary PCI and dialysis.\n\nThis is an interesting, but the authors have to address some issues to make it more interesting:\nMajorly, the discussion is too broad and was not directly in reference to the case study. Since this is a case report the the findings in this patients should be cited throughout the discussion section.\n\nOn the minor side:\nI think the statement in the case report session: 'In this regard, the patient had a history of hypertension' is is not clear and need to be rephrased.\n\nHistory hypertension was mentioned but BP was 116/53mmHg. Is patient on any anti-hypertensives.\n\nWhat is meant by the statement: 'we provided this patient with a diagnosis of inferior STEMI with total AV block and ACKD. What is meant by provided'. I think this has to be rephrased.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": [
{
"c_id": "8216",
"date": "25 May 2022",
"name": "Ni Putu Anggun Laksmi",
"role": "Author Response",
"response": "In this case report the authors report a case of an octogenarian patient suffering from STEMI with ACKD and total atrioventricular block (TAVB), who underwent insertion of a temporary pacemaker and primary PCI.Patient also had improved renal function after dialysis by decreasing the amount of serum creatinine from 8.1 mg/dL at admission to 1.05 mg/dL after primary PCI and dialysis. This is an interesting, but the authors have to address some issues to make it more interesting. Majorly, the discussion is too broad and was not directly in reference to the case study. Since this is a case report the findings in this patient should be cited throughout the discussion section. Response: Thank you very much for the advice. We had already cited the findings in this patient in the 10th paragraph of discussion section On the minor side:I think the statement in the case report session: \"In this regard, the patient had a history of hypertension\" is not clear and need to be rephrased. Response: Thank you for the advice, we have rephrased it. History hypertension was mentioned but BP was 116/53mmHg. Is patient on any anti-hypertensives. Response: The patient said that she had a history of hypertension and had previously taken amlodipine 5 mg, but her blood pressure had been normal for the past months, and she had stopped taking it. Once again, thank you for the advice. We really appreciate it. What is meant by the statement: \"We provided this patient with a diagnosis of inferior STEMI with total AV block and ACKD. What is meant by provided\". I think this has to be rephrased. Response: Thank you for the advice, we have rephrased it."
}
]
}
] | 1
|
https://f1000research.com/articles/10-267
|
https://f1000research.com/articles/10-807/v1
|
16 Aug 21
|
{
"type": "Data Note",
"title": "Early Marriage among young girls in Eastern Ethiopia: trend during 2008-2018",
"authors": [
"Dureti Abdurahman",
"Nega Assefa",
"Yemane Berhane",
"Nega Assefa",
"Yemane Berhane"
],
"abstract": "Early marriage practices undermine girls’ autonomy and seriously affect their physical and mental wellbeing. Monitoring the trends and understanding the drivers is essential in intervening against early marriage. However, many studies on early marriage in Ethiopia are cross-sectional, focusing only on the magnitude at a single point in time. Hence, we extracted data of girls of 10-17 years from Kersa Health and Demographic Surveillance System (Kersa HDSS) database for the period of 2008–2018 in order to examine the trends of early marriage. In this data note we provide the details of a research database of 24,452 girls in the age group of 10-17 years. The extracted data include date of marriage and the girls’ socio-demographic variables. Other variables considered to be potentially associated with timing of marriage were also extracted. The purpose of this publication is to describe the dataset for external researchers who may be interested in making use of it as a secondary use of their routinely collected data. This dataset is available at\n\nhttps://doi.org/10.6084/m9.figshare.15034812.",
"keywords": [
"Key words: adolescent girls",
"incidence",
"early marriage",
"Ethiopia"
],
"content": "Introduction\n\nEarly marriage is any marriage where at least one of the parties is under 18 years of age (OHCHR, 2019). It undermine girls’ autonomy and seriously affects their physical and mental wellbeing (Nour, 2006; Walker, Mukisa, Hashim, & Ismail, 2013). Ethiopia ranks 15th in the prevalence of early marriage and 5th in the total number of early marriages globally. Nearly 40% of girls in Ethiopia are married before they turn 18 years and approximately 14% are married before their 15th birthday (UNICEF, 2018). Monitoring the trend and understanding the drivers is essential in intervening against early marriage. However, evidence on the effectiveness of interventions from longitudinal community-based studies is scarce. Hence, we extracted data of girls of 10–17 years from the Kersa Health and Demographic Surveillance System (Kersa HDSS) database for the period of 2008–2018 in order to examine the trends of early marriage.\n\n\nMethods\n\nThis data note used data from Kersa Health and Demographic Surveillance System (Kersa HDSS). The Kersa HDSS is located in the eastern Hararghe Zone of the Oromia regional state in Ethiopia. The initial baseline household and population census’ were conducted in 2007, and the database is updated every six months with registration of demographic (birth, death and migration) and health (reproductive and morbidity) events (Assefa et al., 2016). The data are collected by trained interviewers who are mainly residents in the study Kebele (the smallest administrative unit in Ethiopia). In each round of data collection, the household head or any adult member of the household is interviewed using structured forms that are prepared to capture a specific demographic or health event.\n\nData was extracted from Kersa HDSS database for the period of January 01, 2008 to December 31, 2018 for girls in the age group of 10 to17 years. The extracted data includes date of marriage and girl’s socio-demographic variables. Other variables considered to be potentially associated with the timing of marriage were also extracted. Microsoft Excel 2010 (Microsoft Excel, RRID:SCR_016137) was used to process the data (an open access alternative to Excel 2010 is Google Sheets).\n\nKersa HDSS has ethical approval from the Institutional Health Research Ethics Review Committee (IHRERC) of Haramaya University at the initiation of the surveillance system and renewed every five years. The approval written informed consent for KHDSS head office for the sharing of girls’ data was obtained from the IHRERC of Haramaya University, Ethiopia with approval number (IHRERC/177/2018). The accessed data were used for this research only.\n\n\nData availability\n\nDatasets are available publicly via:\n\nFigshare: Early Marriage among young girls in Eastern Ethiopia: trend during 2008-2018.\n\nhttps://doi.org/10.6084/m9.figshare.15034812 (Abdurahman et al. 2021).\n\nThe project contains the following underlying data.\n\n• Early marriage data.xlsx. (contains data in excel spreadsheet of ten years of marriage data and girl’s socio-demographic variable)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAuthor contributions\n\nAll authors contributed equally from conception, design, data extraction, and statistical analysis to interpretation of data. They also took part in the drafting of the manuscript and final approval for submission.",
"appendix": "Acknowledgments\n\nWe would like to thank Haramaya University for funding this study. We extend our gratitude for Addis Continental Institute of Public Health for technical support, as well KHDSS head office of Haramaya university collage of Health and medical sciences and data managers for the sharing of girls’ data.\n\n\nReferences\n\nAbdurahman D, Assefa N, Berhane Y: Title page.docx. figshare. Dataset. 2021. Publisher Full Text\n\nAssefa N, Oljira L, Baraki N, et al.: HDSS profile: the Kersa health and demographic surveillance system. Int J Epidemiol. 2016; 45(1): 94–101. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNour NM: Health consequences of child marriage in Africa. Emerg Infect Dis. 2006; 12(11): 1644. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOHCHR: Child and forced marriage, including in humanitarian settings.2019.\n\nUNICEF: Ending Child Marriage: A profile of progress in Ethiopia.2018.\n\nWalker J-A, Mukisa S, Hashim Y, et al.: Mapping Early Marriage in West Africa: a scan of trends, interventions, what works, best practices and the way forward Lagos: Ford Foundation. West Africa Office. 2013."
}
|
[
{
"id": "91981",
"date": "08 Sep 2021",
"name": "İlknur Yüksel-Kaptanoğlu",
"expertise": [
"Reviewer Expertise Domestic violence against women",
"child",
"early and forced marriages",
"qualitative research methods",
"gender equality"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis data note describes the data set of Kersa Health and Surveillance System (Kersa HDSS) for the use of secondary analysis. It is appropriate for the publication in F1000 research. However, some parts of this data note needs information to explain the data set in a more detailed way before indexing.\nMy minor concerns are the following:\nIntroduction section should be elaborated by explaining the benefits of a data set for researchers who study child marriages. The definitions of early marriage, and the choice of using early marriage instead of child marriage should be explained. Since, in many data sets it is measured by the age of marriage before 18 or 15. The reference time should be included about the prevalence of child marriage of Ethiopia.\n\nIn the material and method section (it must be named as), more explanation is needed about the system of KERSA HDHSS. The aim of the system in general, sample size, how data is collected, what are the other specific demographic events, other variables and what are the limitations of the data set some of the questions that should be mentioned.\n\nSome minor grammar mistakes should be reviewed.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? No\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": [
{
"c_id": "7527",
"date": "12 May 2022",
"name": "Dureti Abdurahman",
"role": "Author Response",
"response": "Dear reviewer We greatly appreciate the time and effort put forth to improve our paper. We benefited a lot from their insightful comments and suggestions. Based on the suggestions, we have provided a response to each comment as follows, and we will incorporate it on the main document. General comment This data note describes the data set of Kersa Health and Surveillance System (Kersa HDSS) for the use of secondary analysis. It is appropriate for the publication in F1000 research. However, some parts of this data note needs information to explain the data set in a more detailed way before indexing. My minor concerns are the following: First comment: Introduction section should be elaborated by explaining the benefits of a data set for researchers who study child marriages. The definitions of early marriage and the choice of using early marriage instead of child marriage should be explained. Since, in many data sets it is measured by the age of marriage before 18 or 15. The reference time should be included about the prevalence of child marriage of Ethiopia. Authors’ Response: We greatly appreciate the reviewer’s helpful comment and suggestion This dataset is used as a great source for researchers who study early marriage and interested in making use of it as a secondary use of their routinely collected data. It also enables to generalize the findings for a large community as it is huge in number and shows a trend of early marriage for more than a decade. Early marriage, or child marriage, is defined as the marriage or union between two people in which one or both parties are younger than 18 years of age (OHCHR, 2019). Marriages that take place before age 15 are considered “very early marriages.” (UNFPA, 2020). “Early marriage” has been interpreted, as synonymous with “child marriage” or as more inclusive as child marriage. 'Early' does not have to refer solely to age, however, and could be read to include other factors that would make a person unready to consent to marriage (sri, 2012). Although early is not explicitly defined to mean less than 18 years old, it is frequently found in that context. Several organizations like World Health Organization, UN for instance, use the term ‘early marriage’ consistently(UNICEF, 2005). The highest rate of child marriage is in sub-Saharan Africa, with 37 percent of young women marrying before age 18. According to the Ethiopian demography and health survey (EDHS) 2016, the national prevalence of early marriage was 58% (CSA, 2016). Second Comment In the material and method section (it must be named as), more explanation is needed about the system of KERSA HDHSS. The aim of the system in general, sample size, how data is collected, what are the other specific demographic events, other variables and what are the limitations of the data set some of the questions that should be mentioned. Authors’ Response: Thank you, we appreciate the valuable suggestions. It is explained as suggested. Methods and Materials Kersa HDSS is a demographic and health surveillance and research center established in 2007 by Haramaya University to serve as research center and source health and demographics data for Eastern Ethiopia, thus to create a framework for research at the community level and to be a platform for various health related research by the college of Health and Medical Sciences in Haramaya University. Kersa HDSS does monitoring demographic events such as birth, death, marital status change and migration; and health related conditions such as pregnancy, immunization, and morbidity among children and adults. The baseline census was conducted in 2007 and since then has been updated every 6 months, with registration of demographic and health events (Assefa et al., 2016). Data collectors who know the language of the community are permanently recruited and execute the data collection regularly. This study used data from an open dynamic cohort that gives a leverage of huge set of data from exiting Health and Demographic Surveillance System (Kersa HDSS) with a sample size of (24,452) that helps to generalize the findings to eastern part of the country. KHDSS data collection tool lack some important exposure variables that help to assess the socio cultural factors; like social norms, reason for marriage, parental education, occupation and socioeconomic status of the parents, which had a significant effect on early marriage. Hence, could be considered as a limitation of this study. References Assefa, N., Oljira, L., Baraki, N., Demena, M., Zelalem, D., Ashenafi, W., & Dedefo, M. (2016). HDSS profile: the Kersa health and demographic surveillance system. International Journal of Epidemiology, 45(1), 94-101. CSA. (2016). Ethiopia demographic and health survey. Central Statistical Agency Addis Ababa. Ethiopia ICF International Calverton, Maryland, USA. OHCHR. (2019). Child and forced marriage, including in humanitarian settings. sri. (2012). United Nations General Assembly Resolution 66/140, The Girl Child (2012), A/RES/66/140, p. 4; Beijing Platform for Action (1995), L. The Girl Child para. 259. UNFPA. (2020). Child marriage - Frequently Asked Questions. UNICEF. (2005). EARLY MARRIAGE: A HARMFUL TRADITIONAL PRACTICE: A STATISTICAL EXPLORATION (2005), p. 4. ."
},
{
"c_id": "7677",
"date": "12 May 2022",
"name": "Dureti Abdurahman",
"role": "Author Response",
"response": "Dear reviewer We greatly appreciate the time and effort put forth to improve our paper. We benefited a lot from their insightful comments and suggestions. Based on the suggestions, we have provided a response to each comment as follows, and we will incorporate it on the main document. General comment This data note describes the data set of Kersa Health and Surveillance System (Kersa HDSS) for the use of secondary analysis. It is appropriate for the publication in F1000 research. However, some parts of this data note needs information to explain the data set in a more detailed way before indexing. My minor concerns are the following: First comment: Introduction section should be elaborated by explaining the benefits of a data set for researchers who study child marriages. The definitions of early marriage and the choice of using early marriage instead of child marriage should be explained. Since, in many data sets it is measured by the age of marriage before 18 or 15.| The reference time should be included about the prevalence of child marriage of Ethiopia. Authors’ Response: We greatly appreciate the reviewer’s helpful comment and suggestion. This dataset is used as a great source for researchers who study early marriage and interested in making use of it as a secondary use of their routinely collected data. It also enables to generalize the findings for a large community as it is huge in number and shows a trend of early marriage for more than a decade. Early marriage, or child marriage, is defined as the marriage or union between two people in which one or both parties are younger than 18 years of age (OHCHR, 2019). Marriages that take place before age 15 are considered “very early marriages.” (UNFPA, 2020). “Early marriage” has been interpreted, as synonymous with “child marriage” or as more inclusive as child marriage. 'Early' does not have to refer solely to age, however, and could be read to include other factors that would make a person unready to consent to marriage (sri, 2012). Although early is not explicitly defined to mean less than 18 years old, it is frequently found in that context. Several organizations like World Health Organization, UN for instance, use the term ‘early marriage’ consistently (UNICEF, 2005). The highest rate of child marriage is in sub-Saharan Africa, with 37 percent of young women marrying before age 18. According to the Ethiopian demography and health survey (EDHS) 2016, the national prevalence of early marriage was 58% (CSA, 2016). Second Comment In the material and method section (it must be named as), more explanation is needed about the system of KERSA HDHSS. The aim of the system in general, sample size, how data is collected, what are the other specific demographic events, other variables and what are the limitations of the data set some of the questions that should be mentioned. Authors’ Response: Thank you, we appreciate the valuable suggestions. It is explained as suggested. Methods and Materials Kersa HDSS is a demographic and health surveillance and research center established in 2007 by Haramaya University to serve as research center and source health and demographics data for Eastern Ethiopia, thus to create a framework for research at the community level and to be a platform for various health related research by the college of Health and Medical Sciences in Haramaya University. Kersa HDSS does monitoring demographic events such as birth, death, marital status change and migration; and health related conditions such as pregnancy, immunization, and morbidity among children and adults. The baseline census was conducted in 2007 and since then has been updated every 6 months, with registration of demographic and health events (Assefa et al., 2016). Data collectors who know the language of the community are permanently recruited and execute the data collection regularly. This study used data from an open dynamic cohort that gives a leverage of huge set of data from exiting Health and Demographic Surveillance System (Kersa HDSS) with a sample size of (24,452) that helps to generalize the findings to eastern part of the country. KHDSS data collection tool lack some important exposure variables that help to assess the socio cultural factors; like social norms, reason for marriage, parental education, occupation and socioeconomic status of the parents, which had a significant effect on early marriage. Hence, could be considered as a limitation of this study. References Assefa, N., Oljira, L., Baraki, N., Demena, M., Zelalem, D., Ashenafi, W., & Dedefo, M. (2016). HDSS profile: the Kersa health and demographic surveillance system. International Journal of Epidemiology, 45(1), 94-101. CSA. (2016). Ethiopia demographic and health survey. Central Statistical Agency Addis Ababa. Ethiopia ICF International Calverton, Maryland, USA. OHCHR. (2019). Child and forced marriage, including in humanitarian settings. sri. (2012). United Nations General Assembly Resolution 66/140, The Girl Child (2012), A/RES/66/140, p. 4; Beijing Platform for Action (1995), L. The Girl Child para. 259. UNFPA. (2020). Child marriage - Frequently Asked Questions. UNICEF. (2005). EARLY MARRIAGE: A HARMFUL TRADITIONAL PRACTICE: A STATISTICAL EXPLORATION (2005), p. 4. . VIEW LESS"
}
]
}
] | 1
|
https://f1000research.com/articles/10-807
|
https://f1000research.com/articles/10-423/v1
|
27 May 21
|
{
"type": "Systematic Review",
"title": "Better survival of patients with oligo- compared with polymetastatic cancers: a systematic review and meta-analysis of 173 studies",
"authors": [
"Fausto Petrelli",
"Antonio Ghidini",
"Michele Ghidini",
"Roberta Bukovec",
"Francesca Trevisan",
"Luca Turati",
"Alice Indini",
"Silvia Seghezzi",
"Veronica Lonati",
"Giovanna Moleri",
"Gianluca Tomasello",
"Alberto Zaniboni",
"Antonio Ghidini",
"Michele Ghidini",
"Roberta Bukovec",
"Francesca Trevisan",
"Luca Turati",
"Alice Indini",
"Silvia Seghezzi",
"Veronica Lonati",
"Giovanna Moleri",
"Gianluca Tomasello",
"Alberto Zaniboni"
],
"abstract": "Background: The modern concept of oligometastatic (OM) state has been initially developed to describe patients with a low burden of disease and with a potential for cure with local ablative treatments. We systematically assessed the risk of death and relapse of oligometastatic (OM) cancers compared to cancers with more diffuse metastatic spread, through a meta-analysis of published data. Methods: PubMed, the Cochrane Library, and EMBASE were searched for studies reporting prognosis of patients with OM solid tumors. Risk of death and relapse were extracted and pooled to provide an adjusted hazard ratio with a 95% confidence interval (HR 95%CI). The primary outcome of the study refers to overall mortality in OM vs. polymetastatic (PM) patients. Results. Mortality and relapse associated with OM state in patients with cancer were evaluated among 104,234 participants (n=173 studies). Progression-free survival was better in patients with OM disease (hazard ratio [HR] = 0.62, 95% CI 0.57–0.68; P <.001; n=69 studies). Also, OM cancers were associated with a better OS (HR = 0.65, 95% CI 0.62-0.68; P<.01; n=161 studies). In colorectal (CRC), breast, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) the reduction in the risk of death for OM patients were 35, 38, 30 and 42%, respectively. Conclusions. Patients with oligometastases have a significantly better prognosis than those with more widespread stage IV tumors. We suggest that a treatment strategy that involves bot the primary and the metastases should be identified at the time of diagnosis.",
"keywords": [
"cancer",
"oligometastases",
"survival",
"review",
"meta-analysis",
"tumours"
],
"content": "Introduction\n\nThe vast majority of metastatic solid tumors are incurable, and despite the evolution of treatments, patients ultimately die because of their disease. The modern concept of oligometastatic (OM) state was initially developed in 19951 to describe patients with a low burden of disease (e.g. one to five metastases) with a potential for cure with local ablative treatments. This assumption also relies on the hypothesis that metastatic spread follows a hierarchical pattern in time and number of localizations.2 In some circumstances, the 8th Tumor Node Metastasis (TNM) staging system distinguishes between patients with a single metastasis and those with multiple such metastases. Large consensus on the definition and management of OM patients is currently lacking. Recently, advances in imaging and local ablative therapies have permitted the treatment of these patients with additional locoregional treatment in addition to systemic therapies, and some patients may be cured and attain long term survival.3 This scenario has been best elucidated in prostate, kidney, lung and melanomas.4,5 In these settings oligometastatic cancers may be treated in oligoprogressive sites continuing systemic therapy that control the remaining disease. Also, oligometastatic tumors at presentation can receive local treatments on the primary tumor and on any single oligometastases. In the SABR-COMET randomized study median overall survival (OS) was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the stereotactic body radiotherapy to all metastases group (hazard ratio 0.57, 95% CI 0.30-1.10; P = .09).6\n\nThe aim of this systematic review and meta-analysis was to investigate and establish the prognostic survival of OM compared to non-OM solid tumors. In particular, we evaluated if patients with oligometastatic solid tumors do better than patients with non-oligometastatic tumors defined as tumors with up to three to five metastatic sites.\n\n\nMethods\n\nThis study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.\n\nA comprehensive search was performed with the following terms: (advanced or metastatic or recurrent or relapsed or synchronous or metachronous) and (site or oligo* or “oligometastastic” or oligorecurrence or oligoprogression or single or multiple or 1-3 or >3 or >4 or >5 or 1-2 or 1-3 or 1-5 or number) and (synchronous or metachronous or metastases or relapse or recurrence or progression) and (tumor or tumour or cancer or carcinoma or melanoma or sarcoma) and (“hazard ratio”) and (cox or multivariate or multivariable) and survival. We searched PubMed, the Cochrane Library and EMBASE for studies eligible for this meta-analysis published from inception up to October 30th, 2020. To be eligible, studies needed to have evaluated survival of patients with metastatic cancers regardless of line of therapy and to provide data of outcome according to the number of OM sites used by each author. Studies were excluded if they enrolled less than 10 patients, pediatric subjects, and hematological diseases. Commonly we define polymetastatic cancer as any disease with more than three to five metastases. Studies were searched and screened independently by three authors (FP, MG and GT).\n\nThe primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale (NOS) for observational or retrospective studies (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp).\n\nThe extracted data (from six reviewers) included the type of study, number of patients, cancer type, median age of included patients, performance status 0-1 (rate), treatment received, timing of oligometastases (synchronous or metachronous), number of OM sites used for comparison, and median follow up. Hazard ratios (HR) for OS and PFS with their 95% CIs, were extracted preferentially from multivariate analyses where available. The heterogeneity in the included studies was evaluated by the Chi-square-based Q-test and I2 (I2 = 0% to 25%, no heterogeneity; I2 = 25% to 50%, moderate heterogeneity; I2 = 50% to 75%, high heterogeneity; I2 = 75% to 100%, extreme heterogeneity). When I2 was larger than 50%, a random effects model was used; otherwise, the fixed effects model was used. Sensitivity analyses for OS were performed according to type of cancer, timing and number of oligometastases to find the potential heterogeneity among the included studies. If the number of studies was less than or equal to one, we did not carry out the subgroup analysis. The possibility of publication bias was explored by the Egger's and Begg's tests and Trim and Fill method.7,8 Begg's test explores bias with a funnel plot, conversely Egger's test is a linear regression of the effect estimates (OS) on their standard errors weighted by their inverse variance. The trim-and-fill method aims at estimating potentially missing studies due to publication bias in the funnel plot and adjusting the overall effect estimate. All analyses were performed using RevMan v.3 software.9\n\n\nResults\n\nAmong the publications retrieved using electronic search (n = 7510), 173 studies were eligible for meta-analysis, for a total of 104,234 patients10 (Figure 1). Baseline characteristics of the included studies and treatments received are presented in Table 1.\n\n* M1b single extratoracic organ; CNS, central nervous system; CRC, colorectal cancer; CT, chemotherapy; DMFS, distant metastasis–free survival; DSS, disease-specific survival; EFS, event-free survival; HAI, hepatic artery infusion; HCC, hepatocellular carcinoma; ICIs, immune checkpoint inhibitors; LNs, lymph nodes; MVA, multivariate analysis; MWA, microwave ablation; NPC, nasopharyngeal carcinoma; NSCLC, non-small-cell lung cancer; OM, oligometastatic disease; OS, overall survival; OT, ormonotherapy; PFS, progression-free survival; PMS, post-metastasis survival; PRS, post-relapse survival; PS, performance status; RCC, renal cell carcinoma; RFA radiofrequency ablation; RFS, relapse-free survival; RTDS, recurrence to death survival; S, surgery; RT, radiotherapy; SBRT, stereotactic body radiotherapy; SCLC, small-cell lung cancer; SRS, stereotactic radiosurgery; TACE, transarterial chemoembolization; TKI, tyrosine kinase inhibitor; TTP, time to progression; TTR, time to recurrence; tx, therapy; UVA, univariate analysis.\n\nProgression-free survival was better in patients with OM disease (HR = 0.62, 95% CI 0.57–0.68; P < .01; n = 69 studies; Figure 2). Additionally, in the OS analysis, OM cancers were associated with a better OS (HR = 0.65, 95% CI 0.62–0.68; P < .01; n = 161 studies; Figure 3). Results were significant for all analyzed disease subgroups except biliary tract cancer and cervical cancer (only three studies included). In colorectal (CRC), breast, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC), which constituted the more representative series, the reduction in the risk of death for OM patients were 35, 38, 30 and 42%, respectively (Figure 3). Timing of onset did not influence the risk of death. Most studies reported OS analysis for up to three metastases (152 out of 161 studies). After exclusion of eight studies that reported outcomes for up to five metastases the final results remained unchanged (HR = 0.64, 95%CI 0.61-0.67; P < .01). No cut-off was associated with a better outcome (1 vs 2 vs 1-2 vs 1-3 metastases).\n\nRisk of bias through Begg's funnel plot was not significant for the OS analysis. Conversely, Egger's test showed evidence of bias (P < .01) (Figure 4). Trim and Fill analysis incorporated 29 missing studies. The overall effect measure (95% CI) based on this analysis was 0.7 (0.67-0.73), which became slightly weaker compared to the originally reported overall effect measure. Compared with cancers with more than three to five metastases, high-certainty evidence indicates OM tumors are associated with better prognosis in particular for CRC, breast, NSCLC and RCC.\n\n\nDiscussion\n\nThe definition of oligometastatic refers to malignancies with a limited metastatic spread which may be amenable of radical treatment for both primary and each distant site, and that generally have a better prognosis compared to polymetastatic cancers. A very recently published paper clearly explains the timely clonal evolution of somatic mutations and consequently the metastatic process of many cancer types.11 It may be hypothesized that OM cancer is associated with a more indolent spread and therefore may represent a less fatal disease. With the expansion of the oncological armamentarium, many efforts have been made over the years to improve outcomes of patients with minimal metastatic burden.\n\nWe have performed the most exhaustive systematic review of the literature to quantify the prognostic value of OM stage in various cancers. Overall, OM cancer patients have a risk of death and progression that is a third less than the polymetastatic counterpart. The OM state is frequently calculated as an independent favorable prognostic variable, which means that these patients do well independent from other clinical-pathological characteristics. The effect size was calculated from 173 studies including more than 100,000 patients. The final results were similar in all the most frequent histologies including CRC, breast cancer, NSCLC, RCC and sarcoma with inferior survival in OM gastric, melanoma and head and neck cancers.\n\nThere is evidence from randomized clinical trials12-14 that ablative therapies improve survival in patients with OM cancer. For example, in some cancers small randomized studies12-20 already provide evidence of survival improvement in patients that received both systemic and local therapies compared to those that received systemic therapies alone. As a matter of fact, resection of colorectal cancer liver metastases nowadays represents an essential curative option and a primary endpoint in multiple clinical trails.12 Furthermore, Gomez et al.13 found that in OM NSCLCs, adding local consolidative therapy to active oligometastases and to primary disease may improve OS from 17 to 41 months. Also, in RCC the treatment of indolent lung metastases may permit delaying the start of systemic treatment and obtain an excellent control.14 A large burden of evidence now supports local therapy for minimal oligoprogressive cancers treated with targeted therapies or immunotherapy. Here, metastases-directed therapy could delay the switch of systematic therapy by radical local treatment of all progressive metastatic sites.15,16 With the advent of immunotherapy, the combination of immune check point inhibitors and radiotherapy to single OM lesions may facilitate a potentiation of the immune response, increasing the chances of achieving an abscopal effect. This term describes an event in which focalized radiotherapy discharge systemic anti-tumoral action that can result in distant responses.17 For example, in lung cancer the combination has a good safety profile and achieves high rates of local control and greater chances of obtaining abscopal responses than radiotherapy alone, with a relevant impact on outcome.18 Oligometastatic cancers can also regarded as extended locoregional disease if, after proper conversion therapy, all sites of metastases and primary tumor may be radically resected with curative purposes. Such a strategy has been employed in largely incurable cancers ad gastric and pancreatic carcinomas.19,20\n\nThis meta-analysis has several limitations. First, our review does not evaluate the absolute benefit of any local treatment and the prognosis and management of oligoprogressive disease or down staged polymetastases to an OM state. Second, the literature search covered a large lifetime span and may include older series where radiological evaluation did not include more advanced modalities that can now increase the accuracy of oligometastases detection. Finally, the optimal number of lesions defining the OM state cannot be defined in this paper.\n\nA consensus paper of EORTC and ESTRO societies attempted to provide definitions of various OM conditions either naïve or attained after therapy and either synchronous or metachronous.21\n\nSome large, randomized studies have included local therapies for OM cancers. An NRG Oncology randomized phase II/III trial study compares therapy with stereotactic radiosurgery and/or surgery with standard of care therapy alone in treating patients with breast cancer that has one or two locations in the body (limited metastatic) that are previously untreated. The PREST study will assess the efficacy of ablative radiotherapy (stereotactic body radiotherapy applied to all oligometastases) administered to all tumor sites (metastases and prostate if applicable), in oligometastatic hormone-sensitive prostate cancer patients. Finally, an ECOG-ACRIn phase III study compared standard chemotherapy to consolidative radiotherapy in patients with oligometastatic HER2 negative esophageal and gastric adenocarcinoma (https://clinicaltrials.gov/ct2/show/NCT02364557; https://clinicaltrials.gov/ct2/show/NCT04115007; https://clinicaltrials.gov/ct2/show/NCT04248452).\n\n\nConclusions\n\nIn conclusion, this meta-analysis tried to quantify the prognosis associated with OM compared to cancers with more extensive diffusion. Based on our findings, we suggest that every metastatic patient should be accurately evaluated for the number of distant sites of disease, and a treatment strategy that involves both the primary and the metastases should be carefully considered. Also, we propose that these patients should be stratified when included in clinical trials.\n\n\nData availability\n\nMendeley Data: Extended data for ‘Better survival of patients with oligo- compared with polymetastatic cancers: a systematic review and meta-analysis of 173 studies’.\n\nhttp://dx.doi.org/10.17632/8kycvdnp6v.1.10\n\nThis project contains the following extended data:\n\nSupplementary Table 1: List of included studies.\n\nMendeley Data: PRISMA checklist for ‘Better survival of patients with oligo- compared with polymetastatic cancers: a systematic review and meta-analysis of 173 studies’.\n\nhttp://dx.doi.org/10.17632/8kycvdnp6v.1.10\n\nData are available under the terms of the Creative Commons Attribution 4.0 license (CC-BY 4.0).",
"appendix": "References\n\nHellman S, Weichselbaum RR: Oligometastases. J Clin Oncol. 1995; 13(1): 8–10. PubMed Abstract | Publisher Full Text\n\nWeichselbaum RR, Hellman S: Oligometastases revisited. Nat Rev Clin Oncol. 2011; 8(6): 378–382. PubMed Abstract | Publisher Full Text\n\nChalkidou A, Macmillan T, Grzeda MT, et al.: Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study. Lancet Oncol. 2021 Jan; 22(1): 98–106. PubMed Abstract | Publisher Full Text\n\nDonini M, Buti S, Massari F, et al.: Management of oligometastatic and oligoprogressive renal cell carcinoma: state of the art and future directions. Expert Rev Anticancer Ther. 2020 Jun; 20(6): 491–501. Epub 2020 Jun 1. PubMed Abstract | Publisher Full Text\n\nGlicksman RM, Metser U, Vines D, et al.: Curative-intent Metastasis-directed Therapies for Molecularly-defined Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis. Eur Urol. 2021 Mar 5: S0302–2838(21)00151-2. Epub ahead of print. PubMed Abstract | Publisher Full Text\n\nPalma DA, Olson R, Harrow S, et al.: Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019 May 18; 393(10185): 2051–2058. PubMed Abstract | Publisher Full Text\n\nBegg CB, Mazumdar M: Operating Characteristics of A Bank Correlation Test for Publication Bias. Biometrics. 1994; 50(4): 1088–1101. PubMed Abstract\n\nShi L, Lin L, Omboni S: The trim-and-fill method for publication bias: Practical guidelines and recommendations based on a large database of meta-analyses. Med (United States). 2019. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReview Manager (RevMan) [Computer program]: Version 5.3.Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.\n\nPetrelli F, et al.: Better survival of patients with oligo- compared with polymetastatic cancers: a systematic review and meta-analysis of 173 studies. Mendeley Data. 2021. Publisher Full Text\n\nGerstung M, Jolly C, Leshchiner I, et al.: The evolutionary history of 2,658 cancers. Nature. 2020 Feb; 578(7793): 122–128. Epub 2020 Feb 6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFong Y, Fortner J, Sun RL, et al.: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999; 230(3): 309–321. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGomez DR, Tang C, Zhang J, et al.: Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019 Jun 20; 37(18): 1558–1565. Epub 2019 May 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang Y, Schoenhals J, Christie A, et al.: Stereotactic Ablative Radiation Therapy (SAbR) Used to Defer Systemic Therapy in Oligometastatic Renal Cell Cancer. Int J Radiat Oncol Biol Phys. 2019 Oct 1; 105(2): 367–375. Epub 2019 Aug 1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKroeze SGC, Schaule J, Fritz C, et al.: Metastasis directed stereotactic radiotherapy in NSCLC patients progressing under targeted- or immunotherapy: efficacy and safety reporting from the 'TOaSTT' database. Radiat Oncol. 2021 Jan 6; 16(1): 4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeek MP, Taparra K, Phillips R, et al.: Metastasis-directed Therapy Prolongs Efficacy of Systemic Therapy and Improves Clinical Outcomes in Oligoprogressive Castration-resistant Prostate Cancer. Eur Urol Oncol. 2020 Jun 11: S2588–9311(20)30058-4. Epub ahead of print. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMole RJ: Whole body irradiation – Radiology or medicine? Br J Radiol. 1953; 26: 234–241. PubMed Abstract | Publisher Full Text\n\nChicas-Sett R, Morales-Orue I, Castilla-Martinez J, et al.: Stereotactic Ablative Radiotherapy Combined with Immune Checkpoint Inhibitors Reboots the Immune Response Assisted by Immunotherapy in Metastatic Lung Cancer: A Systematic Review. Int J Mol Sci. 2019 May 2; 20(9): 2173. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDe Simoni O, Scarpa M, Tonello M, et al.: Oligometastatic Pancreatic Cancer to the Liver in the Era of Neoadjuvant Chemotherapy: Which Role for Conversion Surgery? A Systematic Review and Meta-Analysis. Cancers (Basel). 2020 Nov 17; 12(11): 3402. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang F, Huang X, Song Y, et al.: Conversion Surgery for Stage IV Gastric Cancer. Front Oncol. 2019 Nov 7; 9: 1158. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuckenberger M, Lievens Y, Bouma AB, et al.: Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol. 2020 Jan; 21(1): e18–e28. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "87329",
"date": "30 Jun 2021",
"name": "Luca G. Campana",
"expertise": [
"Reviewer Expertise Surgical oncology",
"locoregional therapies (limb perfusion/infusion",
"intraperitoneal chemotherapy",
"electrochemotherapy)",
"melanoma",
"sarcoma",
"breast cancer",
"peritoneal malignancies",
"colorectal cancer."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors of this systematic review and meta-analysis assessed the influence of oligometastatic disease status on OS and PFS in adult patients with solid tumours. To do this, they carried out an extensive literature review including all types of studies with at least ten patients with any histology. Patients with OM disease were found to have significantly longer PFS and OS if they had CRC, BC, NSCLC, RCC, and sarcoma.\nThe literature screening was conducted according to the standard recommendations and the subsequent analysis is methodologically robust. Going across several histotypes, the paper provides a big, and for certain aspects, unique picture of the prognosis of patients with OM. At the same time, however, it makes it challenging summarising and discussing the results.\nHere you can find some comments that you may find useful to improve this review:\nIn the Abstract, I would mention the histotypes in which the OM status do not correlate with patient outcome. Also, in the Conclusions part, second sentence: this seems to be unrelated to the results presented and anyway not applicable in all cases (consider rephrasing/changing).\n\nThe Introduction needs some input because sentences do not always follow a clear pattern. For instance, there are some general considerations regarding tumour progression, tumour staging according to the TNM, detailed results of a specific trial. It needs to be more homogeneous.\n\nGiven the positive results with ablative therapies in patients with OM disease, the authors should explain what this meta-analysis adds to the literature.\n\nFrom the Introduction (and Methods) it is not clear what the definition adopted of OM disease is (\"up to 3 to 5\" metastatic sites). In this regard, is a patient with 6 liver metastases still considered \"oligometastatic\"?\n\nThe great majority of the studies were retrospective in nature. This should be clearly stated and critically discussed as well.\n\nDid the authors detect any imbalance in treatment intensity between OM vs. non-OM patients?\n\nTable 1, 8th column: some of the included studies have \"various\" sites of OM. I think this information should be specified in order to be consistent with the inclusion criteria.\n\nThe studies could be regrouped according to the histology. The same could apply to Figure 2 and Figure 3.\n\nThe prognosis of patients with gastric cancer, melanoma, and head and neck cancer should be discussed in light of the results presented.\n\nIn the Discussion, it is not entirely clear if the authors consider the OM status an opportunity to spare patients from systemic treatment or an opportunity to pursue combined treatment. Again, this should be discussed in light of the results presented.\n\nIn the Discussion, the last paragraph seems more like a list of ongoing trials, including some form of local therapies over standard systemic treatment. How does this relate to the findings of the present study? Please discuss.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly",
"responses": [
{
"c_id": "6865",
"date": "09 Jul 2021",
"name": "Fausto Petrelli",
"role": "Author Response",
"response": "Reviewer 1: Luca Campana The authors of this systematic review and meta-analysis assessed the influence of oligometastatic disease status on OS and PFS in adult patients with solid tumours. To do this, they carried out an extensive literature review including all types of studies with at least ten patients with any histology. Patients with OM disease were found to have significantly longer PFS and OS if they had CRC, BC, NSCLC, RCC, and sarcoma. The literature screening was conducted according to the standard recommendations and the subsequent analysis is methodologically robust. Going across several histotypes, the paper provides a big, and for certain aspects, unique picture of the prognosis of patients with OM. At the same time, however, it makes it challenging summarising and discussing the results. Here you can find some comments that you may find useful to improve this review: In the Abstract, I would mention the histotypes in which the OM status do not correlate with patient outcome. Also, in the Conclusions part, second sentence: this seems to be unrelated to the results presented and anyway not applicable in all cases (consider rephrasing/changing). Author response: OK - requests accepted. The Introduction needs some input because sentences do not always follow a clear pattern. For instance, there are some general considerations regarding tumour progression, tumour staging according to the TNM, detailed results of a specific trial. It needs to be more homogeneous. Author response: OK - sentences added or modified. Given the positive results with ablative therapies in patients with OM disease, the authors should explain what this meta-analysis adds to the literature. Author response: Sentences added in 2nd paragraph of discussion. From the Introduction (and Methods) it is not clear what the definition adopted of OM disease is (\"up to 3 to 5\" metastatic sites). In this regard, is a patient with 6 liver metastases still considered \"oligometastatic\"? Author response: Definition updated. The great majority of the studies were retrospective in nature. This should be clearly stated and critically discussed as well. Author response: Considerations added in the limitations section. Did the authors detect any imbalance in treatment intensity between OM vs. non-OM patients? Author response: This data was not reported. Table 1, 8th column: some of the included studies have \"various\" sites of OM. I think this information should be specified in order to be consistent with the inclusion criteria. Author response: “Various” means that in those articles, sites of metastases were not specific. Only when explicitly reported they are included (e.g liver or lung). Specific comment in inclusion criteria added. The studies could be regrouped according to the histology. The same could apply to Figure 2 and Figure 3. Author response: Table and Figure 2 (OS) arranged according to disease. The prognosis of patients with gastric cancer, melanoma, and head and neck cancer should be discussed in light of the results presented. Author response: Sentences added in the Discussion. In the Discussion, it is not entirely clear if the authors consider the OM status an opportunity to spare patients from systemic treatment or an opportunity to pursue combined treatment. Again, this should be discussed in light of the results presented. Author response: In the final paragraph, some sentences were added about this request. In the Discussion, the last paragraph seems more like a list of ongoing trials, including some form of local therapies over standard systemic treatment. How does this relate to the findings of the present study? Please discuss. Author response: Discussion added."
},
{
"c_id": "6868",
"date": "25 Aug 2021",
"name": "Fausto Petrelli",
"role": "Author Response",
"response": "We have improved the Introduction and criteria for search. We have arranged in the Discussion section a specific discussion about particular settings of patients analysed and the main limitation of the paper (retrospective nature of studies). We also discussed the main meaning of the results: improved prognosis and treatment opportunities with locoregional therapies in an oligometastatic setting. Table was also ordered according to histology."
}
]
}
] | 1
|
https://f1000research.com/articles/10-423
|
https://f1000research.com/articles/11-510/v1
|
11 May 22
|
{
"type": "Study Protocol",
"title": "Protocol for the Ketamine for Postoperative Avoidance of Depressive Symptoms (K-PASS) feasibility study: A randomized clinical trial",
"authors": [
"Bradley A. Fritz",
"Bethany R. Tellor Pennington",
"Ben J.A. Palanca",
"Julie A. Schweiger",
"Jon T. Willie",
"Nuri B. Farber",
"Bethany R. Tellor Pennington",
"Ben J.A. Palanca",
"Julie A. Schweiger",
"Jon T. Willie",
"Nuri B. Farber"
],
"abstract": "Background: Postoperative depressive symptoms are associated with pain, readmissions, death, and other undesirable outcomes. Ketamine produces rapid but transient antidepressant effects in the perioperative setting. Longer infusions confer lasting antidepressant activity in patients with treatment-resistant depression, but it is unknown whether a similar approach may produce a lasting antidepressant effect after surgery. This protocol describes a pilot study that will assess the feasibility of conducting a larger scale randomized clinical trial addressing this knowledge gap. Methods: This single-center, double-blind, placebo-controlled pilot trial involves the enrollment of 32 patients aged 18 years or older with a history of depression scheduled for surgery with planned intensive care unit admission. On the first day following surgery and extubation, participants will be randomized to an intravenous eight-hour infusion of either ketamine (0.5 mg kg-1 over 10 minutes followed by a continuous rate of 0.3 mg kg-1 h-1) or an equal volume of normal saline. Depressive symptoms will be quantified using the Montgomery-Asberg Depression Rating Scale preoperatively and serially up to 14 days after the infusion. To detect ketamine-induced changes on overnight sleep architecture, a wireless headband will be used to record electroencephalograms preoperatively, during the study infusion, and after infusion. The primary feasibility endpoints will include the fraction of patients approached who enroll, the fraction of randomized patients who complete the study infusion, and the fraction of randomized patients who complete outcome data collection. Conclusions: This pilot study will evaluate the feasibility of a future large comparative effectiveness trial of ketamine to reduce depressive symptoms in postsurgical patients. Registration: K-PASS is registered on ClinicalTrials.gov: NCT05233566; registered February 10, 2022.",
"keywords": [
"Depression",
"Feasibility",
"Ketamine",
"Protocol",
"Randomized Clinical Trial",
"Surgery"
],
"content": "Introduction\n\nApproximately 25-50% of patients presenting for surgery have a history of depression.1–5 Patients with a history of preoperative depression are at elevated risk for experiencing depressive symptoms after surgery. In a cohort of 248 neurosurgical patients, lifetime history of depression was an independent predictor of postoperative depressive symptoms.6 Similar risks have been observed in cardiac surgery.1 When scores on various depression scales are analyzed as continuous variables, worse preoperative scores have consistently been significant predictors of worse postoperative scores.7–9 Postoperative depressive symptoms of greater severity have been linked to increased pain,10 more frequent hospital readmissions within six months,11 as well as increased mortality in short-term and long-term follow-up.12\n\nCurrently, prevention and treatment of depressive symptoms generally focuses on continuation, resumption, or initiation of oral antidepressants. The first-line agents include selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors, based on American Psychiatric Association recommendations for treatment of depression in adults and older adults.13 Following initiation or dose titration, these medications take several weeks to achieve their full effect,14–16 limiting their effectiveness to prevent acute depressive symptoms after surgery. Furthermore, it may not be possible to give these medications in some instances due to impaired gastrointestinal absorption or motility or due to concern for medication interactions such as serotonin syndrome. Given that rehabilitation is a common need following major surgery, rapid-acting antidepressants may be both more impactful and more easily administered in the perioperative compared to outpatient setting.\n\nThe N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown promise as a novel, rapid-acting therapy for treatment-resistant depression. In 2006, Zarate and colleagues published an 18-patient randomized trial that demonstrated improved Hamilton Depression Rating Scale scores following 0.5 mg kg-1 ketamine infused over 40 minutes compared to placebo.17 Since then, this finding has been replicated multiple times, with a recent meta-analysis of 19 studies reporting that a single infusion of ketamine led to improved depressive symptoms compared to placebo at four hours and 24 hours.18 Additional trials have demonstrated superiority of ketamine compared to active comparators such as midazolam for treatment of treatment-resistant depression.19,20\n\nThe antidepressant properties of ketamine are potentially mediated by a sequence of events that lead to synaptogenesis and increased electroencephalogram (EEG) sleep slow wave activity (SWA). Ketamine administration results in increased extracellular glutamate in the prefrontal cortex,21–23 initiating a chain of events24,25 that leads to increased prefrontal synaptic density.26 Enhanced synapse creation during wakefulness is followed by enhanced synapse pruning during subsequent sleep, for which sleep SWA (1-4 Hz total EEG power) during non-rapid eye movement (NREM) sleep is a commonly used surrogate.27 Additionally, low sleep SWA during baseline sleep predicts ketamine responsiveness in depressed patients,28 and increases in sleep SWA following ketamine infusion correlate with symptom response.29\n\nAlthough ketamine achieves its antidepressant effect rapidly, the effect of a single bolus wanes over the first week, and strategies to achieve longer effects have been explored, such as repeat intravenous boluses and intranasal administration.30–34 Symptoms can be controlled for multiple weeks, but ongoing therapy is needed to sustain the effect.35 An alternative strategy that reduces repeated dosing is to use a long-duration of infusion. In a pilot study, a 96-hour ketamine infusion titrated to a goal of 0.6 mg kg-1 h-1 led to a rapid reduction in depressive symptoms in a large majority of responders sustained for up to eight weeks.36,37\n\nLessons learned from treatment-resistant depression may guide the mitigation of depressive symptoms in the perioperative arena. Ketamine is already familiar in this setting because it is sometimes used to provide sedation or to augment analgesia.38,39 Boluses of 0.25-0.5 mg kg-1 during Cesarean section have been associated with either no effect40 or with reductions in postpartum depression.41,42 In surgery with general anesthesia, ketamine boluses near the time of induction have been associated with reduced postoperative depressive symptoms among patients with a history of depression43,44 but not in a general population of older adults.45 In those studies where a significant beneficial effect was observed, the effect quickly waned over the first few days after surgery. Treatment strategies that produce longer-lasting effects are desirable, but the longer-duration infusion that has shown promise in treatment-resistant depression has not been tested in the postoperative setting.\n\nThe aim of this pilot study is to assess the feasibility of conducting a phase three clinical trial, which will test the hypothesis that a postoperative sustained, low-dose ketamine infusion can prevent postoperative depressive symptoms in surgical patients with a history of depression. Therefore, this feasibility trial has three primary objectives: to evaluate the feasibility of recruiting participants to the randomized trial, to evaluate the feasibility of delivering the study medication, and to evaluate the feasibility of collecting depression outcome data. Secondary objectives are to estimate the effect sizes for two efficacy outcomes: postoperative depressive symptoms as quantified using the Montgomery-Asberg Depression Rating Scale on post-infusion day four and delta sleep ratio on EEG collected the first night following the study medication.\n\n\nMethods\n\nThis trial will follow a randomized, placebo-controlled, double-blinded, parallel design. It will be conducted at Washington University in St. Louis School of Medicine/Barnes-Jewish Hospital, a large academic hospital that serves as a quaternary referral center for a multi-state area in the Midwest region of the United States. The overall trial structure is shown in Figure 1. This protocol has been designed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.46\n\nAbbreviations: ICU = intensive care unit; MADRS = Montgomery-Asberg Depression Rating Scale; EEG = electroencephalogram.\n\nInclusion criteria for this trial will include patients (1) aged 18 years or older, (2) scheduled for surgery with planned intensive care unit (ICU) admission at Barnes-Jewish Hospital, (3) past medical history of depression, (4) ability to provide written, informed consent, and (5) stated willingness to comply with all study procedures. Past medical history of depression will be defined by previous diagnosis documented in the electronic health record or by previous use of an oral antidepressant.\n\nExclusion criteria will include (1) bipolar depression, (2) outpatient antipsychotic medication use, (3) emergent surgery, (4) known or suspected elevation in intracranial pressure, (5) subarachnoid hemorrhage, (6) carotid endarterectomy or arteriovenous malformation repair, (7) allergy to ketamine, (8) any condition in which a significant elevation of blood pressure would constitute a serious hazard (e.g., aortic dissection, pheochromocytoma), (9) outpatient use of an anticonvulsant with significant voltage-gated sodium channel activity,47 (10) known history of dementia, (11) pregnancy or lactation, (12) inability to converse in English, (13) concurrent enrollment in another interventional trial, and (14) postoperative mechanical ventilation continuing past 07:00am on postoperative day three.\n\nRecruitment strategy\n\nPatients will primarily be recruited at the Center for Preoperative Assessment and Planning (CPAP). Potentially eligible patents will be identified by screening the CPAP schedule. Patients identified via screening will be approached by telephone prior to their CPAP appointment or in person at CPAP. In addition, the operating room schedule will be reviewed to identify potentially eligible patients admitted to the hospital before surgery who did not visit CPAP. These patients will be approached in person in the hospital prior to the day of surgery.\n\nOn the first morning following surgery and extubation, participants will be randomized in a 1:1 fashion to receive either ketamine or normal saline, in blocks of four. The randomization scheme will be held by the Barnes-Jewish Hospital Investigational Drug Service. Participants, research team members, and clinical staff (ICU nurses, physicians, pharmacists) will be blinded to treatment allocation. To facilitate blinding, study medication for both groups will be delivered in 100 mL bags with identical appearance except for a unique study identifier. The adequacy of blinding will be assessed on post-infusion day one by asking the participant to guess which treatment they received. The attending intensivist may request unblinding if a serious adverse event occurs and the intensivist feels knowledge of the treatment allocation will impact clinical decision making.\n\nThe study medication will be administered as a bolus loading dose followed by a continuous infusion. For participants in the ketamine group, the loading dose will consist of ketamine 0.5 mg kg-1 administered intravenously over 10 minutes (or over 20 minutes if body mass index > 40). This will be followed by a continuous infusion at 0.3 mg kg-1 h-1 for an additional 7 hours 50 minutes. In the control group, an equal volume of normal saline will be administered over the same infusion rate schedule as for the ketamine group (loading dose of 0.1 mL kg-1 followed by a continuous infusion at 0.06 mL kg-1 h-1). Study intervention dosing will be based on actual body weight. The study medication will be initiated between 05:00am and 08:00am. To improve adherence to intervention protocols, detailed instructions will be available in the electronic health record and on a laminated card given to the ICU nurse. In addition, research staff will check on the participant every few hours and be available throughout the infusion. Adherence will be monitored by reviewing the medication administration record in the electronic health record.\n\nJustification for dose\n\nIn the intervention group, the dosing regimen has been designed to quickly achieve an expected blood level of ketamine of 225 ng mL-1, with maintenance of that level throughout the infusion. A targeted blood level of 225 ng mL-1 represents half of the serum concentration obtained during steady state for a 96-hour infusion.36 This level is also only slightly higher than the peak blood level obtained after patients receive a 0.5 mg kg-1 bolus dose delivered over 40 minutes, first described by Krystal in 199448 and used frequently in subsequent studies. Such a dosing approach would address the question of clinical utility in prolonging the length of anticipated NMDA receptor blockade from several minutes to several hours.\n\nTo load the patient with an amount equal to 100% of the desired steady state, the loading dose should be equal to the product of the volume of distribution and the desired plasma concentration. Per Wagner and O’Hara,49 the volume of distribution of ketamine is 2.4 L kg-1. As noted above, the desired plasma concentration is 225 ng mL-1, which is equal to 0.225 mg L-1. Thus, the loading dose is 2.4 L kg-1 × 0.225 mg L-1 = approximately 0.5 mg kg-1.\n\nThe dose for the continuous infusion is based on a previous study of 23 patients with treatment-resistant depression who received a 96-hour infusion of intravenous ketamine; serum ketamine levels were directly measured.37 An infusion of 0.6 mg kg-1 h-1 produced a steady-state blood level of about 450 ng mL-1. Therefore, an infusion at half that rate (0.3 mg kg-1 h-1) would be expected to produce a 50% lower steady-state blood level of 225 ng mL-1.\n\nDose adjustments\n\nRichmond Agitation and Sedation Scale (RASS) scores will be monitored per standard ICU nursing protocols.50 If the participant experiences sedation to a RASS score ≤ -2, then the study medication will be halted until recovery to RASS > -2. Then the infusion will be resumed at a reduced rate. If the RASS score is ≤ -2 before initiation of the study medication, then the study medication will not be initiated at that time. The participant will be re-evaluated the following day, and the study medication will be initiated when the RASS is no longer ≤ -2. If RASS remains ≤ -2 on postoperative day three, the patient will be withdrawn from the study.\n\nConcurrent therapy\n\nParticipants should not receive open-label ketamine at any time intraoperatively or postoperatively. Otherwise, all components of the anesthetic care plan will be at the discretion of the attending anesthesiologist. Postoperatively during the eight-hour study infusion, concurrent infusions of propofol, midazolam, or other sedative agents with gamma-aminobutyric acid (GABA) receptor activity will not be permitted. Concurrent dexmedetomidine will be permitted, but administration of benzodiazepines or gabapentin will not be permitted. All other components of postoperative care will occur as directed by the clinical team.\n\nAll data points will be collected for all patients, including those who deviate from the intervention protocols. To promote participant retention and complete follow-up, postoperative assessments can be made via telephone if the patient discharges from the hospital before the day of the final study assessment.\n\nBaseline factors potentially related to depression\n\nAt the time of enrollment, the patient will complete several surveys evaluating factors that may be related to their depressive history or that may predict treatment responsiveness. These surveys will include the Generalized Anxiety Disorder 7-item scale (GAD-7),51 the Alcohol Use Disorders Identification Test (AUDIT),52 the Drug Abuse Screening Test (DAST-10),53 and the Childhood Trauma Questionnaire (CTQ).54\n\nDepressive symptoms\n\nDepressive symptoms will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) preoperatively and on post-infusion days 1, 2, 4, 7, and 14. The MADRS rates the severity of 10 depressive symptoms based on a targeted clinical interview, yielding a total score zero (no symptoms) and 60 (severe symptoms).55,56 The scale has been found to correlate highly with a global clinician assessment (Pearson correlation = 0.71)57 and to have high inter-rater reliability.55 The MADRS has been modified to assess symptoms over the previous day rather than the previous week.36,37 This modified version will be used on the post-infusion days.\n\nThe MADRS will be administered by a trained research team member. Post-infusion assessments will be conducted between 07:00am and 12:00pm on the specified days. The time of day for the preoperative assessment will be variable, depending on the time of the patient’s CPAP appointment or in-hospital visit. If the patient is discharged from the hospital before the day of the final study assessment, the MADRS will be conducted over the telephone.\n\nConcurrent with each MADRS assessment, the research team member will use the Clinical Global Impression-Severity scale (CGI-S) to rate the overall severity of the patient’s mental illness.58 At each postoperative follow-up, the Clinical Global Impression-Improvement scale (CGI-I) will also be used to rate the overall level of improvement compared to the previous assessment. Concurrent with each MADRS assessment, self-reported depressive symptoms will be collected using the self-report version of the Quick Inventory of Depressive Symptomatology (QIDS-SR).59\n\nThe MADRS includes questions about suicidal ideation. If the patient reports any suicidal ideation, then the Suicide Risk Management Protocol will be initiated. This includes a structured assessment allowing stratification of the risk for self-harm, notification of the principal investigator, and (if risk is moderate or high) notification of an on-call psychiatrist.\n\nEEG measurement\n\nEEG will be captured using the Dreem headband (DREEM, Rhythm, New York, NY), a consumer-grade wireless device using dry electrodes. The device uses five EEG channels (F7, F8, FpZ, O1, O2), accelerometry, and pulse plethysmography. It samples EEG electrode potentials at a rate of 250 Hz and applies a 0.4-30 Hz bandpass filter.\n\nAt the baseline visit, the research team member will teach the participant how to use the Dreem headband for data collection. If the participant is recruited in the CPAP clinic, then the participant will take the Dreem headband home with them. They will be instructed to wear the headband and activate data collection while sleeping for one night. They will bring the headband back to the hospital with them on the day of surgery. If the participant is recruited in the hospital, then the participant will wear the headband and activate data collection while sleeping the night following enrollment. The headband will be retrieved the following day.\n\nAdditional data collection using the Dreem headband will occur during the study medication infusion, the night following the study medication infusion, and the night following post-infusion day one. Each EEG will be analyzed by an experienced sleep technician to identify sleep stages. Within each time epoch captured, SWA will be defined as the total power in the 1-4 Hz frequency band. The delta sleep ratio will be defined as the ratio of SWA during the first NREM Stage three cycle to SWA during the second NREM Stage three cycle.\n\nPostoperative pain\n\nPain will be measured at the baseline visit and on post-infusion days 1, 2, 4, 7, and 14 using the visual analog scale and an 11-point numeric rating scale. The participant will rate their pain at rest, when taking a deep breath, and with movement. If the participant is discharged from the hospital before the day of the final study assessment, remaining pain assessments will be conducted over the telephone using the numeric rating scale only.\n\nPostoperative delirium\n\nDelirium is assessed routinely by the ICU nurses using the Confusion Assessment Method for the ICU (CAM-ICU) once per shift.60 CAM-ICU scores between the day of the infusion and post-infusion day five will be retrieved from the electronic health record.\n\nPsychotomimetic side effects\n\nPsychotomimetic effects will be quantified using the Brief Psychiatric Rating Scale (BPRS) four-item positive symptom subscale36,61 and using the modified seven-item Clinical Administered Dissociative State Scale (CADSS-7).62 The BPRS four-item subscale yields a score between four (no symptoms) and 28 (extremely severe). The CADSS-7 yields a score between zero (no symptoms) and 35 (severe symptoms). Both scales will be administered by a research team member midway through the study medication infusion (approximately four hours +/- one hour after the start of the bolus loading dose).\n\nClinical and adverse events checklist\n\nAdditional side effects of ketamine will be monitored using the Clinical and Adverse Events Checklist.63 This checklist will be administered by a research team member midway through the study medication infusion (approximately four hours +/- one hour after the start of the bolus loading dose). The checklist will be repeated on post-infusion day 14 to monitor for resolution of any side effects.\n\nVital signs during study medication infusion\n\nDuring the infusion, participants will receive vital sign monitoring per ICU standard of care. This will include continuous telemetry, continuous pulse oximetry, and either intermittent noninvasive blood pressure (at least hourly) or continuous invasive blood pressure (if an arterial catheter is present). Vital signs will be documented in the electronic health record by the clinical bedside nurse per unit standard of care. The research team will retrieve vital signs from the electronic health record.\n\nSafety events will include significant hypertension during the infusion, defined as systolic blood pressure > 180 mmHg or the administration of an antihypertensive medication that is not one of the patient’s home medications. Another safety event will be tachycardia, defined as heart rate > 100 beats per minute, during the infusion.\n\nNausea and vomiting\n\nAt each post-infusion study visit, participants will be asked if they have experienced nausea or vomiting in the past 24 hours. If present, the patient will be asked to classify the event as mild, moderate, or severe. In addition, the electronic medical record will be reviewed for administration of antiemetic medication.\n\nPrimary endpoints\n\nFor primary objective one, the endpoint will be the fraction of approached patients who enroll in the trial and are randomized. This endpoint will be described using a proportion and 95% confidence interval. The numerator will include all participants who are randomized to receive either ketamine or the placebo. The denominator will include all patients who are approached by the research team in person or by telephone to evaluate eligibility and offer consent.\n\nFor primary objective two, the endpoint will be the fraction of randomized participants who complete the study medication infusion. This endpoint will be described using a proportion and 95% confidence interval. The numerator will include all participants who receive the study medication for at least seven of the planned eight hours. The denominator will include all participants who are randomized.\n\nFor primary objective three, the endpoint will be the fraction of randomized participants who have MADRS scores available at all the specified time points. This endpoint will be described using a proportion and 95% confidence interval. The numerator will include all participants with MADRS scores documented ate baseline and post-infusions days 1, 2, 4, 7, and 14. The denominator will include all participants who are randomized.\n\nSecondary endpoints\n\nFor secondary objective one, the endpoint will be the difference in MADRS score on post-infusion day four compared to the preoperative baseline visit. Participants with missing MADRS scores at either time point will be excluded. For secondary objective two, the endpoint will be the EEG delta sleep ratio on the second night following the study medication infusion. Point estimates and standard deviations for the between-group differences in these endpoints will be obtained, but this pilot study will not be powered to perform formal statistical testing. These analyses will follow the intention-to-treat principle. There will be no imputation of missing data.\n\nSample size\n\nThe sample size of 32 has been selected to allow the primary descriptive endpoints to be measured with acceptable levels of precision. For endpoint one, if 25% of approached patients enroll (which is a conservative estimate), then this sample size will allow this proportion to be measured with a 95% confidence interval width of ±15%. For endpoint two, if 90% of randomized participants complete the study medication infusion, then this sample size will allow this proportion to be measured with a 95% confidence interval width of ±10%. For endpoint three, if 95% of randomized participants have MADRS scores available at all specified time points, then this sample size will allow this proportion to be measured with a 95% confidence interval of ±7%.\n\nThis sample size does not provide power to test the secondary endpoints for superiority. However, the observed values will be used to determine effect sizes, as well as standard deviations for the observed values. These quantities will inform the sample size calculation for the full-scale clinical trial. A minimum of 24-30 patients has previously been recommended for estimating effects sizes,64,65 so this feasibility trial should be large enough to provide the necessary estimates.\n\nThis trial will employ an independent safety monitor (ISM) to serve as an impartial advocate for the safety of study participants. The ISM will be a physician with relevant expertise in the care of postoperative critically ill patients and must be independent from the study conduct. Any reportable adverse events (including unexpected adverse drug events and unanticipated problems) will be reported to the ISM and to the institutional review board within one business day if it involves a death or within 10 business days if it does not involve a death. The ISM will determine the degree to which the adverse events is thought to be related to the study intervention and whether any additional action is required in response to the event. In addition to reviewing reportable adverse events, the ISM will review the prespecified safety outcomes in aggregate every six months. These safety outcomes include psychotomimetic side effects, the Clinical and Adverse Events Checklist, RASS scores during the infusion, and significant hypertension and tachycardia during the infusion.\n\nThis study has been approved by the Human Research Protection Office at Washington University (approval #202201107) on February 15, 2022. Any protocol modifications will be approved by this IRB, and significant modifications will be communicated by updates to the trial registration and/or direct communication with participants. The study has also been registered at ClinicalTrials.gov (NCT05233566, posted February 10, 2022). All participants will provide written, informed consent prior to their involvement in research activities. Participants will be informed that their participation is voluntary, that they may withdraw from the study at any time, and that declining to participate will not adversely affect their planned surgery or any other aspect of their medical care. The informed consent form that will be used and the completed SPIRIT checklist can be found as Extended data.66\n\nConfidentiality\n\nAll research activities will be conducted in as private a setting as possible. To protect against the risk of confidentiality breach, only the minimum necessary protected health information will be retrieved from the electronic health record. All paper documents will be stored behind two locked doors. All electronic data will be kept in an encrypted, password-protected environment accessible only to the research team. Study participant research data, to be used for statistical analysis and scientific reporting, will be stored on the Research Electronic Data Capture (REDCap) system managed by Washington University School of Medicine.\n\nThe results of this trial will be disseminated via presentation at scientific meetings and publication in peer-reviewed journals, with potential audiences including anesthesiologists, psychiatrists, surgeons, and critical care physicians. In addition, key results will be published to ClinicalTrials.gov. For publications, authorship will be determined based on International Committee of Medical Journal Editors guidelines. Per National Institute of Mental Health data sharing policy, the deidentified dataset will be deposited to the National Data Archive after the study has been completed.\n\nAt the time of initial protocol submission (April 21, 2022), no participants had yet enrolled in the study. As of the date of this revision (April 26, 2022), one participant has enrolled in the study.\n\n\nConclusions\n\nThe trial described in this protocol will establish the feasibility of conducting a larger randomized clinical trial studying postoperative ketamine in patients with depression. This line of work will yield knowledge about whether a postoperative ketamine infusion can prevent or mitigate subsequent depression. Investigation of concurrent EEG markers may also yield insights regarding the effects of ketamine infusion on sleep architecture and potential mechanistic associations between sleep architecture and postoperative depressive symptoms. This knowledge will benefit future patients by informing treatment decisions that will enhance mental health following surgery.\n\n\nData availability\n\nNo data are associated with this article.\n\nOpen Science Framework: Ketamine for Postoperative Avoidance of Depressive Symptoms (K-PASS) Feasibility Study: A Randomized Clinical Trial. https://doi.org/10.17605/OSF.IO/TDGXK.66\n\nThis project contains the following extended data:\n\n- KPASS Informed Consent.pdf\n\n- SPIRIT checklist for ‘Protocol for the Ketamine for Postoperative Avoidance of Depressive Symptoms (K-PASS) feasibility study- A randomized clinical trial’.pdf\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAuthor contributions\n\nFritz: Conceptualization, Funding Acquisition, Methodology, Supervision, Writing – Original Draft Preparation\n\nPennington: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing\n\nPalanca: Conceptualization, Funding Acquisition, Resources, Writing – Review & Editing\n\nSchweiger: Methodology, Writing – Review & Editing\n\nWillie: Conceptualization, Methodology, Writing – Review & Editing\n\nFarber: Conceptualization, Funding Acquisition, Methodology, Writing – Review & Editing",
"appendix": "References\n\nHorne D, Kehler S, Kaoukis G, et al.: Depression before and after cardiac surgery: do all patients respond the same?. J. Thorac. Cardiovasc. Surg. 2013; 145(5): 1400–1406. PubMed Abstract | Publisher Full Text\n\nTheunissen M, Peters ML, Schepers J, et al.: Prevalence and predictors of depression and well-being after hysterectomy: An observational study. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017; 217: 94–100. PubMed Abstract | Publisher Full Text\n\nBooth H, Khan O, Prevost AT, et al.: Impact of bariatric surgery on clinical depression. Interrupted time series study with matched controls. J. Affect. Disord. 2015; 174: 644–649. PubMed Abstract | Publisher Full Text\n\nHellstadius Y, Lagergren J, Zylstra J, et al.: Prevalence and predictors of anxiety and depression among esophageal cancer patients prior to surgery. Dis. Esophagus. 2016; 29(8): 1128–1134. PubMed Abstract | Publisher Full Text\n\nWeekes DG, Campbell RE, Shi WJ, et al.: Prevalence of clinical depression among patients after shoulder stabilization: a prospective study. J. Bone Joint Surg. Am. 2019; 101(18): 1628–1635. PubMed Abstract | Publisher Full Text\n\nBarbieri V, Cardinale F, Gozzo F, et al.: Risk factors for postoperative depression: A retrospective analysis of 248 subjects operated on for drug-resistant epilepsy. Epilepsia. 2015; 56(10): e149–e155. PubMed Abstract | Publisher Full Text\n\nAi AL, Smyth SS: Depression after open heart surgery: influences of optimism, sex, and event-related medical factors. J. Nerv. Ment. Dis. 2021; 209(3): 212–217. PubMed Abstract | Publisher Full Text\n\nCaspi-Avissar N, Grosman-Rimon L, Gohari J, et al.: Clinical, surgical, and sociopsychological factors and depression after cardiothoracic surgery. Ann. Thorac. Surg. 2021; 111(3): 1064–1070. PubMed Abstract | Publisher Full Text\n\nPatron E, Messerotti Benvenuti S, Palomba D: Preoperative and perioperative predictors of reactive and persistent depression after cardiac surgery: a three-month follow-up study. Psychosomatics. 2014; 55(3): 261–271. Publisher Full Text\n\nGoebel S, Steinert A, Vierheilig C, et al.: Correlation between depressive symptoms and perioperative pain: a prospective cohort study of patients undergoing orthopedic surgeries. Clin. J. Pain. 2013; 29(5): 392–399. Publisher Full Text\n\nTully PJ, Baker RA, Turnbull D, et al.: The role of depression and anxiety symptoms in hospital readmissions after cardiac surgery. J. Behav. Med. 2008; 31(4): 281–290. PubMed Abstract | Publisher Full Text\n\nTakagi H, Ando T, Umemoto T: Perioperative depression or anxiety and postoperative mortality in cardiac surgery: a systematic review and meta-analysis. Heart Vessel. 2017; 32(12): 1458–1468. Publisher Full Text\n\nSummary of the clinical practice guideline for the treatment of depression across three age cohorts. Am. Psychol. 2021. [published online 2021/11/30]. PubMed Abstract | Publisher Full Text\n\nTaylor MJ, Freemantle N, Geddes JR, et al.: Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch. Gen. Psychiatry. 2006; 63(11): 1217–1223. PubMed Abstract | Publisher Full Text\n\nNierenberg AA, Farabaugh AH, Alpert JE, et al.: Timing of onset of antidepressant response with fluoxetine treatment. Am. J. Psychiatry. 2000; 157(9): 1423–1428. PubMed Abstract | Publisher Full Text\n\nTrivedi MH, Rush AJ, Wisniewski SR, et al.: Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am. J. Psychiatry. 2006; 163(1): 28–40. Publisher Full Text\n\nZarate CA Jr, Singh JB, Carlson PJ, et al.: A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry. 2006; 63(8): 856–864. Publisher Full Text\n\nMarcantoni WS, Akoumba BS, Wassef M, et al.: A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 - January 2019. J. Affect. Disord. 2020; 277: 831–841. PubMed Abstract | Publisher Full Text\n\nMurrough JW, Iosifescu DV, Chang LC, et al.: Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am. J. Psychiatry. 2013; 170(10): 1134–1142. PubMed Abstract | Publisher Full Text\n\nPhillips JL, Norris S, Talbot J, et al.: Single, repeated, and maintenance ketamine iInfusions for treatment-resistant depression: a randomized controlled trial. Am. J. Psychiatry. 2019; 176(5): 401–409. Publisher Full Text\n\nChowdhury GM, Behar KL, Cho W, et al.: 1H-[13C]-nuclear magnetic resonance spectroscopy measures of ketamine‘s effect on amino acid neurotransmitter metabolism. Biol. Psychiatry. 2012; 71(11): 1022–1025. PubMed Abstract | Publisher Full Text\n\nLi M, Demenescu LR, Colic L, et al.: Temporal dynamics of antidepressant ketamine effects on glutamine cycling follow regional fingerprints of AMPA and NMDA receptor densities. Neuropsychopharmacology. 2017; 42(6): 1201–1209. PubMed Abstract | Publisher Full Text\n\nAbdallah CG, De Feyter HM, Averill LA, et al.: The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology. 2018; 43(10): 2154–2160. PubMed Abstract | Publisher Full Text\n\nZanos P, Moaddel R, Morris PJ, et al.: NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016; 533(7604): 481–486. PubMed Abstract | Publisher Full Text\n\nWoelfer M, Li M, Colic L, et al.: Ketamine-induced changes in plasma brain-derived neurotrophic factor (BDNF) levels are associated with the resting-state functional connectivity of the prefrontal cortex. World J. Biol. Psychiatry. 2020; 21(9): 696–710. PubMed Abstract | Publisher Full Text\n\nLi N, Lee B, Liu RJ, et al.: mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010; 329(5994): 959–964. PubMed Abstract | Publisher Full Text\n\nTononi G, Cirelli C: Sleep function and synaptic homeostasis. Sleep Med. Rev. 2006; 10(1): 49–62. Publisher Full Text\n\nDuncan WC Jr, Selter J, Brutsche N, et al.: Baseline delta sleep ratio predicts acute ketamine mood response in major depressive disorder. J. Affect. Disord. 2013; 145(1): 115–119. PubMed Abstract | Publisher Full Text\n\nDuncan WC, Sarasso S, Ferrarelli F, et al.: Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder. Int. J. Neuropsychopharmacol. 2013; 16(2): 301–311. PubMed Abstract | Publisher Full Text\n\nSingh JB, Fedgchin M, Daly EJ, et al.: A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am. J. Psychiatry. 2016; 173(8): 816–826. PubMed Abstract | Publisher Full Text\n\nAlbott CS, Lim KO, Forbes MK, et al.: Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment-resistant depression. J. Clin. Psychiatry. 2018; 79(3) PubMed Abstract | Publisher Full Text\n\nDaly EJ, Singh JB, Fedgchin M, et al.: Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2018; 75(2): 139–148. PubMed Abstract | Publisher Full Text\n\nPopova V, Daly EJ, Trivedi M, et al.: Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am. J. Psychiatry. 2019; 176(6): 428–438. Publisher Full Text\n\nWajs E, Aluisio L, Holder R, et al.: Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J. Clin. Psychiatry. 2020; 81(3) PubMed Abstract | Publisher Full Text\n\nDaly EJ, Trivedi MH, Janik A, et al.: Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2019; 76(9): 893–903. PubMed Abstract | Publisher Full Text\n\nLenze EJ, Farber NB, Kharasch E, et al.: Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial. World J. Biol. Psychiatry. 2016; 17(3): 230–238. PubMed Abstract | Publisher Full Text\n\nSiegel JS, Palanca BJA, Ances BM, et al.: Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacology. 2021; 238(4): 1157–1169. PubMed Abstract | Publisher Full Text\n\nBrinck EC, Tiippana E, Heesen M, et al.: Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst. Rev. 2018; 12(12): Cd012033. Publisher Full Text\n\nWang J, Xu Z, Feng Z, et al.: Impact of ketamine on pain management in cesarean section: a systematic review and meta-analysis. Pain Physician. 2020; 23(2): 135–148. PubMed Abstract\n\nXu Y, Li Y, Huang X, et al.: Single bolus low-dose of ketamine does not prevent postpartum depression: a randomized, double-blind, placebo-controlled, prospective clinical trial. Arch. Gynecol. Obstet. 2017; 295(5): 1167–1174. Publisher Full Text\n\nMa JH, Wang SY, Yu HY, et al.: Prophylactic use of ketamine reduces postpartum depression in Chinese women undergoing cesarean section. Psychiatry Res. 2019; 279: 252–258. PubMed Abstract | Publisher Full Text\n\nYao J, Song T, Zhang Y, et al.: Intraoperative ketamine for reduction in postpartum depressive symptoms after cesarean delivery: A double-blind, randomized clinical trial. Brain Behav. 2020; 10(9): e01715. Publisher Full Text\n\nKudoh A, Takahira Y, Katagai H, et al.: Small-dose ketamine improves the postoperative state of depressed patients. Anesth. Analg. 2002; 95(1): 114–118. table of contents. PubMed Abstract | Publisher Full Text\n\nWang J, Wang Y, Xu X, et al.: Use of various doses of S-ketamine in treatment of depression and pain in cervical carcinoma patients with mild/moderate depression after laparoscopic total hysterectomy. Med. Sci. Monit. 2020; 26: e922028. Publisher Full Text\n\nMashour GA, Ben Abdallah A, Pryor KO, et al.: Intraoperative ketamine for prevention of depressive symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Br. J. Anaesth. 2018; 121(5): 1075–1083. PubMed Abstract | Publisher Full Text\n\nChan AW, Tetzlaff JM, Altman DG, et al.: SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann. Intern. Med. 2013; 158(3): 200–207. PubMed Abstract | Publisher Full Text\n\nFarber NB, Jiang XP, Heinkel C, et al.: Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol. Psychiatry. 2002; 7(7): 726–733. Publisher Full Text\n\nKrystal JH, Karper LP, Seibyl JP, et al.: Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch. Gen. Psychiatry. 1994; 51(3): 199–214. PubMed Abstract | Publisher Full Text\n\nWagner BK, O‘Hara DA: Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin. Pharmacokinet. 1997; 33(6): 426–453. PubMed Abstract | Publisher Full Text\n\nSessler CN, Gosnell MS, Grap MJ, et al.: The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am. J. Respir. Crit. Care Med. 2002; 166(10): 1338–1344. Publisher Full Text\n\nSpitzer RL, Kroenke K, Williams JB, et al.: A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch. Intern. Med. 2006; 166(10): 1092–1097. Publisher Full Text\n\nSaunders JB, Aasland OG, Babor TF, et al.: Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption–II. Addiction. 1993; 88(6): 791–804. PubMed Abstract | Publisher Full Text\n\nSkinner HA: The drug abuse screening test. Addict. Behav. 1982; 7(4): 363–371. Publisher Full Text\n\nBernstein DP, Stein JA, Newcomb MD, et al.: Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl. 2003; 27(2): 169–190. PubMed Abstract | Publisher Full Text\n\nMontgomery SA, Asberg M: A new depression scale designed to be sensitive to change. Br. J. Psychiatry. 1979; 134: 382–389. PubMed Abstract | Publisher Full Text\n\nWilliams JB, Kobak KA: Development and reliability of a structured interview guide for the Montgomery Asberg Depression Rating Scale (SIGMA). Br. J. Psychiatry. 2008; 192(1): 52–58. PubMed Abstract | Publisher Full Text\n\nMaier W, Heuser I, Philipp M, et al.: Improving depression severity assessment--II. Content, concurrent and external validity of three observer depression scales. J. Psychiatr. Res. 1988; 22(1): 13–19. PubMed Abstract | Publisher Full Text\n\nBusner J, Targum SD: The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007; 4(7): 28–37. PubMed Abstract\n\nRush AJ, Trivedi MH, Ibrahim HM, et al.: The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol. Psychiatry. 2003; 54(5): 573–583. PubMed Abstract | Publisher Full Text\n\nEly EW, Inouye SK, Bernard GR, et al.: Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001; 286(21): 2703–2710. Publisher Full Text\n\nFlemenbaum A, Zimmermann RL: Inter- and intra-rater reliability of the Brief Psychiatric Rating Scale. Psychol. Rep. 1973; 32(3): 783–792. PubMed Abstract\n\nRodrigues NB, McIntyre RS, Lipsitz O, et al.: A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions. J. Affect. Disord. 2021; 282: 160–164. PubMed Abstract | Publisher Full Text\n\nNewcomer JW, Farber NB, Jevtovic-Todorovic V, et al.: Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999; 20(2): 106–118. Publisher Full Text\n\nLancaster GA, Dodd S, Williamson PR: Design and analysis of pilot studies: recommendations for good practice. J. Eval. Clin. Pract. 2004; 10(2): 307–312. PubMed Abstract | Publisher Full Text\n\nJulious SA: Sample size of 12 per group rule of thumb for a pilot study. Pharm. Stat. 2005; 4(4): 287–291. Publisher Full Text\n\nFritz B: Ketamine for Postoperative Avoidance of Depressive Symptoms (K-PASS) Feasibility Study: A Randomized Clinical Trial. [Dataset].2022, April 26. Publisher Full Text"
}
|
[
{
"id": "137483",
"date": "09 Jun 2022",
"name": "Boris D Heifets",
"expertise": [
"Reviewer Expertise Perioperative mental health",
"translational neuroscience"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript by Fritz et al describes a highly innovative clinical trial protocol to determine the feasibility of a larger study of the effects of postoperative ketamine infusion on subsequent depression rates and sleep architecture. Overall, the manuscript was exceptionally clear and well written. The feasibility outcome measures are very reasonable and well considered, and I very much appreciate this stepwise approach to clinical trial design prior to launching a much larger trial. I think this merits indexing and discussion. I do have several comments on some of the trial design components which the authors may wish to address prior to indexing, as I suspect other readers may have similar reactions.\nPatient selection\nThe authors will enroll patients with planned admission to an ICU after surgery. I assume the ICU criterion exists to accommodate the requirement for an 8 hour ketamine infusion, which in many centers can only be performed in some care areas. Have the authors done a preliminary assessment of what types of surgery they are likely to encounter? Postoperative depression in cerebral aneurysm repair and AVR patients, for example, might reflect quite different pathogenesis (eg prolonged frontal lobe retraction, long pump times & neuroinflammation).\n\nAre patients on high dose opioids included in this trial? Is there any issue with randomizing chronic pain patients undergoing ICU-level surgery to ketamine vs placebo when there is an arguably independent indication for intraoperative ketamine as a multimodal opioid-sparing agent?\n\nAuthors are measuring alcohol use (AUDIT) as a predictor of outcome, will they be recruiting patients with alcohol use disorder? Withdrawal in the postoperative period, even if it does not require treatment, may significantly influence mood ratings.\n\nPatients with a history of depression are being recruited, but there is no mention of whether they have to meet a symptom severity criterion (eg minimal MADRS). As the authors are likely aware, the majority of patients with a chart diagnosis of depression or using an antidepressant may only have mild or moderate symptoms of depression. Therefore, the change in depression score that the authors are likely to see may be quite small and may require large sample sizes.\n\nTreatment paradigm\nAs described, the placebo control is unlikely to result in effective blinding given the fairly obvious effects of ketamine. I appreciate the difficulty in coming up with an active placebo that one can infuse for 8 hours without impacting patient care, so changing the comparator to ketamine may not be realistic. Given the role of expectancy bias and placebo effect, authors may wish to measure expectancy bias prior to treatment (eg Stanford Expectations of Treatment Scale). Re: measuring the blind, blinding should ideally also be assessed immediately after dosing – patients asked 24h post infusion may incorporate their response to treatment as part of their guess.\n\nNot sure I agree with the PK calculations – empirically, TCI methods (see https://stanpumpr.io) which incorporate a 3 compartment model (Domino et al 1984 Clin Pharm Ther1) predict blood levels very accurately (Bowdle et 1998 Anesthesiology2, Vogt et al 2021 Anesthesiology3). Plugging into STANPUMP online the same parameters in the proposed study (3mg/kg/hr * 10 min then 0.3mg/kg/hr for 8 hrs) gives a steady state concentration of about 180ng/mL. It’s not obvious that this will be clearly inferior to a steady state of 225ng/mL, but the authors may want to take this information into consideration.\n\nOutcome Measures\nWhy are the authors measuring MADRS change from baseline (preop) compared to postop? Why not take the baseline measure as their last pre-ketamine score? Is it hypothesized that postoperative depression presents nearly immediately after surgery? The confound, potentially, is that patients' moods may be driven by the stress of upcoming surgery, so the authors may find that patients appear to improve before they are even randomized.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": []
},
{
"id": "188595",
"date": "21 Jul 2023",
"name": "Octavian Vasiliu",
"expertise": [
"Reviewer Expertise Psychiatry"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis protocol for a study exploring the impact of ketamine on postoperative avoidance of depressive symptoms is interesting and may be useful for practitioners dealing with patients presenting with depressive disorders. Some aspects need to be addressed, in order to enhance the accuracy of the data this study will collect; please see below:\nAccording to the data on https://classic.clinicaltrials.gov/ct2/show/NCT05233566, this study is expected to enroll \"neurosurgical patients\", but there is no similar specification in the \"Abstract\" section of the submitted manuscript. Also, the duration of iv infusion is 3 h on the clinicaltrials.gov, and 8 h in the manuscript. I think it would be useful to insert in the \"Abstract\" the fact that tolerability and safety aspects will be monitored, also.\nWill there be no superior age limit as an inclusion criterion? Geriatric depression may have different evolution under treatment, although reports on the use of iv ketamine in this population exist- Bryant et al., (2019)1, Medeiros da Frota Ribeiro & Riva-Posse (2017)2.\nThe \"pain\" outcome is not mentioned in the online protocol published on the US NLM site.\nWhat does \"past medical history of depression\" mean? Please specify if only patients diagnosed with recurrent major depressive disorder (MDD) can participate, or if subjects with treatment-resistant MDD will also be enrolled. Any cut-off MADRS value at the baseline? Will partially remitted patients also be included, according to their MADRS scores? Will IV ketamine be an add-on to the currently administered antidepressant? Please specify if any type of antidepressant will be prohibited during the 14 days of the monitoring period. Will the patients present MDD with psychotic features be enrolled? Because this may be a confounding factor when interpreting the evolution of BPRS and CADSS-7 scores, for example.\nWhat kind of surgery procedures will be allowed? Only neurosurgical (as specified on the clinicaltrials.gov site), or just any type?\nThere are some measurement tools with unclear purposes in the \"Daya collection\" section. If the authors wish to make a complete screening for other psychiatric disorders (including substance use disorders) - which would be highly recommendable - then they should also use a dedicated instrument, like MINI+, SCID5, or any other structured interview.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-510
|
https://f1000research.com/articles/11-509/v1
|
11 May 22
|
{
"type": "Data Note",
"title": "Datasets on the variations of minerals in biofortified cassava (Manihot esculenta Crantz) as a function of storage root portion, maturity and environment",
"authors": [
"Emmanuel Oladeji Alamu",
"Busie Maziya-Dixon",
"Alfred Dixon",
"Busie Maziya-Dixon",
"Alfred Dixon"
],
"abstract": "Background: The accurate measurements of the mineral content of cassava roots are vital from a nutritional perspective. The research datasets were from the study assessing the influence of storage root portion, maturity, and environment on the variations of minerals in biofortified cassava roots. Methods: Twenty-five biofortified clones with three varieties as checks were harvested 12 months after planting from five different environments. Also, a different thirty-nine (39) biofortified cassava clones from the unlimited yield trials (UYTs) that included five (5) white-fleshed varieties (as control) were harvested at the age of 9 and 12 months after planting. In addition, two different methods of sample preparations were employed, using a cork borer and without a cork borer. The samples’ elemental (minerals) analysis was determined using a standard laboratory method. Results and conclusion: The breeders could use the data in their biofortification cassava programs to know the distribution of minerals in the roots and identify the best promising pipelines. Also, the data could be used by food scientists and nutritionists to understand the parts of the roots with optimum minerals to design their processing protocols and to know those genotypes specific to different environments that could be used for various nutrition intervention programs.",
"keywords": [
"minerals",
"biofortified cassava roots",
"clones",
"environment",
"sample preparation method",
"maturity"
],
"content": "Introduction\n\nBiofortified cassava roots with yellow flesh colour could be a good source of essential minerals and micronutrients and potential functional food. The different values of minerals composition of cassava roots found in the literature have shown many discrepancies beyond those caused by genetic and environmental factors. However, this could be due to inaccurate laboratory measurements, especially errors due to the sample preparation method employed during the analysis. The documented data could help the analysts and processors choose the best sample preparation method to evaluate the mineral compositions of cassava roots. The accurate measurements of the mineral content of cassava roots are vital from a nutritional perspective, especially during the selection stages of the breeding program and for providing quality information on the mineral intake in sub-Saharan Africa. However, there is a shortage of data on the spatial distribution of biofortified cassava storage roots’ mineral contents. The datasets presented the spatial distribution of minerals in biofortified cassava root genotypes and established the sampling method’s effect and harvesting time on their mineral content.\n\nThe datasets provide information on the effect of clone and environment on the minerals in biofortified cassava root. Furthermore, they establish which of the two factors strongly influences the mineral contents. In addition, they provide information on the essential minerals in biofortified cassava roots and show any association between the mineral properties assessed. The information the datasets reveals is the distribution of the minerals and their concentrations within the cassava tuber (head, middle, and tail root portions) would primarily benefit cassava breeders, food scientists and nutritionists. Also, the datasets on the effect of clones and environment could help the cassava breeders and processors identify what cassava variety is suitable for growth in all the environments and contains optimum minerals.\n\nBreeders could use the data in their biofortification cassava programs to investigate the distribution of minerals in the roots and identify the best promising pipelines. The data could also be used by food scientists, nutritionists, and processors to understand the parts of the roots with optimum minerals and understand those genotypes specific to different environments used for various nutrition intervention programs. The data could also contribute to Nigeria’s food composition databases.\n\n\nMaterials and methods\n\nThe genetic materials used to generate the presented datasets were from two trials. The first one comprised of the 39 biofortified cassava genotypes from the unlimited yield trial (UYT) stage of the breeding program and 5 white-fleshed varieties (as checks), totalling 44 genotypes. They were grown in two sets at the research farm of IITA, Ibadan, Nigeria. Set one had 22 biofortified genotypes with white roots varieties as checks, totalling 25 genotypes, while set two had 17 biofortified genotypes with two varieties with white roots as control (totalling 19 genotypes). The source (parent lines with different quality traits) used for the breeding crosses that could dictate the mineral properties of the genotypes was the main difference between the two sets.1 The second one was a multi-environment field trial. It had 25 biofortified cassava genotypes and three varieties with white roots grown in five environments. The five growth locations were from six different agro-ecological zones of Nigeria, namely Ibadan, Ubiaja, Onne, Mokwa and Zaria. The latitude and longitude for the collected samples/data are as follows: Ibadan 7° 38′ N, 3° 89′ E; Onne 4° 41′ N, 7° 09′ E; Ubiaja 6° 65′ N, 6° 38′ E; Mokwa 9° 28′ N, 5° 05′ E; Zaria 11° 16′ N, 7° 63′ E.2 The cassava clones in these trials were planted during the rainy season of July 2005 and 2006 and were grown without fertilizers or herbicides under rainfed conditions. The harvesting of the storage roots was done in April 2006 (9 months) and July 2006 (12 months) after planting (MAP), respectively, where the two middle rows were harvested per plot. Three plants per genotype were harvested and pooled. Six cassava roots of different sizes (two each of the large, medium, and small) were randomly selected and placed in a labelled polythene bag from the pooled roots per genotype. The sample bags were transferred to the laboratory and processed within 24 hours of harvest.\n\n\nPreparation of cassava roots for analysis\n\nThe method described by Maziya-Dixon et al.3 was employed for the first sample preparation method. The three non-damaged storage roots of different sizes of 900–2300 g (large), 500 to 899 g (medium), and 200 to 499 g (small) were selected at the laboratory level. The roots were washed thoroughly with potable water to remove dirt and sand particles and air-dried on a clean concrete floor for about 5–10 min under atmospheric conditions. After that, the cleaned roots were peeled using a stainless-steel knife and further washed with deionized water to ensure the samples were free of soil contaminants. Next, the peeled and cleaned storage roots were bored through using a cork borer, size 8. The bored depth ranged from 4.6 to 9.7 cm for the head, 3.8 to 7.1 cm for the middle and 3.6 to 6.4 cm for the tail parts of the roots, and each portion was pooled and homogenized.3 The procedures were repeated for each genotype.\n\nThe second sample preparation method also followed the protocol described by Maziya-Dixon et al.3 It involved selecting a new set of the three non-damaged storage roots of different sizes (large, medium, and small) cleaned using potable water and air-dried on a clean concrete floor as indicated for Method 1. The storage roots were peeled manually using a stainless-steel knife and rinsed with deionized water. The peeled, cleaned roots were cut longitudinal into four equal parts from the proximal to distal ends. For each root, the two opposite sections were taken, chopped into small pieces, and mixed thoroughly before subsampling. The procedures were repeated for each genotype.\n\n\nDetermination of macro- and microelement content\n\nThe samples for mineral analysis were carefully sub-sampled from the batch samples from the two described sample preparation methods. After sub-sampling, the samples were placed in an already cleaned petri dish using deionized water and dried in an uncorroded conventional oven (Memmert UN 55, GmbH) at 40°C for three days. The dried samples were transferred into well-labelled mineral-free paper envelopes for analysis. The mineral contents were analyzed according to the validated method using inductively coupled optical emission spectrometry (ICP-OES).1,2,4 Specifically, a radial view Spectro Ciros CCD ICP-OES (Spectro Analytical Instruments, Kleve, Germany) model was used. Each of the dried samples were weighed (0.03 g) into 1 mg into 50 ml screw-cap polypropylene tubes, and initiation of sample digestion was achieved using 2 ml of HNO3 and 0.5 ml of H2O2. The digestion was completed at 125°C for 120 min using 72-position DigiPrep digestion blocks (SCP Scientific, Baie D’Urf e, Quebec, Canada). An 18 MΩ.cm of water was used to make the final volume of 25 ml of the sample. The digested sample was injected at the flow rate was 2.0 ml/min, and the total analysis time per sample was approximately 2.5 min. The calibration curves for all elements were constructed using the mixtures of high-purity single-element standard solutions in a 4% (v/v) HNO3 matrix. The software algorithms were used for the background correction of all wavelengths and spectral interferences, as described by Wheal et al.4\n\n\nDataset description and validation\n\nThe samples from the two trials (44 + 28 biofortified clones and check varieties) were run in duplicate at the laboratory level. However, for quality data collection, there was an analysis of a mixture of all elements in 4% HNO3 (drift correction solution) at every 25 samples. It helped to account for within-run variation in the flows. Furthermore, the blank subtraction, drift correction, and mass and volume adjustments were made offline. The study used six different reference materials (RMs) for the data quality establishment purchased from the US National Institute of Standards and Technology (NIST, Gaithersburg, MD, USA).4 The macro elements of focus in the data include calcium (Ca), magnesium (Mg), sodium (Na), potassium (K), phosphorus (P), and sulphur (S). At the same time, the microelements were Iron (Fe), Manganese (Mn), Boron (B), Copper (Cu), Molybdenum (Mo), Cobalt (Co), Nickel (Ni), Zinc (Zn) and Aluminium (Al), respectively. They were measured on an mg/kg dry weight basis. The storage portions included the proximal (A), middle (B), distal (C), the average ABC (AV) and longitudinal (L).\n\n\nData availability\n\nDryad: Quantitative Assessment of Trace and Macro Element Compositions of Cassava (Manihot esculenta) Storage Roots Enriched with Β-Carotene as Influenced by Genotypes and Growing Locations, https://doi.org/10.5061/dryad.k3j9kd59r.5\n\nThis project contains the following underlying data:\n\n• Data_on_the_Variations_of_Macro_and_Microelements_as_influnced_by_sampling_method.xlsx\n\n• Data_on_Trace_and_Macro_Element_in_cassava_roots_as_influenced_by_Genotype_and_environment.csv\n\n• README.csv\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "Acknowledgments\n\nWe acknowledged the CGIAR Research Program on Roots, Tubers and Bananas (RTB) and HarvestPlus for their support. Also, the support of the entire staff of Food and Nutrition Sciences Laboratory, IITA, Ibadan, Nigeria, and Cassava Breeding Unit, IITA, Ibadan, Nigeria, especially Drs Kulakow Peter and Parkes Elizabeth, was acknowledged. All authors have read and approved the manuscript and are aware of its submission.\n\n\nReferences\n\nAlamu EO, Maziya-Dixon B, Sibeso C, et al.: Variations of Macro- and Microelements in Biofortified Cassava (Manihot esculenta Crantz) Genotypes as a Function of Storage Root Portion, Harvesting Time, and Sampling Method. Appl. Sci. 2020; 10(16): 5396. Publisher Full Text\n\nAlamu EO, Maziya-Dixon B, Dixon AG: Quantitative Assessment of Trace and Macro Element Compositions of Cassava (Manihot esculenta) Storage Roots Enriched with β-Carotene as Influenced by Genotypes and Growing Locations. Agriculture. 2020; 10: 613. Publisher Full Text\n\nMaziya-Dixon B, Alamu EO, Dixon AG: Variation in the evaluation of cis-and trans–carotene in biofortified cassava (Manihot esculenta Cranz) varieties as a function of the storage root portion and sampling method. LWT. 2016; 70: 296–301. Publisher Full Text\n\nWheal MS, Fowles TO, Palmer LT: A cost-effective acid digestion method using closed polypropylene tubes for inductively coupled plasma optical emission spectrometry (ICP-OES) analysis of essential plant elements. Anal. Methods. 2011; 3: 2854. Publisher Full Text\n\nAlamu E, Maziya-Dixon B, Dixon AG: Quantitative assessment of trace and macro element compositions of Cassava (Manihot esculenta) storage roots enriched with Β-Carotene as influenced by genotypes and growing locations, Dryad, Dataset.2022. Publisher Full Text"
}
|
[
{
"id": "162494",
"date": "06 Apr 2023",
"name": "Treenut Saithong",
"expertise": [
"Reviewer Expertise Plant metabolism",
"systems biology",
"plant computational modeling"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis dataset presented the variation of mineral contents in cassava roots from different genetic varieties and cultivated conditions. The data collection is basic information that could benefit various researches on cassava yield and quality improvement, and also food processing industry. While the data is interesting, I recommended revising the following issues before indexing:\n\nThe current version of the manuscript contained various confusing sentences, especially in the Introduction,\ne.g. \"In addition, they provide information on the essential minerals in bio-fortified cassava roots and show any association between the mineral properties assessed. The information the datasets reveals is the distribution of the minerals and their concentrations within the cassava tuber (head, middle, and tail root portions) would primarily benefit cassava breeders, food scientists and nutritionists.\"\nand the first part of Materials and Methods\ne.g. \"The source (parent lines with different quality traits) used for the breeding crosses that could dictate the mineral properties of the genotypes was the main difference between the two sets\".\n\nIt would be useful for later research work, if the source of the size category specified in this study (i.e. \"The three non-damaged storage roots of different sizes of 900–2300 g (large), 500 to 899 g (medium), and 200 to 499 g (small) were selected at the laboratory level.\") is described.\n\nThe data set in Excel file was presented in a user-friendly style. However, I found that it might increase the usefulness of the data if the author could also add information on genotype background of trait characteristics. Also, all measured number of mineral content should present with a clear unit.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": []
},
{
"id": "167845",
"date": "11 Apr 2023",
"name": "Peng Zhang",
"expertise": [
"Reviewer Expertise Cassava genetic improvement and molecular breeding."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript reported the building of datasets on the variation of minerals from twenty-five biofortified cassava clones with cassava growth status and environment. Basically, the work is very meaningful and important for guiding cassava breeders and producers for cassava field management. The methods used are suitable and sufficient for the detection of the difference among the parameters. If the authors could provided the data related to the soil nutrient status, including macro and micro-nutrients, it would be more significant.\n\nIs the rationale for creating the dataset(s) clearly described? Yes\n\nAre the protocols appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and materials provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-509
|
https://f1000research.com/articles/11-508/v1
|
11 May 22
|
{
"type": "Opinion Article",
"title": "High-level biocontainment laboratories: risks and necessity for society",
"authors": [
"Monica Zoppè"
],
"abstract": "Advancements in the biological sciences have made it possible to manipulate life forms in unprecedented ways. Recognizing the possible dangers connected with this activity, as well as with work involving natural pathogens, countries have promoted the building of High Safety and High Containment Laboratories, classified as Biological Safety Levels 3 and 4. In this article I briefly summarize the major features of these laboratories, exemplify some of the research that they host, highlight the possible dangers, and argue for the opportunity of a reduction of possibly dangerous research, and for more transparency and openness about activities that imply risks not only for those involved, but for human and environmental health as well.",
"keywords": [
"BioSafety",
"Biosecurity",
"Biological risk",
"BSL-4",
"Gain of Function"
],
"content": "Introduction\n\nHumans and infectious diseases have always cohabited. Understandably, humans have always tried to escape diseases and counter their effects as best as they could, with varying success.\n\nWith the advent of modern science, we have started a ‘fight on disease’ which, although it has not been won (and can never be), has brought much better means of escape and also has provided us with considerable knowledge. We now have a discrete understanding of many biological processes, with a significant part relating to pathogenic organisms.\n\nThe study of pathogens is useful and important, as it helps us prevent or cure many transmissible diseases through diagnostic, therapeutical and clinical research; yet it is also intrinsically dangerous, as it poses the risk of contamination for laboratory workers (Laboratory Acquired Infections 1 – 4 ), possibly leading to community outbreaks; furthermore, knowledge gained with the purpose of better understanding and managing disease may have the potential for malicious uses (known as dual-use research), which poses another layer of dilemma for scientists and science policy. 5 – 7 However, it is difficult to trace a clear line separating danger and utility, and it often occurs that an activity is both dangerous and very useful, in science as in other fields (e.g. fire extinguishing). The risks and benefits of researching potentially pandemic pathogens has been the subject of several articles, documents and regulatory guidelines. 8 – 11\n\nIn order to mitigate the risks connected with exposure to pathological organisms, scientists perform studies and experiments in High Level Biosafety Laboratories (designated as BioSafety Level 3 or 4 (BSL-3 or BSL-4), also called High-Containment, Containment Level 3 or 4, Physical Containment Level 4 or similar). Depending on the perceived risk and danger, some experiments are done in labs with more or less stringent measures to control possible contamination of workers and the environment (see following section).\n\nThe perception of safety has fostered a number of experiments that could be extremely dangerous, such as so-called Gain of Function (GoF) or the creation of new, synthetic organisms with ‘designed features’ 12 that will be discussed in the “Dangerous experiments” section.\n\nUnfortunately, we have always lived with accidents and mistakes in addition to disease (see “Accidents”): in relation to laboratories, even the highest BSL labs cannot fully guarantee that no accident will ever happen, leading to escape of material from the lab.\n\nThe following questions then arise: to what extent is it acceptable that dangerous experiments are performed? Does the knowledge that we hope to gain from such experiments balance the risks? Who should decide? On which basis?\n\nAnswers to these questions are not easy, and depend on many different considerations, based on cultural, social and personal priorities. Yet, they demand answers at a global level. In this article, the following section reports a brief summary of the classification of laboratories at different safety levels, as well as their presence and distribution. The work performed in these laboratories is summarized in the third section, highlighting its role in health protection and its associated risks, with a few examples. The fourth section is dedicated to the occurrence of accidents, showing how they are unavoidable, with their possible consequences, and with some examples. Finally, we discuss the necessity and risks of dangerous research in the fifth section, and conclude (final section) with some considerations.\n\n\nHigh-containment laboratories\n\nThe vast majority of experiments and studies on pathogenic organisms (mostly viruses and bacteria) is performed in laboratories at low bio-safety level (BSL-2); this is also where the vast majority of the knowledge that leads to the development of treatments is produced. [Note. The definition and designation of levels of containment vary in different countries, according to national definitions; we will refer to BSL Levels as defined in the Biosafety in Microbiological and Biomedical Laboratories—6th Edition 13 ]. The BSL designation can be replaced by a more functional approach, exposed in the Laboratory Biosafety Manual of the WHO- 4th Edition, 10 in which a risk assessment process is the basis for the selection and implementation of control and containment measures. However, as BSL levels are still widely used, their designation will be used throughout this article.\n\nIn general, BSL-2 labs are built with a higher emphasis on the protection of biological cultures from contamination derived from researchers and the environment than vice versa: these are the typical laboratories in which most biological research is performed, spanning all fields of biology from plant biology to cancer, from cell biology to genetics. Cells and their guest pathogens are delicate material, prone to be spoiled from many possible sources of contamination. For this reasons, BSL-2 labs are separated from the other laboratories, are always kept very clean, workers wash their hands, use dedicate coats and wear gloves at all times; cultures are handled with care in specifically designed hoods or cabinets (with laminar air flowing away from the work surface towards a filter), and materials, both incoming and outgoing, are sterilized. These conditions are in general sufficient to protect the biological cultures from contamination, together with some additional precautions, such as using specific antibiotics and other compounds to impede growth of unwanted organisms like fungi. In BSL-2 labs, it is allowed to grow mildly pathogenic organisms that cause treatable diseases: the very precautions that protect the cultures also protect the workers; in case of accident, workers know how to respond because the cultured pathogens are well known, symptoms are recognized and treatments or cures are readily available.\n\nMore dangerous pathogens can also be studied in BSL-2 labs, because scientists can use versions modified to be non-pathogenic: deactivated versions (i.e. in which essential or pathological functions are disabled and/or replaced by reporter genes), or pseudotyped forms (in which a harmless virus is used as a carrier for only a subset of genes), or vectors that only contain one or few proteins (components of the toxins, or some enzymes necessary in the viral cycle).\n\nIn order to transform the information obtained through basic research performed in BSL-2 labs into usable therapeutic solutions, however, it is necessary to test their activity in conditions that better reproduce the pathogen’s natural cycle, often involving live, fully infectious particles. These studies are usually performed in BSL-3 laboratories. Technical features of these labs are reported in Table 1: it can be seen that the emphasis is on measures meant to protect workers and the environment from getting contaminated by the pathogens in culture. In addition to the measures of BSL-2, here we find: double doors (which cannot be open at the same time), negative pressure (so that eventual breaches would result in flow into rather that out from the laboratory, thus impeding escape), sealed piping for liquid waste (including hand washing, and the eventual shower on the way out), and special autoclave with double access (entry from the lab, exit to the rest of the world). Laboratory personnel (usually already expert biologists) receive specific additional training, which should be rehearsed regularly, and wear additional protective equipment: face mask, double gloves, shoe covers, among others. On top of the regular recording of experiments (normal good laboratory practice), detailed logs must be kept for all in- and out-going material, all the experiments, and all the times that any personnel spend in the BSL-3. BSL-3 laboratories can be ‘enhanced’ with additional precautionary measures, such as control cameras, respirators or other devices.\n\nThe most dangerous research is relegated to BSL-4 labs. In addition to the safety measures described for BSL-3, at Level 4 properly trained and approved personnel work wearing a positive pressure suit, connected to an external source of breathing air: in case of puncture or other damage, air will flow from the worker to the environment and not the other way round. The surface of their sealing coats is chemically sterilized before being removed, and they go through a shower before reaching the outside world. Not only objects and other items are sterilized through an autoclave (or by other approved means) on the way out, but the air is also filtered through double high-efficiency particulate air (HEPA) filters, and all effluents are decontaminated. Cameras monitoring work inside the BSL4 are always on, and special rules apply for workers: for example, the two-person rule states that nobody can work alone in these environments. The experiments performed in these laboratories often involve studies on transmission, meaning that live animals (mammals, birds, insects) are kept alive for certain periods of time; as experiments are larger and more complex, more workers need to access the facility and more often, increasing the complexity of management of both people and materials. These laboratories are often very large and articulate, including parts of high containment, as well as laboratories at lower level of containment.\n\nBefore moving forward, a note on safety and security; the two terms, in many languages, are expressed by the same word, sometimes creating confusion. Safety refers to the possible accidental or unintentional dangers that can arise during experimental procedures, and is pursued with the development of practical rules on equipment, maintenance, instruction and behavior of personnel, aimed at minimizing the risks of exposure. Security, on the other hand, is a term that refers to the possible intentional release or misuse of harmful biological material and is aimed at preventing theft, loss and other possible misuse; therefore, emphasis is placed on control, including authorizations. Checks are performed on the personal history of scientists and workers; biological material is controlled as much as possible, with numbered vials, plates and thorough recording of their use; responsibility and issues about the military potential of biological organisms are considered. In many countries, national authorities compile a list of organisms or toxins for which it is necessary to obtain clearance, including many deadly viruses, bacteria and toxins, on the basis of their perceived bio-warfare or bio-terror potential. These lists are regularly updated and are obviously different for different countries: in places where plague or Ebola are endemic, it would make no sense to ‘prohibit’ or ‘control’ a naturally occurring disease.\n\nThe Biological and Toxin Weapon Convention (BTWC), established in 1972 and effective since 1975, 14 prohibits the development, production, acquisition, transfer, stockpiling and use of biological and toxin weapons, but does not restrain research on potential weaponizable organisms as long as their type and quantity is justified for ‘prophylactic, protective, or other peaceful purposes’. The convention is periodically reviewed in the Review Conference, in which the operation of the convention is updated to keep pace with the development of biological science and technology.\n\nHigh-level biosafety labs are present in many institutions around the world: they are used for the characterization and identification of pathogens from clinical sources, for research on therapeutics, for vaccine testing, and for surveillance, among other practices. Most countries keep a register, and guidelines for their maintenance and control are issued by national and other authorities, although a role for international and supranational organizations is growing, as shown by the recent publication of International Organization for Standardization on Biorisk Management, ISO 35001. 15\n\nFor the highest level of security (BSL-4), a precise count of their number is difficult: a very recent resource for information about the major complexes can be found at globalbiolabs.org, 16 which lists 59 locations (August 2021), most of them in Europe, North America and Asia. Many of the facilities in the list include two or more independent units, and sometimes few adaptations are sufficient to upgrade a lower-level laboratory into one with high-containment capacity. 17 Furthermore, they are sometimes hidden under some layer of secrecy, as could be the case for some of those managed by the military (that operate 20% of the facilities 18 ), connected with industrial property protection or considered easily amenable to misuse by clandestine operators. 19\n\nRecent estimates 17 indicate that there are over 3,000 BSL-3 laboratories in 86 countries worldwide. The distribution of the highest containment laboratories reflects the fact that high containment does not come cheap: their cost, in fact, can reach hundreds of million US dollars (USD), depending on the size and equipment (they are all custom built). As an example, the Australian Animal Health Laboratory (AAHL) in Geelong, Australia (now renamed Australian Centre for Disease Preparedness), a facility with 15,000 m2 of lab space, including 2,900 m2 of BSL-3 space (28 rooms) and 100 m2 of BSL-4 space, two BSL-4 animal rooms, one of which can hold up to six horses, and 955 m2 of animal biosafety level (ABSL)-3 space, cost 200 million Australian dollars (AUD) to build in 1985, 20 equivalent to about 350 million USD today. The smallest BSL-4 labs can be small enough to be transported on trucks, as the self-contained portable cabinets used for rapid identification and work during the latest (and ongoing) Ebola outbreaks. Large facilities (among which are probably those run by the military) may include hospital beds for human patients, indoor agriculture, animal husbandry for small and large mammals, birds, and insects.\n\nOnce built, the running costs, often not anticipated when the lab is built, easily reaches 10 million USD per year. 21 This is due to both the continuing running expenses and the necessity to keep the personnel technically proficient, to avoid losing skills.\n\nMost BSL-4 labs reported in Ref. 16 are hosted in public health hospitals, about 20% in university buildings, two of them are privately owned, and the remaining 20% are linked to military facilities. The location of such facilities poses important issues of public safety: ideally, perfect isolation of the labs is achieved through built-in measures. However, even a minor accident resulting in infection of a single person can have very different outcomes in relation to where the facility is located: big cities, university setting or public hospitals are the ideal places to spread infections; more secluded locations, such as islands or isolated compounds could mitigate the risk, even if it would be less practical for workers.\n\n\nWork in high-level biosafety labs\n\nWorking with biological material requires attention, training and experience with various laboratory practices, in order to manage all the small steps involved in growing live and very delicate material, even before considering aspects of research (organizing the proper experimental design, including for example dose/response scale and proper controls). From careful cleaning and sterilization of all materials, surfaces, liquids etc., to understanding how the many machines work, beyond deep knowledge of the organism subject of study, scientists that work in high containment laboratories are typically senior experts. However, the work conditions are quite demanding: all workers always wear gloves and goggles, and time is often a limit, forcing people to work fast, while at the same time clean, and, of course, without making mistakes.\n\nAt the highest level of biocontainment (BSL-4) all difficulties are amplified: people are enclosed in a completely sealed ‘astronaut suit’ with internal pressure; breathing air is delivered through pipes, gloves are doubled, making it harder to handle plates, bottles, vials and other materials, including the microscope knobs. Some people may feel re-assured by the camera watching and recording their work, but others could feel harassed and nervous by the constant control. 22 Furthermore, additional stress could be related to the known dangers associated with each specific organism, typically dangerous for oneself and for the community.\n\nSo, why are people willing to expose themselves and others to danger? The benefits of research that cannot be conducted in other settings are related to human and animal health: identification of pathogens, and development of diagnostics, vaccines, new therapies and treatments for new and very dangerous diseases, for which there are no available treatments nor vaccines. An obvious example is Ebola, that, with a high infectivity and lethality, would not be investigated in less safe conditions. Other diseases include the severe acute respiratory syndrome and Middle East respiratory syndrome (SARS and MERS, respectively) particularly virulent strains of influenza virus such as the H5N1, other hemorrhagic fever virus related to Ebola, including Marburg, Crimean Congo, Lassa and Yellow fever, and Zika, among others. Studies are aimed at understanding the pathogen’s biology, the immunology of host defense, the mechanisms of transmission of the pathogens and the diseases they produce, with the objective of identifying measures of detection, prevention and/or intervention. Therefore, experiments can be conducted in vitro, in vivo and in animal models. In the latter case, animal models can be naturally occurring (for example the wild reservoir of a zoonotic pathogen), or can be specifically developed for these studies. In some cases, it can be necessary to also include the vectors that transmit the pathogen, like ticks and mosquitoes (see Discussion). Organisms under study belong to the Risk Group 3 or 4, defined, respectively, as “high individual risk, low community risk” and “high individual and community risk: A pathogen that usually causes serious human or animal disease and that can be readily transmitted from one individual to another, directly or indirectly. Effective treatment and preventive measures are not usually available”. 10\n\nThe decision on the appropriate safety level for any given study depends on a number of considerations, and varies according to local regulations; in general, and in accordance with the latest indications from the WHO guidelines, 13 the process implies a Risk Assessment procedure that takes into account the organism, the experiment, the facility and the worker(s).\n\nUnfortunately, these risk assessment procedures are rarely available to the public; it is therefore impossible to evaluate how the risks balances with the societal value of the expected benefits. This issue is further worsened by the fact that many high-level labs are engaged with secret work, be it because of security concerns, industrial protection, or military reasons.\n\nDespite the general opacity, some information can be accessed from the annual reports of the Federal Select Agents Program (FSAP) of the USA. The reports are not solely concerned with high-containment labs, and are focused on security: they report the number of entities (facilities and personnel) that obtained permission to work with material listed as ‘select agents’, i.e. agents (viruses, bacteria, toxins or prions) potentially dangerous for humans, other animals or plants, and for which there is a potential for intentional abuse, or that pose a particularly severe threat from the point of view of the USA. Not all select agents belong to high-risk group, and it is permitted to work with some of them (once clearance from the relevant authority is obtained) in lower safety level laboratories. The latest edition of the FSAP report 23 reports that in the USA, during 2019, there were 247 entities and 8,360 individuals “approved to access biological agents and toxins”. Although there is no complete overlap between high-containment laboratories and workers and the number of laboratories and workers approved for access to select agents, these numbers, which refer to the USA only, provide indication about the extension of the high-containment issue.\n\nIt must be noted that, in many countries, besides the research described above, an unknown fraction of the work performed in BSL-4 laboratories is related to biodefense, and is even less accessible. In some laboratories, in addition to safety, security concerns induce a high level of secrecy, especially where the subjects of study are agents with a strong potential to be used in war or bioterror settings. As mentioned above, the BTWC does not prohibit research on pathogens with the potential to be used as a means of aggression, it is therefore considered legitimate to study organisms for ‘defense purposes’. However the distinction between offensive and defensive research rests largely in the intention of the user, a problem that will be address in the Discussion.\n\nWhat is a dangerous pathogen? In some sense, all pathogens are dangerous, but the degree of danger is related to a number of features. Danger for whom? human health; economically important agricultural species; farmed animals; environment or wild species.\n\nIn parallel with the definition commonly used in the financial setting, we can define risk as the product of the possible harm if something happens, by the probability that it will happen. The problem is that both terms are hard to quantify: different people can quantify harm in different ways, and they may be more or less prone to accept probability and the resulting risk.\n\nThe first half of the term (the possible harm) considers gravity of the disease (from minor, like a head ache, a short burst of fever, to mortal), infectivity (how easily the pathogen spreads), transmissibility (the mean of transmission, e.g. by breath, by ingestion or by mucosal contact, via insects, etc), treatability (the availability of treatment or cure, its ease of production and cost), susceptibility of a specific population. For example, malaria is transmitted by some species of mosquitoes (Anopheles): in places where those species do not thrive, it is safe to work at a low to medium level of safety; in places in which transmission could occur, but the disease has been eradicated, it is more important to keep it enclosed; finally, in places where the disease is still endemic, precautions always make sense, but might not be the prime thought for workers which could be already naturally infected. The human immunodeficiency virus (HIV) is a lethal virus (nearly 100% mortality if untreated), but it does not easily spread (it requires mucosal contact), and since the 1990s has been manageable through medications: it is classified as a Risk Group 2 pathogen. The virus responsible for the 2002–2004 pandemic of SARS, is in itself less lethal than HIV (30–40%); however, there are no known cures, and it spreads easily through the air: it is therefore in the Risk Group 3. As mentioned in the second section, some work can be performed in less stringent environment, by exploiting techniques that exclude the possibility of infection. Poliovirus is nowadays almost extinct, except for a few cases in remote areas in which vaccination is difficult; precisely because it is almost extinct, a large fraction of the population is not vaccinated against it anymore, and the extremely rare cases could pose a serious danger. For this reason, surveillance is still active, and is in part dependent on work performed in BSL-4 laboratories, despite being in itself considered in the Risk Group 2. 24 , 25 The case of Polio highlights the difficulty of interpreting risk: the possible harm is very high, and the probability very low.\n\nAs a reference, the American Biological Safety Association maintains a database 26 with the risk classification of a large number of organisms, as classified in different countries. Furthermore, it must be kept in mind that risk, its perception and the way we deal with it can change in time and according to circumstances.\n\nMedical practice is largely based on scientific understanding of diseases: here we only consider infectious diseases, which are mostly caused by bacteria, viruses and, occasionally, prions. This understanding spans from the molecular (including the genetic features of the pathogen and its cellular interactions), to the physiological (the clinical manifestations of the diseases), and the epidemiological (how the disease spreads) dynamics.\n\nNot all research however is necessarily or directly connected to health, or even presents any ‘use’: curiosity is a strong driver, and it has served us well in innumerable cases. 27 Studies based on non-pathogenic viruses, in particular, have fostered a very large base of information, knowledge, and understanding, very often leading to use way downstream of the initial research: possibly the best-known case nowadays is the CRISPR-Cas9 system and its analogues, derived from the study of a phenomenon linked to bacterial phages (virus) and the response actuated by the infected bacteria. 28\n\nGain of function (GoF) experiments are intended to force a system (virus, bacterium, or even an artificial construct) to acquire new functionalities, more or less well defined a priori. It can be achieved through different means, including genetic manipulation (e.g. inserting specific genes to induce a new activity), or through ‘directed evolution’, in which an organism is grown in conditions presenting features that ‘push’ selection towards specific traits. 29 Considering the almost inconceivably high number of single individual organisms (that count in the 106–10 or even more) that can be grown in a laboratory, it is possible to produce events that in nature would occur at an extremely low frequency. Procedures of selection or amplification makes it easier for researchers to isolate the resultant ‘new’ variant, which can then be studied in detail. 7 , 30\n\nThe possible risks and possible benefits related to GoF research, and of other applications of biotechnology, have been and still are discussed extensively. 7 – 9 , 30 – 34 With new scientific developments, regulations and guidelines are updated regularly (for example, the Biosafety in Microbiological and Biomedical Laboratories reached its 6th edition in 2020 13 ), and for GoF research that carries a possible dual use capability, additional regulations apply, for example in Europe 35 and in the USA. 36\n\nThe case of the Influenza A H5N1 virus, also called ‘avian flu’, is worth considering. H5N1 first appeared in the 1970s, showing mildly pathogenic features. By the end of last century, after decades of circulation among birds, a new strain appeared in East Asia that was highly infectious and lethal to birds, also causing sporadic infections in humans (18 infected people, six of whom died in Hong Kong, in 1997); as a containment measure, all domestic birds of Honk Kong were culled (killed and destroyed). 37 However, the measures could not completely stop the circulation of the strain, which reappeared in the early 2000s worldwide, in both domestic and wild birds, also infecting other animals such as pigs. Human infections increased in frequency, 38 prompting research on a vaccine and drugs. 39 , 40 Human to human transmission had not been observed (except for possibly few cases, 37 ). In 2012 scientists managed to obtain an outcome that had not occurred in nature: direct airborne transmission of the highly virulent strain among mammals. 41 , 42 This case is further addressed in the Discussion.\n\nAnother example of dangerous experiments is the work aimed at recreating the ‘Spanish flu’, an influenza strain that in the years 1918–20 killed an estimate of 20–60 million people worldwide (1 to 3% of the human population at the time). The pandemic naturally extinguished over a couple of years, to never resurrect, at least so far. At the time, samples were taken and conserved in paraffin. These samples, together with ‘naturally conserved samples’ in the graves of a victim in Alaska, have been used extensively in the laboratory to recreate the virus, whose molecular features were characterized by numerous research groups as reviewed in Watanabe and Kawaoka. 43 Also, this research has been the subject of discussion, and has contributed to a debate that led to an initial self-imposed year-long moratorium on flu research established in 2012. 44 Subsequently, the US Government imposed a moratorium on GoF research also involving SARS and MERS, 45 which remained in place until the new policy was released in 2017, with the Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens. 36\n\nBacillus anthracis is a prominent member in the list of the FSAP, which regulates the agents and toxins considered to pose severe threats to human, animal or plant health. In other words, it is considered a potential biological weapon. The only intentional use of Anthrax spores on record is the episode of 2001, soon after the 9/11 attacks. As it became evident after few years of investigations, reported in the Amerithrax investigation, 47 the origin of the material was a military high-containment laboratory in the USA, in which research had been conducted on ‘methods of weaponization’, aimed at identifying and understanding vulnerability to possibly weaponized bacteria (presumably by other countries or terrorist groups). 47 , 48 The result of such research is precisely what made it possible for what the Federal Bureau of Investigation (FBI) says was a single American scientist, Bruce Ivins, to kill five people, to disseminate terror, and to cause a major economic disruption by mailing letters containing somehow weaponized spores. 47 Apparently, the scientist suffered from mental health disorders, but the Army (his employer) failed to recognize them. 49 A secondary outcome was that this episode strongly contributed to the USA deciding to spend 60 billion USD on research related to biodefense, 50 aimed at protecting the country from biological agents, including purchase of antidotes, vaccines and any medical countermeasure, and starting the new wave of building of several high-containment laboratories.\n\nOther experiments that can be considered dangerous, or unreasonably risky, are conducted with other select agents, such as the botulinum toxin, 51 which was mutated (via directed evolution) to attack several different protein substrates, or the modification of insects to deliver viral vectors with human specified genetic material to plants. 52\n\nPossibly the most dangerous studies are those on smallpox, an organism that is listed both among the 66 pathogens in the select agents of the FSAP, 23 and in the Risk Group 4. Smallpox virus (Variola major) has circulated in humans for centuries, sweeping in waves that infected between a third and half of the populations, killing many of the infected and leaving the survivors blind, deformed and/or disfigured. It has been used as a biological weapon by the British against Native American people in the XVIII century, 53 and it was eradicated from the wild, thanks to a major vaccination campaign, completed in the 1970s. 54 Nowadays most humans are not vaccinated against it, and many voices in the WHO have repeatedly requested the destruction of the viral samples still existing in some freezers in the USA and Russia. 55 , 56 The request has not been satisfied for the opposition mainly from the USA delegates, who claim that, in case of a resurgence (which they are de facto encouraging simply by thawing the samples), the knowledge gained with their experiments would be of medical interest. 57 – 59 The possibility of finding live smallpox virus in quantity sufficient to start even a single infection is extremely low to nonexistent, as demonstrated by the difficulties encountered by scientists in recovering fragments of viral genome from multiple sources. 59\n\n\nAccidents\n\nPeople that work in BSL-4 labs are usually experienced biologists who have completed additional training both on general safety and on the specific organism used. However, they are humans and, precisely because they are experienced, they know well that accidents and mistakes do happen. 60 One might be distracted because of personal reasons (a date in the evening, or a sick child at home, a recent argument with a boss), or might be in a hurry, or may feel slightly sick, possibly in a way that would not be a problem in normal conditions: consider a sneeze in the positive-pressure personnel suit. Rules may well contemplate some of the situations, and suggest that work is handed to colleagues who should be able to perform equally well. But who would leave to someone else the final steps of an experiment that they have cultivated for months? Each one of us is naturally inclined to consider that no one could be as careful as oneself, when our own study is being performed, and an incipient cold might not seem problematic. Or one could think it unfair to call someone else to do our work, just because of a slight headache. Or an expert colleague might not be available at the requested time.\n\nAccidents are frequently the result of several contributing factors, among which are human errors, which are typically due to carelessness, inadequate training and knowledge, poor judgment, fatigue, distraction, and high stress level. 61 – 63 The most frequent small accidents involve spills or drops, sample mix-up, handling needles and sharps, and animal bites or scratches. 64 Other occurrences are linked to incomplete inactivation, leading to work being performed in conditions that, although safe for the inactive virus, can lead to infection from an active pathogen: this case is frequent in diagnostic and in vaccine research, and is due to non-compliance with rules that (should) impose verification of full inactivation of samples; multiple cases have been described in the 2016 report of the United States Government Accountability Office on high-containment laboratories. 65\n\nHowever, a small mistake is often easily corrected, but not always; sometimes, it represents the beginning of a chain of events, that can lead to disastrous consequences (see next section).\n\nOther sources of accidents are machine failures, power outages, or structural breakages, as exemplified by the release of foot-and-mouth disease from a major animal research institute in Pirbright, UK, where in 2007 a leakage from a drainage pipe released enough virus to start an outbreak that lasted several months, involving eight farms, over 200 animals (cattle and sheep) 66 and costed an estimate 200 million UK pounds. 67\n\nA third source of accidents is related to natural factors: earthquakes, floods (including hurricanes, tornadoes, and storms), and fires. A record of the instances involving select agent facilities which were affected by such events is made available, for the USA, by the Annual Reports of the Federal Select Agent, 23 which reveal that around one hundred events are reported each year. Buildings that host high-containment laboratories have additional safety measures to ensure secondary containment, according to national legislations. Fortunately, up to now, no cases of release due to accidents caused by natural disasters have been recorded. But this is no guarantee for the future: major climate disruption will lead to an increase in the frequency, in the geographical expansion and in the severity of weather extremes, including floods, heat waves and fires. 68 On the other hand, the lesson form Fukushima should warn that, although rare, “double-hit” (earthquake and tsunami, in the Fukushima case) are not impossible, and major accidents can never be excluded. In the case of a major flooding, the last thing that people might want is the circulation of mice or rats bearing a lethal disease.\n\nIt is obvious that occasional mistakes and small accidents happen, including in BSL-4 labs. But what happens in these cases? First of all, if they are aware of the mishap, the researcher(s) involved try to fix it. They should report the case to the lab supervisor; however, according to expert estimates (see, for example, the WHO report of the Consultative Meeting on High/Maximum Containment cited before 21 ) often refrain from doing so, fearing the consequences (temporarily isolation, restriction of permission to work in lab), or for a sense of shame, or for lack of understanding the relevance. 21 A non-punitive method for reporting might encourage a more thorough assessment of problematic instances, and lead to a safer environment and procedures. 69\n\nIf they are not aware of the accident, or if the ‘fix’ does not work, the most likely next step is that the workers themselves become infected. Well-known examples are the case of Brucella episode at Texas A&M university (TAMU, 70 ) and the case of SARS in 2004. 71 At this point the chain of events can take a more serious path: if the disease is easily transmitted, a chain of infection might start, leading to local or large outbreaks. This path has been suggested as the possible source of the ongoing COVID-19 pandemic, prompting many scientists to request a deeper investigation. 72 – 74\n\nWhen an accident leads to problems, a possible, and possibly frequent reaction by all involved (sometimes including the personnel directly involved) is to hide it: investigations are dreaded because they slow down work, and might uncover responsibility of laboratory directors, control system, failure of maintenance, among others. They may lead to suspension of permissions, fines and even criminal charges. 65 Furthermore, bad reputation might compromise the possibility of future work, raise public attention, opposition and mistrust, and jeopardize future grant acquisition, as in the examples below.\n\nA common solution is to blame the victim and close the case without much publicity; we cannot know how many and which cases were concluded with this modality. 62 , 75 Some cases, however, do come to light: for example, the well documented case of Brucella infection at Texas A&M University, in which one worker became ill and at least three other showed signs of previous infection with another bacterium listed as select agents. 76 The episode was revealed months later, thanks to the activity of a watchdog organization, now unfortunately closed (The Sunshine Project 77 ). It prompted a major investigation by the US Center for Disease Control (CDC), which ordered the closure of all work performed at the facility, in which at least five laboratories were working with select agents. 76 A second episode 78 in which the classical procedure of hiding the fact, blaming the victim, then admitting and finding a scapegoat happened in Boston, with the Tularemia case starting in May 2004 (first infection of three), which became public only in January 2005, with publication in a local newspaper. 78\n\nIt is fortunate that up to now no major laboratory-induced outbreak has happened. However, the list of accidents is long, even considering only those that have been publicly reported, most likely only a fraction. A possible exception to the statement above is related to the origin of SARS-CoV-2, the cause of the current COVID-19 pandemic, which is at present unknown. Some investigation has been conducted, with no conclusive result. 79 It has been proposed 73 , 74 , 80 that the virus may have originated during some of the research aimed at ‘investigating new emerging viruses’ carried out in research institutions in Wuhan, including the Wuhan Institute of Virology, which have been studying SARS and other coronaviruses from bats, and keeps the largest collection of this viral family. Curiosity, or the drive to explore the unknown is a natural human drive, 81 and it is only natural that Chinese scientists may have wanted to gather new information and knowledge about a family of viruses that already demonstrated its lethality with SARS and MERS; the fact that in Wuhan SARS strains were studied does not necessarily imply, nor exclude, that a leakage has been at the origin of the pandemic. The origin of SARS-CoV-2 from a natural spillover is favoured by many scientists, 82 but the precise route is still unknown, and both hypotheses (a lab and a natural origin) should be investigated.\n\nA selection of publicly accessible episodes of accidental release of dangerous pathogens is reported in Table 2. The table is compiled from information gathered from several sources, including publications from the Government Accountability Office of the USA, in the “High Containment Laboratories” series, and collected information from the FSAP program and CDC reports. In these reports, the Office repeatedly remarks that the extent of occurrences is not known. Another public repository of Laboratory-Acquired Infections (LAI) is maintained by ABSA, 4 where an impressive list of 524 episodes of exposures is reported, not necessarily leading to actual infection, including diseases ranging from Ebola 2 , 83 , 84 to Influenza A and B.\n\nCDC: American Center for Disease Control.\n\n\nDiscussion\n\nBasic knowledge\n\nModern medicine is largely based on a detailed understanding of pathogen biology: genetic (sequence identification, used for molecular and evolutionary studies), biochemical (proteins’ role, structural and topological information, for development of drugs and vaccines), cellular and physiological (interactions with host components and reaction of the organism, for drugs and patient management), and epidemiological (for societal management).\n\nEach pathogen differs from any other by some of the aspects broadly described above, and a good knowledge of each one is the best basis on which to build a response in case of an outbreak, or, worse, a pandemic.\n\nSome experimental knowledge can be acquired in safe conditions, while other requires the handling of live pathogens and animal models, sometime including vectors, as explained in the previous pages. In the latter cases, a balance between the opportunity of (possibly) getting the desired knowledge and the risks associated with conducting the research 64 must be found (see below). High-containment laboratories provide the safest conditions for performing experiments that, although dangerous, are considered necessary.\n\nThe case of Smallpox, mentioned before, represents a case worth discussing. Its presence in nature has not been documented for over 40 years. An effective vaccine has been available for over 200 years, and, along with others (possibly based on mRNA technology), it can be produced relatively fast. Infected people present highly characteristic symptoms and the disease is easily recognized: any small outbreak would be quickly identified, isolated and treated. The opportunity for further research, as requested by some scientists, 57 – 59 is therefore doubtful.\n\nTreatments and vaccines\n\nThe COVID-19 pandemic is an ongoing demonstration of what the scientific community as a whole can do to face a new pathogen. The effort has been huge, with thousands of world scientists switching from their current focus to research on COVID-19; however, we should not forget that any new knowledge is based on previous knowledge. Coronaviruses have been extensively studied (just like many other viruses, e.g. Influenza) for many years, especially after the SARS and MERS emergencies. 85 Similarly, platforms for vaccine development have been pursued in the last 20 years, providing a solid base for new preparation, such as in this case. 86 Thanks to this knowledge base, it has been possible, in less than two years, to produce several vaccines (10 currently approved for Emergency Use by WHO 87 ), based on different technologies, and tested rapidly using the actual pandemic virus. Pharmaceutical interventions are based mainly on repurposed drugs 88 and have been characterized in vitro and in cell culture in several laboratories at BSL-2 and BSL-3 levels, respectively. Patient management has been learned ‘the hard way’ by countless medical staff, engaged night and day for many months. The case of COVID-19 makes it very obvious that, in case of a new pandemic, the last concern will be with shortage of material for study and research.\n\nHighly lethal hemorrhagic fevers (Ebola being a prime example) for which we do not yet have a safe vaccine nor a cure, must be studied at the highest level of containment. The possibility of accidents must always be kept in mind, and risks should be minimized not only by safety measures but also by careful experimental design, i.e. choosing the least dangerous experimental options.\n\nSurveillance\n\nThe possibility of controlling any emergent or re-emergent disease is linked to the capability of rapid identification and diagnosis. The case of poliomyelitis, caused by poliovirus and described earlier, is an example of a disease that is still circulating in some parts of the world and requires growing suspect samples, 24 , 89 which must be done in fully safe conditions. Other pathogens can be more difficult to spot, in particular those not yet known (as was the case of SARS-CoV-2 at the start of the pandemic), and maximum precaution is warranted when analyzing unknown samples.\n\nGain of function research\n\nResearch on enhanced potential pandemic pathogens (PPP), also known as Gain of Function by virtue of the technique applied, explores possible emerging diseases by essentially ‘constructing’ new pathogens, that may (or may not) arise in nature. This research is subject to regulation. For example, the USA framework governing research on ‘enhanced Potential Pandemic Pathogens’ (P3CO), released in 2017 by the US Department of Health and Human Services (HHS) 36 allows “research that involves […] enhanced PPPs” in the case that the pathogen created is “reasonably judged to be a credible source of a potential future human pandemic”.\n\nSome examples of GoF research have been mentioned in the third section, and all have raised discussions. The case of Influenza A H5N1, called avian flu and mentioned earlier, is an interesting example: the genome of influenza virus is composed of eight different parts, circulating in several variations (for example, there are 16 HA and nine NA types), that can recombine in a very large number of ways, even without considering further mutations arising along the way. 90 Most of the combinations are unproductive and will never develop into a disease that infects humans; however, this still leaves the ‘possibly productive’ number at a level that cannot be possibly experimentally explored. The purpose of the studies that led to the generation of a strain H5N1 which can be directly transmitted among a mammal model (ferrets), 41 , 42 was to “address the concern that the virus could acquire this ability under natural conditions”, and reached the tautological conclusion that Influenza A H5N1 “constitutes a risk for human pandemic influenza”. 42 Nature has always surprised scientists, and it is sure to continue doing so, as most recently demonstrated with the emergence of COVID-19 and its thousands of mutations 91 : the number of possible emerging diseases is so high that it is extremely unlikely that the very disease created in the labs will arise spontaneously, while others are to be expected. In the case an outbreak was to emerge spontaneously, as the COVID-19 experience shows, much of the knowledge already obtained (largely from non-GoF experiments) would be helpful for fast reaction and, to understand the mechanism that led to human transmission, the outbreak strain itself could be studied. The risks associated with the creation of previously unknown pathogen must be weighed in relation to the possible utility of the knowledge gained. As nature is much more creative than humans in a lab, we can reasonably expect that, given the appropriate conditions, adaptive solutions will emerge that were not forecast by experts.\n\nAs mentioned, GoF research is strictly regulated, 35 , 36 yet decisions on what research is worth pursuing (considering risks and benefits) is always based on expert judgment. In this respect, it is remarkable that a document released in 2016, the final report on Risk and Benefit Analysis of Gain of Function Research, 8 concluded that “the coronaviruses are insufficiently transmissible to have a significant chance of causing a global pandemic” (page 2). This example illustrates how difficult it is, even for competent experts, to foresee evolution, and how their judgment cannot always be fully trusted.\n\nIt is also important to consider that any new disease developed in the laboratory, even in the case that it actually coincides with a natural pandemic one, poses the risk of escape and spread long before the identification of treatments and/or vaccines.\n\nDefense\n\nAnother reason that leads to perform risky research relates to biowarfare and bioterror. It is true that we can hardly think of a means of aggression that has never been used, but in relation to biological warfare, while several countries in Europe, Asia and North America developed bioweapons programs, especially in the first half of the past century, 48 , 53 , 92 , 93 very few episodes of effective use have been documented: the distribution of smallpox-tainted blankets to Native Americans by the British colonizers in the XVIII century, 48 and some attempts during World War II especially by Japan, but also by Germany and possibly others. Nowadays, scholars, notably Cross and Klotz, 94 doubt that biological agents will be used in warfare, due to”the widespread belief that biological weapons have no military utility”, 94 , 95 and thanks to the fact that the Biological Weapon Convention has been signed by almost all countries. 14\n\nThe possible use of biology for terrorism, or by non-state actors, can be considered somewhat easier, as it would “only” take few knowledgeable scientists to prepare a sufficient amount of an agent capable of infecting a few people, sufficient to disseminate terror. In the last 50 years or so, documented episodes include the intoxication of over 750 people in 1984 in Oregon by a religious sect 96 and the 2001 mailing of letters containing anthrax spores produced in a military facility in the USA, to politicians and members of the media in the USA. 47 The latter episode prompted a vast program of biodefense research in the USA aimed at developing countermeasures for possible further attacks. During the last 15 years in the USA, biodefense programs have been developed for the detection, identification, and characterization of an attack; prophylaxis against and treatment of cases of illness; and decontamination/recovery from an attack. These programs also contributed to the proliferation of high containment laboratories, at both the BSL-3 and BSL-4 level.\n\nStill, the use of biological agents as bioterror cannot be excluded: single persons or small organizations willing to disrupt ordinary life by seeding fear might pursue this option. Nowadays, with modern techniques, it is certainly possible for an expert biologist to ‘create’ a pathogen (likely a virus) with specific properties, but it is also certainly not easy. Previous research could ‘guide’ the activity, 97 but it would still require an expert virologist, a complex and expensive facility, supply of materials and reagents not easily obtained, and years of work. The few documented cases mentionned above, 47 , 96 and other failed attempts such as those pursued by the Japanese sect Aum Shinrikyo, 98 indicate that the use of traditional weapons vastly exceeds the use of biological ones. Even in the case that such individuals or groups were to develop their programs, what are the chances that it could be prevented by biodefense research?\n\nThe proliferation of laboratories and personnel authorized and capable of handling dangerous pathogens also poses the issue of the distinction between defensive and offensive research, which is defined by the ‘intention’, and is therefore prone to interpretation: a country’s defensive research program may be viewed by other countries as a threat, 99 with consequences that could lead them to start their own defensive research, possibly triggering a vicious circle.\n\nWe can also note that the word ‘defense’ has been used as a euphemism for ‘war’ since after World War II, 100 with the renaming of ministries in many countries (UK, Italy, USA and more). Indeed, the concept of defense implies a situation of hostile aggression and is strongly associated with weapons and war.\n\nAccidents happen\n\nIn section 4 the conditions that can lead to accidents have been explored. Table 2 reports examples to illustrate the variety of situations that represent danger. Documented accidents have happened in research laboratories, in military facilities, in vaccine production and/or in surveillance entities. Causes include scratches with needles and other equipment, leaks through exhaust of air and liquids, failure of inactivation (often coupled with failure to check), or has sometimes remained unexplained. Consequences can be minor in the luckiest cases, or can lead to widespread infection of humans and/or animals, leading to loss of lives and considerable costs.\n\nAt least 59 maximum containment laboratories exist worldwide\n\nThe globalbiolabs.org website 16 reports the list of all publicly known laboratories registered as BSL-4 or equivalent. Possibly dangerous research is also performed in lower-level laboratories, and it is impossible to estimate how many people (scientists, technicians and other staff ) have access, are trained and can handle dangerous pathogens.\n\nIn the WHO report from the consultative meeting cited before, 21 as arguments in favor of the large number of high-containment laboratories, were mentioned ‘benefits at global level’ such as the availability of “highly trained bio-containment workforce [that] can be deployed in emergency outbreaks and provide expertise based on experience with diagnostics, packaging of samples for shipping, and correct PPE usage for people at risk”. It seems that such ‘benefits’ could be obtained in much less dangerous conditions and lower cost, and that this reason hardly justifies the building and maintenance of large numbers of BSL-4 labs. At the same time, having more people handling dangerous material statistically augments the risk of actual contamination, as well as of intentional theft. Furthermore, the know-how of experimental practices constitutes a risk (or a valuable asset) if terrorist groups were to recruit scientists with practical knowledge (and little ethical concern).\n\nIt is therefore legitimate to ask if the number of BSL-4 labs is proportionate to the needs. Arguably, a reduction of authorized laboratories would allow for better control and more efficient performance. Similarly, a reduction in the number of personnel with both authorization and experience in handling dangerous pathogens would greatly reduce the risk of malign use. It would also limit the number of travelling samples, a critical time in which dangerous material exits the high-containment labs. Furthermore, reduction of the number of BSL-4 laboratories might also facilitate interaction among the labs, possibly leading to the adoption of a set of best practices. At present, there is little international governance for such facilities, and although any kind of binding international regime seems highly remote, there could be prospects for informal coordination among the labs that could improve safety. In this direction, we can notice the initiative of the International Federation of Biosafety Associations, the Global Health Security Agenda, and the Global Biological Policy and Program of the Nuclear Threat Initiative, all of which are private, non-government associations. 111 – 113\n\nThe geographical distribution of such labs and personnel (biological, medical, veterinary and agricultural scientists, technicians, maintenance) should also be discussed at international level, as laboratories might be more useful at or near the places in which new diseases are likely to arise, and surveillance is more important.\n\nThe location of facilities, as mentioned in the second section, is another sensitive problem. The protests that have accompanied the construction of new facilities, when the relevant information reached the public, demonstrate that people are deeply concerned; in addition, no matter which arguments the government, universities or private sector engage with, strong opposition is likely to persist, especially as the other major problem of these facilities, i.e. full transparency, is not addressed.\n\nTransparency and trust\n\nAt the Consultative Meeting of December 2017, 21 practitioners devoted a session to remark on the benefits of research performed in high-containment labs, while carefully abstaining from mentioning dangerous and controversial research, some of which are linked to military interest and biological weapon-related research. 16 Another session was devoted to ‘earning support and trust from the public’, indicating how support and trust are missing. The partial picture described in this article seems to justify fears, since at least some of the research performed in high-containment labs presents an extremely high potential risk. Furthermore, past performance 76 , 78 , 105 is an indication that the chain of authorities that bear responsibility towards both their employees and society is not inclined to respond to society’s request for transparency.\n\nThe specific projects performed in high-containment laboratories worldwide are partially unknown, an issue that questions democracy and societal control, and potentially involves the military sector, as it is estimated that 20% of known BSL-4 facilities are defense-related. 17 However, in case of accident, it is society that will pay the consequences, especially if the unavoidable accident happens in populated areas. A good understanding of the work performed in the laboratories, which organisms are used and their associated diseases, details of risk assessment, external auditing, and other measures, would be useful in mitigating the consequences of accidental release, thus limiting the danger to some extent. In case laboratories were accepted by (or forced on) local people, citizen awareness could also contribute to set limits to the kind of research being conducted.\n\n\nConclusions\n\nRisk perception is subjective, depending on personal, cultural, and societal factors. Differing risk perceptions drive differing preferred policies. For example, if the risk of a bioterrorist or biological attack is perceived to be higher than the risks of accidental release from biological laboratories, it could make sense to undertake risky biological research for the purpose of preparing for or defending against an attack. The discussion about the opportunity to take one or more risks should involve those who would pay the consequences, i.e. society at large. Some discussions are very complex, and an understanding of biology and other aspects may be necessary: society has means of addressing complex problems, through trusted organizations (typically NGOs) that can mediate dialogue. The case of COVID-19 has shown that the majority of citizens are capable of understanding and willing to follow governmental indications. The minority of (vocal) anti-vaccination (anti-vaxxers) protesters, or their analogues in similar situations, could in part be convinced with a more transparent and open attitude.\n\nA role for encouraging a wide discussion, already proposed, 31 could be in the hands of the WHO, that is still the only worldwide agency that can organize such an admittedly difficult enterprise at a global level.\n\nMatthew Meselson, a driving force in the development of the Biological Weapon Convention, argued that “Every major technology—metallurgy, explosives, internal combustion, aviation, electronics, nuclear energy—has been intensively exploited, not only for peaceful purposes but also for hostile ones”. 95 Chemists have ‘paid their duty’ with the invention of dynamite, which was the reason behind the institution of the Nobel prize, as a form of penance. Physicists, after the production and use of the nuclear bombs, started a thorough reflection on the responsibility of science and scientists. 114\n\nBiologists must learn the lesson, and stop taking huge, useless risks before a major outbreak forces them (us) to spend some thoughts on the opportunity and the danger of our work.",
"appendix": "Acknowledgements\n\nThis article originated as a webinar organized on October 13, 2020, for the series Global Peace and Insecurity, organized by Subrata Ghoshroy at the Radius Initiative of the Massachusetts Institute of Technology. I am grateful to Prof. Ghoshroy and to anonymous reviewers.\n\n\n\n\nReferences\n\nOrellana C:Laboratory-acquired SARS raises worries on biosafety.Lancet Infect. Dis.2004 Feb; 4(2): 64. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGünther S; Feldmann H; Geisbert TW; et al.:Management of Accidental Exposure to Ebola Virus in the Biosafety Level 4 Laboratory, Hamburg, Germany.J. Infect. Dis.2011 Nov; 204(suppl_3): S785–S790. Publisher Full Text\n\nRussian scientist dies of Ebola after lab accident.CIDRAP;2004.Reference Source\n\nAmerican Biological Safety Asssociation:Laboratory Acquired Infection (LAI) Database.Reference SourceReference Source\n\nRisks and benefits of dual-use research.Nature.2005 Jun; 435(7044): 855–855.\n\nNational Research Council:Challenges and Opportunities for Education About Dual Use Issues in the Life Sciences.National Academy Press;2010.Reference Source\n\nSelgelid MJ:Gain-of-Function Research: Ethical Analysis.Sci. Eng. Ethics.2016; 22(4): 923–964. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCasagrande R:Assessing the Risks and Benefits of Conducting Research on Pathogens of Pandemic Potential.Gryphon Scientific;2016.\n\nCompeting Responsibilities? Report Addresses the Security Risks of Biological Research.American Association for the Advancement of Science;2010.\n\nWHO:Laboratory biosafety manual.fourth ed.Geneva:World Health Organization;2020; 124.Reference Source\n\nRodgers J; Lentzos F; Koblentz GD; et al.:How to make sure the labs researching the most dangerous pathogens are safe and secure.Bull. At. Sci.2021. Reference Source\n\nHutchison CA 3rd; Chuang RY; Noskov VN; et al.:Design and synthesis of a minimal bacterial genome.Science.2016 Mar 25; 351(6280): aad6253. Publisher Full Text\n\nBeecham P; Potts J:Biosafety in Microbiological and Biomedical Laboratories—6th Edition.2020; 604 p.\n\nWHO:Biological Weapons Convention – UNODA.Reference Source\n\nInternational Organization for Standardization:ISO 35001:2019. ISO.2020.Reference Source\n\nGlobalBioLabs:2021.Reference Source\n\nPeters A:The global proliferation of high-containment biological laboratories: understanding the phenomenon and its implications.Revue scientifique et technique (International Office of Epizootics).2019 Jan 1; 37: 857–883. Publisher Full Text\n\nCameron E; Nuzzo J; Bell JA:Global Health Security Index.Nuclear Threat Initiative.2019. Reference Source\n\nKoblentz GD:Living weapons: biological warfare and international security.Ithaca:Cornell University Press; 2009. (Cornell studies in security affairs). Publisher Full Text\n\nBiosecurity Challenges of the Global Expansion of High-Containment Biological Laboratories: Summary of a Workshop (2012). Chapter 8: Requirements for and Challenges Associated with BSL-4 Labs. 2012. http\n\nReport of the WHO Consultative Meeting on High/Maximum Containment (Biosafety Level 4) Laboratories Networking, Lyon, France.Geneva:World Health Organization;2017.\n\nRiso S:Employee monitoring and surveillance: The challenges of digitalisation.Luxembourg:Publications Office of the European Union;2020.\n\n2019 Annual Report of the Federal Select Agent Program:Reference Source\n\nWHO:Guidelines for Implementing Poliovirus Surveillance among Patients with Primary Immunodeficiency Disorders (PIDs).WHO;2019.Reference Source\n\nWorld Health Organization:WHO Global Action Plan to minimize poliovirus facility-associated risk after type-specific eradication of wild polioviruses and sequential cessation of oral polio vaccine use (GAPIII).2015.Reference Source\n\nAmerican Biological Safety Asssociation:Riskgroups.Reference SourceReference Source\n\nEinstein A:statement to William Miller, as quoted in Death of a genius.LIFE Magazine.1955 May 2; 64.\n\nDoudna JA; Charpentier E:The new frontier of genome engineering with CRISPR-Cas9.Science.2014 Nov 28; 346(6213). PubMed Abstract | Publisher Full Text Reference Source\n\nHendel SJ; Shoulders MD:Directed evolution in mammalian cells.Nat. Methods.2021 Apr; 18(4): 346–357. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDuprex WP; Fouchier RAM; Imperiale MJ; et al.:Gain-of-function experiments: time for a real debate.Nat. Rev. Microbiol.2015 Jan; 13(1): 58–64. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCasadevall A; Imperiale MJ:Risks and Benefits of Gain-of-Function Experiments with Pathogens of Pandemic Potential, Such as Influenza Virus: a Call for a Science-Based Discussion.MBio.2014 Aug 1; 5(4): e01730–e01714. Publisher Full Text\n\nFears R; ter Meulen V :What next for gain-of-function research in Europe?elife.2015; 4: e13035. Publisher Full Text\n\nImperiale MJ; Casadevall A:A New Approach to Evaluating the Risk–Benefit Equation for Dual-Use and Gain-of-Function Research of Concern.Front. Bioeng. Biotechnol.2018; 6: 21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEvans NG:Dual-Use and Infectious Disease Research.Infectious Diseases in the New Millennium.2020 May 16; 82: 193–215. Publisher Full Text\n\nDeutsche Akademie der Naturforscher Leopoldina, European Academies Science Advisory Council, editors:Gain of function: experimental applications relating to potentially pandemic pathogens. Halle (Saale): EASAC Secretariat, Deutsche Akademie der Naturforscher Leopoldina.2015; 36 p. (EASAC policy report).\n\nDept of Humand and Health Services:Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens.USA HHS;2017.Reference Source\n\nChan PKS:Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997.Clin. Infect. Dis.2002 May 1; 34 Suppl 2: S58–S64. Publisher Full Text\n\nWHO:Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003–2021.15 April 2021.\n\nLeroux-Roels I; Leroux-Roels G:Current status and progress of prepandemic and pandemic influenza vaccine development.Expert Rev. Vaccines.2009 Apr 1; 8(4): 401–423. Publisher Full Text\n\nHerold S; Sander LE:Toward a universal flu vaccine.Science.2020 Feb 21; 367(6480): 852–853. PubMed Abstract | Publisher Full Text\n\nImai M; Watanabe T; Hatta M; et al.:Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets.Nature.2012 Jun; 486(7403): 420–428. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHerfst S; Schrauwen EJA; Linster M; et al.:Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets.Science.2012 Jun 22; 336(6088): 1534–1541. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWatanabe T; Kawaoka Y:Pathogenesis of the 1918 Pandemic Influenza Virus.PLoS Pathog.2011 Jan 27; 7(1): e1001218. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKaiser J:The catalyst.Science.2014 Sep 5; 345(6201): 1112–1115. PubMed Abstract | Publisher Full Text\n\nUS Government:U.S. Government Gain-of-Function Deliberative Process and Research Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS, and SARS Viruses.2014.\n\nBitsilli PM; Clyman TW; Cruise EJ:Chekhov’s art, a stylistic analysis.Ann Arbor:Ardis;1983.\n\nAmerithrax or Anthrax Investigation.Federal Bureau of Investigation;Reference Source\n\nCarus S:A Short History of Biological Warfare: From Pre-History to the 21 st Century.2017.\n\nBhattacharjee Y:Army Missed Warning Signs About Alleged Anthrax Mailer.Science.2011 Apr 1; 332(6025): 27–27. Publisher Full Text\n\nCheck Hayden E:Biodefence since 9/11: The price of protection.Nature.2011 Sep; 477(7363): 150–152. Publisher Full Text\n\nBlum TR; Liu H; Packer MS; et al.:Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity.Science.2021 Feb 19; 371(6531): 803–810. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReeves RG; Voeneky S; Caetano-Anolles D; et al.:Agricultural research, or a new bioweapon system?Science.2018 Oct 5; 362(6410): 35–37. Publisher Full Text\n\nBarras V; Greub G:History of biological warfare and bioterrorism.Clin. Microbiol. Infect.2014 Jun; 20(6): 497–502. PubMed Abstract | Publisher Full Text\n\nFenner F; Henderson DA; Arita I; et al.:Smallpox and its eradication.World Health Organization;1988.\n\nWorld Health Assembly:WHA49.10 - Smallpox eradication: destruction of variola virus stocks.1996.Reference Source\n\nMeyer H; Ehmann R; Smith GL:Smallpox in the Post-Eradication Era.Viruses.2020 Jan 24; 12(2): 138. PubMed Abstract | Publisher Full Text\n\nHarrison SC; Alberts B; Ehrenfeld E; et al.:Discovery of antivirals against smallpox.PNAS.2004 Aug 3; 101(31): 11178–11192. PubMed Abstract | Publisher Full Text\n\nDamon IK; Damaso CR; McFadden G:Are We There Yet? The Smallpox Research Agenda Using Variola Virus.Rall GF, editor.PLoS Pathog.2014 May 1; 10(5): e1004108. PubMed Abstract | Publisher Full Text\n\nReardon S:Infectious diseases: Smallpox watch.Nature News.2014 May 1; 509(7498): 22–24. PubMed Abstract | Publisher Full Text\n\nWilde O:The Picture of Dorian Gray.Philadelphia:Lippincott’s Monthly Magazine;1890; 72.\n\nReinach S; Viale A:Application of a human error framework to conduct train accident/incident investigations.Accid. Anal. Prev.2006 Mar 1; 38(2): 396–406. Publisher Full Text\n\nBogner MS:Human Error in Medicine.CRC Press;1994.\n\nAlonso IJ; Broadribb M:Human error: A myth eclipsing real causes.Process. Saf. Prog.2018; 37(2): 145–149. Publisher Full Text\n\nKlotz L:Human error in high-biocontainment labs: a likely pandemic threat.Bull. At. Sci.2019 Feb 25.\n\nGAO USGA:High-Containment Laboratories: Improved Oversight of Dangerous Pathogens Needed to Mitigate Risk.2016.Reference Source\n\nCottam EM; Wadsworth J; Shaw AE; et al.:Transmission Pathways of Foot-and-Mouth Disease Virus in the United Kingdom in 2007.PLoS Pathog.2008 Apr 18; 4(4): e1000050. Publisher Full Text\n\nFurmanski M:Threatened pandemics and laboratory escapes: Self-fulfilling prophecies.Bull. At. Sci.2014.\n\nCore Writing Team:Pachauri RK; Meyer LA, editors.IPCC, 2014. Climate Change 2014. Synthesis Report. IPCC, Geneva, Switzerland.2014.Reference Source\n\nGAO USGA:High-containment laboratories: Coordinated Actions Needed to Enhance the Select Agent Program’s Oversight of Hazardous Pathogens. Washington, DC; 2017 Oct p. 68. Report No.: gao-18-145.\n\nGAO USGA:High-Containment Biosafety Laboratories: Preliminary Observations on the Oversight of the Proliferation of BSL-3 and BSL-4 Laboratories in the United States.2007.\n\nLiang WN; Zhao T; Liu ZJ; et al.:Severe Acute Respiratory Syndrome-Retrospect and Lessons of 2004 Outbreak in China.BES.2006; 19(6): 445–451. PubMed Abstract\n\nButler:Calls for Further Inquiries Into Coronavirus Origins.The New York Times;2021 Apr 7.\n\nBloom JD; Chan YA; Baric RS; et al.:Investigate the origins of COVID-19.Science.2021 May 14; 372(6543): 694–694. Publisher Full Text\n\nButler C; Cap H; Claverie JM; et al.:Call for a full investigation into the origins of Covid-19.2021 Apr 7.\n\nSchmidt M:Safety Incidents: Blaming the Victim.Bluefield Process Safety.Reference Source\n\nSafety clause (Editorial).Nature.2007 Jul; 448(7150): 105–106. Publisher Full Text\n\nSunshine Project:Wikipedia.2021.Reference Source\n\nDembner A; Smith S:BU scientists missed bacteria-illness link.The Boston Globe;2005 Feb 5.\n\nWHO:Virus origin/Origins of the SARS-CoV-2 virus.Reference Source\n\nChan A; Ridely M:Viral: The Search for the Origin of Covid-19.HarperCollins;2021.\n\nKidd C; Hayden BY:The psychology and neuroscience of curiosity.Neuron.2015 Nov 4; 88(3): 449–460. Publisher Full Text\n\nHolmes EC; Goldstein SA; Rasmussen AL; et al.:The origins of SARS-CoV-2: A critical review.Cell.2021 Sep; 184(19): 4848–4856. Publisher Full Text\n\nKortepeter MG; Martin JW; Rusnak JM; et al.:Managing Potential Laboratory Exposure to Ebola Virus by Using a Patient Biocontainment Care Unit1.Emerg. Infect. Dis.2008 Jun; 14(6): 881–887. Publisher Full Text\n\nCDC:Report on the Potential Exposure to Ebola Virus.2015; 16.\n\nde Wit E ; van Doremalen N ; Falzarano D; et al.:SARS and MERS: recent insights into emerging coronaviruses.Nat. Rev. Microbiol.2016 Aug; 14(8): 523–534. Publisher Full Text\n\nPardi N; Hogan MJ; Porter FW; et al.:mRNA vaccines — a new era in vaccinology.Nat. Rev. Drug Discov.2018 Apr; 17(4): 261–279. Publisher Full Text\n\nWHO – COVID19 Vaccine Tracker:2022.Reference Source\n\nMaldonado R; Drago F:Drug Repurposing for COVID-19. Therapy.Front. Pharmacol.2021; 12: 2188.\n\nGPEI:weekly polio analyses.Reference Source\n\nNelson MI; Holmes EC:The evolution of epidemic influenza.Nat. Rev. Genet.2007 Mar; 8(3): 196–205. Publisher Full Text\n\nGISAID:GISAID - Initiative.Reference Source\n\nLeitenberg M:Biological Weapons in the Twentieth Century: A Review and Analysis.Crit. Rev. Microbiol.2001 Jan; 27(4): 267–320. Publisher Full Text\n\nFrischknecht F:The history of biological warfare: Human experimentation, modern nightmares and lone madmen in the twentieth century.EMBO Rep.2003 Jun; 4(S1): S47–S52. PubMed Abstract | Publisher Full Text\n\nCross G; Klotz L:Twenty-first century perspectives on the far-from-toothless Biological Weapons Convention.Bull. At. Sci.2020 Jul; 76: 185–191. Publisher Full Text\n\nMeselson M:The challenge of biological and chemical weapons.Bull. World Health Organ.1999; 77(2): 102–103. PubMed Abstract\n\n1984 Rajneeshee bioterror attack:Wikipedia.2021.Reference Source\n\nSelgelid MJ; Weir L; Jackson R; et al.:The mousepox experience: An interview with Ronald Jackson and Ian Ramshaw on dual-use research.EMBO Rep.2010 Jan; 11(1): 18–24. PubMed Abstract | Publisher Full Text\n\nLeitenberg M:Biological weapons and bioterrorism in the first years of the twenty-first century.Politics and the life sciences: the journal of the Association for Politics and the Life Sciences.2002 Oct 1; 21: 3–27.\n\nWerlau MC:Does Cuba Have Biochemical Weapons? In Cuba’s pursuit of biological weapons: fact or fiction?U.S. Government Printing Office;2002.Reference Source\n\nWatts D:Military Euphemisms in English: Using language as a weapon. Bulletin of Faculty of Foreign Studies.Aichi Prefectural University;2013.\n\nMeselson M; Guillemin J; Hugh-Jones M; et al.:The Sverdlovsk anthrax outbreak of 1979.Science.1994 Nov 18; 266(5188): 1202–1208. Publisher Full Text\n\nNikiforov VV; Turovskii Y; Kalinin P:The laboratory case of Marburg hemorrhagic fever.Zurnal Mikrobiologii Epidemiologii Immunologii.1994: 104–106.\n\nBrault AC; Powers AM; Medina G; et al.:Potential Sources of the 1995 Venezuelan Equine Encephalitis Subtype IC Epidemic.J. Virol.2001 Jul; 75(13): 5823–5832. Publisher Full Text\n\nFeng Z:Officials punished for SARS virus leak.2004.Reference Source\n\nLawler A:Boston University Under Fire for Pathogen Mishap.Science.2005 Jan 28; 307(5709): 501–501. Publisher Full Text\n\nCasassus B:France halts prion research amid safety concerns.Science.2021 Jul; 373: 475–476. Publisher Full Text\n\nCDC:Report on the inadvertent cross-contamination and shipment of a laboratory specimen with influenza virus H5N1.2014.Reference Source\n\nCenters for Disease Control and Prevention:Report on the Potential Exposure to Anthrax.CDC;2014.Reference Source\n\nChina lab leak infects thousands with bacterial disease.Medical Xpress;2020.Reference Source\n\nCyranoski D:Chinese institutes investigate pathogen outbreaks in lab workers.Nature.2019 Dec 17; d41586–019-03863-z. PubMed Abstract | Publisher Full Text\n\nIFBA:International Federation of Biosafety Association.Reference Source2001.\n\nGlobal Health Security Agenda:Global Health Security Agenda.2014.Reference Source\n\nBiological - NTI:The Nuclear Threat Initiative.Reference Source\n\nSB:Statement: The Russell-Einstein Manifesto. Pugwash Conferences on Science and World Affairs.1955.Reference Source"
}
|
[
{
"id": "145945",
"date": "23 Aug 2022",
"name": "Jean Pascal Zanders",
"expertise": [
"Reviewer Expertise Chemical and biological weapons disarmament",
"education in support of disarmament"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript provides a broad overview of the many aspects of biorisk management and issues related to research in high-level bio-containment laboratories. While each aspect could be the subject of more detailed analysis, the great contribution of this paper is that the contents are accessible to non-experts or people working on issues relating to illicit or unintended transfers of dual-use technologies to malevolent actors. As such, it can provide an excellent educational introduction to questions on technology governance, responsible science, risk management and non-proliferation.\nSome comments (page references drawn from the PDF version of the manuscript):\npp 4-6 (just above header ‘How many and where’)\nThe BTWC is briefly touched upon, but the issue is not further elaborated in the manuscript. The paragraph does not make clear why the treaty is important to the subject of the paper or how it contributes to the mitigation of the risks described in the paper.\n\nFor instance, the next paragraph refers to ISO 35001 on biorisk management. It may be worth noting that the origins of this standard are in the 7th Review Conference of the BTWC (2001), when states parties recognised the possible contribution of biorisk management to to the objectives of the BTWC (e.g. Increasing assurance under the BTWC through biorisk management standards).\n\np 8 (above header ‘Dangerous experiments’)\nDiscussion polio virus (top para): might benefit from update in view of detection in Europe and USA.\n\nNext para, perceptions of risk: it may also vary depending on culture or political system.\n\nBottom page: Honk Kong (typo).\n\np. 9 (header ‘Resurrecting extinguished influenza virus’)\nReference to number of deaths from the 1918 influenza pandemic: several recent authors place it at 50-100 million fatalities. (The sentence may require specific sourcing).\n\n(header: ‘If there is a gun in the scene …’)\nThis reviewer would hesitate to name Bruce Ivins unless there is broader discussion of the anthrax letters. He committed suicide, as a consequence of which the FBI stopped the investigation into this person. In consequence, there is no final verdict or further review of available evidence.\n\n(Header: ‘The most dangerous’, end of paragraph)\nHow about mutations in related viruses, or possible re-emergence as a consequence of global warming (permafrost, etc.)?\n\np. 10 (para. above header: Once the accident has happened)\n‘the Annual Reports of the Federal Select Agent’: add ‘Program’ at end.\n\nFukushima: add some context. It is not clear this concerns a nuclear plant and what the consequences of the event were.\n\np. 12 (sub-header ‘Basic knowledge’)\n3rd para, on smallpox: see earlier comment on why research might still be useful.\n\np. 13 (sub-header ‘Defense’, 2nd para.)\nIt might be good to indicate that the Rajneesh cult spread salmonella bacteria (non-lethal), which made it easy to acquire and release.\n\nConcerning the anthrax letters: 5 fatalities and 17 infected persons, despite complex preparation.\n\nIt may also be good to point out that Aum Shinrikyo failed across the board in its BW programmes, despite having large funds available.\n\np. 15, Conclusions\nMeselson: earlier (p. 4) the treaty was identified as Biological and Toxin Weapons Convention with as acronym BTWC.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
},
{
"id": "192406",
"date": "16 Aug 2023",
"name": "Javed Muhammad",
"expertise": [
"Reviewer Expertise Molecular Epidemiology of infectious diseases",
"Diseases surveillance and diagnosis",
"biorisk management."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe author in this article has described different levels of laboratories working on pathogenic organisms. The author has highlighted the different types of research work conducted in these different levels of research labs and all possible risks arising from these labs and what should be the preventive measures.\nIn my opinion, the author is still using biosafety level 1, 2, 3 and 4 but the author needs to get updated with WHO latest edition of high containment and maximum containment levels. The article needs to review the language and grammar. Most of the sentences are very long and difficult to review.\n\nRecognizing the possible dangers connected with this activity……. Rephrase the sentence structure and length.\n\nIn this article I briefly summarize the major features of these\nlaboratories, exemplify some… The whole paragraph should not be in one sentence, suggest splitting it in 2-3 and make more logical/scientific.\n\nBioSafety, Biosecurity, Biological risk,…. Keywords should be the same that are described in abstract. Also, BSL-4 and all levels are omitted so add updated information.\n\nThe study of pathogens is useful and important, as it helps… Very long sentence, difficult to keep tracking of information.\n\nwith exposure to pathological…. pathogenic not pathological\n\nUnfortunately, we have always lived with accidents and mistakes in addition to…. Once the author is switched from diseases to their testing etc in labs, onwards discussion should be about labs as the title of article is concerned. switching again to diseases doesn't make any sense.\n\nlaboratories at low bio-safety level (BSL-2);… as mentioned earlier, all BSLs are abolished and replaced with 3 levels of labs (core, heightened and maximum) so whole article needs to be re written in context of updated information. Author is suggested to read latest literature about lab safety levels. BSLs can be used for previous reference but latest information needs to be added.\n\nwe can define risk as the product of the possible… use of appropriate definitions is recommended. Risk is defined elsewhere ISO 35001, WHO etc.\n\nthat can lead to disastrous consequences (see next section)…. not recommended to mention. author needs to establish relationship between two ideas with logical reasoning and references. \"see next section\" is not a scientifically good term to use.\n\nIf they are not aware of the accident, or if the ‘fix’ does not work… what types of fixes? some examples just likes the examples of accidents should be mentioned.\n\nThe discussion section should be renamed as solutions/ possible measures to manage lab accidents etc. Discussion is usually recommended in research articles.\n\nRisks: Accidents happen on page 14… Repetition needs to be avoided.\n\nWHO, that is still the only worldwide agency that can organize… reviewer does not agree, provide reference.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Partly\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-508
|
https://f1000research.com/articles/11-507/v1
|
10 May 22
|
{
"type": "Case Study",
"title": "IT Service management system for EMBL’s European Bioinformatics Institute’s IT department",
"authors": [
"Montserrat González Ferreiro",
"Steven Newhouse",
"Steven Newhouse"
],
"abstract": "EMBL-EBI, Europe's biomolecular data hub, is a world leader in managing and analysing big data in biology and making it freely available to scientists worldwide. Research infrastructures (RI) like EMBL-EBI rely extensively on information technology (IT) services to conduct research and support the delivery of scientific services. These IT services are complex and diverse and IT service management (ITSM) has been shown in other domains to help to improve efficiency and productivity. ITSM is a collection of standards that help organisations develop a process-based approach for managing the full lifecycle of IT services, while keeping their users' needs at the forefront and promoting continuous improvement. However, many organisations struggle with the design and implementation of an ITSM system as it involves the need for organisational change, and because the process approach can seem rigid and bureaucratic on the surface. This article aims to share the experience of the EMBL-EBI IT department in designing and implementing an ITSM system. ITSM implementation steps, benefits, challenges, opportunities, and practices are highlighted, critically analysed, and discussed.",
"keywords": [
"Service management",
"ITSM",
"implementation practises",
"research infrastructures",
"FitSM",
"ITIL",
"governance",
"control",
"ServiceNow"
],
"content": "Introduction\n\nThe European Molecular Biology Laboratory (EMBL) is the only intergovernmental laboratory for life science research in Europe. Aimed at advancing the study and understanding of molecular biology, training young scientists and fostering innovation in science and technology alike. It has six sites in five host nations and one of which is EMBL’s European Bioinformatics Institute (EMBL-EBI).\n\nIn total, 85 members of the EMBL-EBI IT department provide IT services for more than 800 employees and visitors, operating IT services and a complex infrastructure, which is distributed across multiple data centres and buildings. The type of services provided by the EMBL-EBI IT department are access to and usage of systems and networks (Lovelock and Gummesson, 2004). The IT services include provision of robust and secure frameworks for deploying public bioinformatics services, virtualisation and cloud computing, database administration, software development, communications, authentication, desktop management, platforms for web services, website management, user experience design, web development and IT infrastructure management.\n\nFour years ago, the EMBL-EBI IT department embarked on a journey to improve its efficiency and productivity by establishing a formal and strategic approach to design, deliver, manage, and continuously improve the IT services it provides, in order to align with the organisation's strategic goals and focus on user needs.\n\n\nSelecting the right ITSM framework\n\nThe first step of our ITSM initiative was to select the right ITSM framework. An ITSM framework - a detailed method and a set of supporting tools - encompasses all procedures, processes, and policies that help organisations manage and deliver their IT service. We reviewed some of the most globally recognised ITSM frameworks: ITIL (Rudd, 2010), COBIT (Harmer, 2014), ISO/IEC 20000 (Clifford, 2011) and TOGAF (Desfray et al., 2014). The frameworks were useful and detailed, but it also seemed difficult to move from a very early maturity level to one at the level of these frameworks. Hence after reviewing FitSM (FitSM.eu, 2014), it seemed the right fit.\n\nFitSM is a lightweight ITSM framework with 14 processes. It is an open standard developed taking research centres into consideration and it is compatible with ITIL, COBIT and ISO/IEC 20000 should we want to implement these frameworks in the future.\n\nIn order to construct an ITSM system based on the FitSM standard, we need to implement three levels: governance, control, and operational. The governance level involves top management and process owners, and includes the ITSM policy and other relevant policies, such as IT security, the ITSM plan on how to implement the overall ITSM system, process-specific plans, the communication plan, as well as the assessment program. At the control level are the process managers and process teams, as well as all the process definitions that outline the expected inputs, outputs, roles, and responsibilities. The operational level is made up of the teams and staff who create and implement the procedures.\n\n\nEstablishing the ITSM governance level\n\nThe governance framework provides a mechanism for senior management, as well as for team members at the operational level, to have a clear understanding and oversight of each other's expectations, objectives, performance, risk appetite, and reporting requirements. In addition, these aspects are effectively communicated to relevant persons in the organisation (Smith and Brooks, 2013).\n\nOur first step was to use the FitSM-6 capability/maturity assessment tool to identify what our ITSM maturity level was, which turned out to mostly be initial, as there is some awareness, but not defined. We also decided to use it as a tool for future internal assessments.\n\nSecond, a simple ITSM governance structure was created, which optimised the use of existing ITSM governance structures in the EMBL-EBI IT department and clarified all ITSM roles in a way that facilitates the implementation of ITSM. The governance structure also considers the role model recommendations by FitSM (FitSM.eu, 2016) and the EMBL-EBI organisation model, which has a dominant rational component. As a rational model clearly defines roles and procedures, it is perfectly aligned with the intent of integrating an ITSM system. Figure 1 summarises the main elements of the ITSM governance structure.\n\nThis figure is an original figure produced by the authors for this review article.\n\nFor the third step, we created an ITSM problem statement to identify the issues that must be addressed by the ITSM system, and we created balanced scorecards (Kaplan and Norton, 1992) that considered perspectives from the financial, user, internal business process, and the innovation and learning aspects that are depicted in Figure 2. Next, we developed an ITSM policy that addressed the issues identified in the ITSM problem statement and helped us achieve the balanced scorecard targets. The policy structure has the following elements: a purpose, a motivation, a scope statement, an IT-business alignment and definition of objectives, a description of the process approach, commitment to continuous improvement, leadership and contact information, and policy revision plans.\n\nThis figure is an original figure produced by the authors for this review article.\n\nAs a fourth step in developing the governance framework, we conducted a stakeholder analysis (Mendelow, 1981) to identify the key actors in ITSM and assess their level of interest and power to influence the actions to be developed. We used this analysis to determine the engagement strategy with all stakeholders and how we could involve them in co-creating and delivering services.\n\nIn the fifth step, we developed specific process plans for the FitSM processes we considered to be the building blocks of our ITSM: Service Portfolio Management, Service Level Management, Service Reporting Management, Incident and Service Request Management, and Problem Management.\n\nFinally, a communication plan was created to inform all stakeholders how, when, and why communication would occur around the ITSM system, rather than individual processes and services, which will be described elsewhere.\n\n\nThe start of the ITSM control level\n\nITSM Control Frameworks are similar to Internal Control Systems in organisations, but instead of focusing on the overall activities, they focus on specific ITSM activities. Using the control framework, the organisation can establish processes that will assist it in making decisions and allocating resources to meet ITSM goals and objectives described in the IT Service Management Policy that support IT-Business alignment and try to fill service quality gaps.\n\nIn our case, we adapted the FitSM implementation template for a process definition (FitSM.eu, 2014) by adding a section with the overall process inputs and outputs, a section with a communication matrix for the process team and stakeholders, and a section on risk assessment for the process implementation using a SWOT analysis and an impact and probability matrix.\n\nWith the template in place, we defined the Service Portfolio Management process and Service Level Agreement process. The ITSM Committee made the decision that our department would create a Service Portfolio and a Service Catalogue internally, since our ITSM maturity level was still low and it was premature to invest in an ITSM platform. The ITSM Committee also decided to define a corporate Service Level Agreement (SLA) covering all IT services provided and to implement a triage system in Request Tracker, the ticketing system at the time. Thus, we focused on addressing the department's cultural change through FitSM training and incrementally introducing ITSM processes using well-known tools.\n\n\nSetting up the ITSM operational level\n\nAlong with the internal development of the control level, the different teams in the IT department began identifying services and collecting and centralising step-by-step instructions in procedures that other colleagues could follow easily. The procedures were defined using the FitSM template (FitSM.eu, 2014), but workflows were added to make it more visual and taking into consideration that they would be useful if an ITSM software platform was implemented in the future.\n\nHaving procedures documented allowed teams to delegate simple tasks to junior members, and repetitive tasks were automated using in-house development tools.\n\n\nEvolving the ITSM governance, control and operational levels\n\nTwo-and-a-half years after we started our ITSM journey, we had reached a maturity level that prompted the IT department to consider other options, such as centralising information in a way that it is easy to read and understand, expanding self-service opportunities, taking advantage of automation, and incorporating governance into change management.\n\nAt the time the IT department used a combination of software products and services to track incident and user requests (mainly Request Tracker), share knowledge (Wikis, Confluence, Google Docs, and the intranet content database), the internally developed Service Portfolio and Service Catalogue, and internally developed service monitoring and service request management.\n\nThe number of tools we had made it difficult to integrate and centralise management to benefit our users' experience and IT team's productivity. Furthermore, the current tools could not meet previous requirements such as implementing SLAs and producing reports. That's when we decided to search for an ITSM software platform.\n\n\nChoosing the right platform for ITSM implementation\n\nThe ITSM Committee of the IT department evaluated five ITSM platforms based on their Gartner Magic Quadrant For ITSM Tools score (Doheny et al., 2019), recommendations from similar research supporting organisations and their professional experience with them.\n\nThe assessment took about three and a half months and included establishing requirements, demos, forming working groups, facilitating workshops, testing, and extensive communication and meetings to clarify requirements and scope, exploring solutions with regard to the tool and accompanying training, business implementation, and meetings with similar organisations.\n\nThe full list of requirements that we shared with different ITSM software platform providers can be seen in Table 1.\n\nWe eventually selected ServiceNow as the ITSM platform because it meets our requirements, it follows the ITIL framework which is compatible with FitSM by simplifying its implementation, is financially sustainable, has a pool of experts and staff trained to support it (including staff among the IT department who have used it in other companies and similar organisations), and is modular and flexible. Also, despite being outside the scope of the project, it was also considered as a potential resource for other EMBL-EBI departments in the future.\n\n\nITSM platform proof of concept\n\nIn view of the limited ServiceNow expertise of the EMBL-EBI IT department, we decided to start the implementation with a proof of concept, together with a ServiceNow Implementation Partner, Engage ESM.\n\nDevelopment of the proof of concept took two and a half months. It covered the following areas: Core system setup and core data, Authentication design, Service Portal (the ServiceNow equivalent of the Service Portfolio and the Service Catalogue), implementation of a corporate Service Level Agreement, Service Request management, Incident and Problem management, Change management, basic knowledge base creation, and reporting.\n\nIn addition to the functionality in scope, information assets were created to support the proof of concept that were extremely valuable for documenting the ITSM processes. As an example, a matrix for incidents categories and assignment groups.\n\nCreating a basic Configuration Management Database was initially also in scope but was not achieved as time constraints meant priority was given to finishing work on other areas and learning more about how to integrate legacy systems and automate tasks.\n\nAlso, it must be mentioned that we faced some challenges during the proof-of-concept development due to the pandemic situation in 2021, since the team was working fully remotely, which presented challenges for clear and efficient communication with all the stakeholders.\n\n\nITSM platform implementation current and future work\n\nHaving completed the proof-of-concept phase, our platform was one step closer to being offered to the users of the IT services and the IT department staff.\n\nWhen evaluating how the ITSM platform should be implemented, we have always considered which would be the processes that would create the greatest value for the end users and increase efficiency for the IT department. Hence, the current steps for the fully in-house development of ServiceNow involve building a comprehensive user-facing knowledge base as well as replacing our current RT-based ticketing system with a basic Service Portal, which allows end-users to report incidents and submit service requests.\n\nIt is important to note that a comprehensive knowledge base was not one of our initial goals, but this changed in response to suggestions from organisations using mature ServiceNow platforms, stressing how up-to-date instructions and information can empower end users to resolve issues themselves without contacting the IT department, thus saving IT support effort.\n\nConfiguration management is one of the first processes that many IT department members were focused on. Despite exploring autodiscovery for our configuration management database, we discussed it with other organisations (RIs and private companies) who recommended we not consider it a priority at this stage of our ITSM maturity level, since the effort would outweigh the benefits.\n\nIn the future, we are planning to develop a more comprehensive Service Portal that will allow granular types of incidents and service requests to be defined, as well as fully fledged problem and change management processes.\n\n\nConclusion\n\nIn this document, we present an example of the steps and results of the formal and strategic approach adopted by EMBL-EBI's IT department for designing, providing, managing, and continuously improving IT services aligned with business goals. In order for an ITSM system to be successful, it should be based on standards that consider the ITSM maturity level of the organisation, a solid governance framework, a well-established control framework, and an operational level that is backed by a technology platform that standardised and simplified ITSM tasks while also providing a user-oriented interface. We have shared an example of how to select an ITSM standard, a governance structure, a control, and an operational level, as well as the requirements considered to select a software platform and the steps to follow in order for other organisations to benefit from our experience.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "Acknowledgements\n\nThe authors would like to thank all their colleagues working in the EMBL-EBI IT department (the Technical Services Cluster), the Technical Services Cluster Service Management Committee for providing feedback on discussions about the implementation of ServiceNow, to Oihane Fano-Bilbao for her work as support project manager of the proof-of-concept project, and to Daniel Gant for reviewing the text of this article.\n\nMoreover, the authors would like to thank Gyorgy Balazs and Natalie Kane from CERN, the École Polytechnique Fédérale de Lausanne, James Fleming from the Francis Crick Institute, and the Science and Technology Facilities Council who kindly shared their ITSM expertise and experience.\n\nAnd finally, the authors would like to thank the Milano-Bicocca faculty members Benedetta Trivellato and Laura Mariani, who supervised Montserrat’s field project on the governance and control framework for the EMBL-EBI IT department as part of the Executive Masters in Management of Research Infrastructures programme (EMMRI), as well as all the academic team and students who shared their knowledge.\n\nAn earlier version of this article can be found on OSF preprints (DOI: 10.31219/osf.io/9quxj).\n\n\nReferences\n\nClifford D: ISO/IEC 20000 An introduction to the global standard for service management. 2nd ed.IT Governance Publishing; 2011.978-1-84928-316-8.\n\nDesfray P, Raymond G: Modeling Enterprise Architecture with TOGAF. Morgan Kaufmann; 2014.978-0-12-419984-2.\n\nDoheny R, Matchett C, Shetty S: Magic Quadrant for IT Service Management Tools. Gartner; 2019. ID G00373111. Reference source\n\nFitSM Part 0: Overview and Vocabulary: FitSM.eu.2016. Reference source\n\nFitSM Part 3 -Role Model “Recommended Role Model”: FitSM.eu.2016. Reference source\n\nFitSM Part 4 - Samples and Templates “FitSM Template: Process definition”: FitSM.eu.2014. Reference source\n\nFitSM Part 4 - Samples and Templates “FitSM Template: Procedure”: FitSM.eu.2014. Reference source\n\nHarmer G: Governance of Enterprise IT based on COBIT® 5. IT Governance Publishing; 2014.978-1-84928-520-9.\n\nKaplan RS, Norton DP: The Balanced Scorecard - Measures that Drive Performance. Harvard Business Review; 1992. Reference source\n\nLovelock C, Gummesson E: Whither Services Marketing? In Search of a New Paradigm and Fresh Perspectives. J. Serv. Res. 2004; 7(1): 20–41. Publisher Full Text Reference source\n\nMendelow AL: Environmental Scanning - The Impact of the Stakeholder Concept. ICIS 1981 Proceedings. 1981; 20. Reference source\n\nRudd C: ITIL v3 Planning to Implement Service Management. The Stationery Office; 2010.978-0-11331-109-5.\n\nSmith CL, Brooks DJ: Security Science. Butterworth-Heinemann; 2013.978-0-12-394436-8."
}
|
[
{
"id": "137452",
"date": "04 Jul 2022",
"name": "Álvaro López García",
"expertise": [
"Reviewer Expertise Distributed computing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper presents the steps taken by the EMBL-EBI IT department to implement an ITSM system, based on the lightweight standard FitSM. The article provides a good reference for ITSM implementation in science and research data centers and is a commendable effort that will be helpful as a guidance for other IT departments with similar backgrounds and needs.\nSpecific comments are provided in what follows:\nI'd suggest the authors add references to the tools that are cited in the paper (FitSM-6, RT, etc.).\n\nI'd suggest the authors merge the \"Introduction\" and \"Selecting the right ITSM framework\", providing a bit more explanation about the implications of adopting an ITSM system on an organization. Also, a brief description of the ITSM terminology that will be used afterward is needed (i.e. process, FitSM committee, etc.).\n\nThe next three sections describe the ITSM levels, whereas the next four sections describe the tooling (current and future) used to implement the ITMS system. I would suggest grouping the first three as subsections of a new section (as they relate to the whole ITSM system) and the next four again as subsections of a new section (as they related to the platform and technologies used to implement the ITSM system).\n\nSection \"Establishing the ITSM governance level\":\nFigures 1 and 2 are too verbose and acronyms can be used to improve readability.\n\nFigure 2 can be improved if the \"Users perspective\" cards have their position switched (arrows will be better positioned).\n\nThere are six steps that have been carried out. For each of them, it could be possible to add a name (emphasized in bold), so that the text readability is improved.\n\nSection \"The Start of the ITSM control level\":\nITSM Committee is undefined.\n\nAs a suggestion, I would also consider adding some real examples of how these three levels are implemented, without entering into too many details but providing enough information to get a more comprehensive view of what each of the steps and implementation levels implies. It would be commendable if all the examples are somehow related across the three levels, but it may not be possible to do so. What type of processes have been implemented?\n\nI would like also to request the authors to include a new section about their qualitative experience in implementing the system: what are the problems, friction points, and rough edges that have been found both at the IT department and at the organization level? What are the perceived benefits after implementing it?\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Partly",
"responses": []
},
{
"id": "146066",
"date": "15 Aug 2022",
"name": "Muhammad Hafizhuddin Hilman",
"expertise": [
"Reviewer Expertise Distributed systems",
"IT infrastructure",
"Cloud computing"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present an interesting case study of an organisation that has a long history of managing important data minimum compliance to the IT service management best practices.\nThe history of EMBL is clearly presented. Readers can see how big the organisation is and the level of complexity in managing such resources. However, it will be better if the authors provide the readers with the current assessment of the organisation to complete the picture.\nNoted that the authors did their research on various ITSM frameworks, such as ITIL, COBIT, ISO/EIC 20000, TOGAF, and FitSM. In this case, they chose FitSM for their ITSM framework. Readers will have more valuable knowledge if the authors can present their framework selection process in a detailed report. Why other frameworks didn't fit with the current level of EMBL maturity level and how this aspect became an important factor for framework selection where the reader is unable to assess its level from the report.\nI will suggest the authors add more current literature and cite more recent similar case studies. I believe there are tons of current projects on adopting the ITSM framework for organisations with an early maturity level. Currently, the latest cited literature was in 2016, and that is the tool being used for the study.\nAs for the data, I believe some of them are organisational-only reports, but it will be great if the authors can share the general blueprint with the readers to ensure the reproducibility of the study.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-507
|
https://f1000research.com/articles/10-679/v1
|
28 Jul 21
|
{
"type": "Data Note",
"title": "Dataset for measuring the conceptual understanding of optics in Rwanda",
"authors": [
"Kizito Ndihokubwayo",
"Michael Ralph",
"Irénée Ndayambaje",
"Jean Uwamahoro",
"Michael Ralph",
"Irénée Ndayambaje",
"Jean Uwamahoro"
],
"abstract": "This dataset is an accumulation of data collected to test Rwandan physics students’ conceptual understanding of light phenomena and to assess instructional tools for active learning of optics. We collected and analysed data from 251 grade 11 (senior 5) students using our Light Phenomena Conceptual Assessment (LPCA) tool and from 136 grade 10 (senior 4) students using Geometric Optics Conceptual Understanding Test (GOCUT) in 2019. Before collecting data, we designed and validated LPCA and GOCUT, and tested their reliability. Data were collected before and after students learnt about the unit of light. Both day and boarding schools in rural and urban areas were included in our sampling. Data collected were test scores from students after performing a 30-item LPCA test or 25-item GOCUT test in 40 minutes. The data may be reused to extend students' understanding of optics concepts through item analysis, analysis of school characteristics such as location and school type, or by analysing students' characteristics such as subject combinations.",
"keywords": [
"light phenomenon",
"optics",
"conceptual understanding",
"Rwandan students"
],
"content": "Introduction\n\nAssessment inventories data provide insights into the classroom atmosphere and show students’ progress in grasping certain concepts, and these are essential for teachers, educationists, educational evaluators, and researchers. Such inventories may be used to test students’ understanding of a certain concept or may be used to test the effectiveness of a particular teaching approach or instructional tool. This dataset is an accumulation of data collected for the first author’s doctoral research project “Assessment of Instructional Tools for Active Learning of Optics at Advanced Level Secondary Schools in Rwanda”.1–6 In this project, there was a need to first assess students’ conceptual understanding of light phenomena and, second, to assess the effectiveness of instructional tools (such as University of Colorado Boulder’s interactive PhET simulations, and YouTube videos) to improve the learning of optics. Thus, this article presents data from two different inventories or tests that were designed. (i) the Light Phenomena Conceptual Assessment (LPCA) and (ii) Geometric Optics Conceptual Understanding Test (GOCUT). Both these datasets are useful to researchers that will use LPCA, or GOCUT data, or to those who want to understand Rwandan physics students’ performance. This will enable researchers to reanalyse the data in different contexts, such as item analysis theory, comparing school characteristics such as students’ performance in day schools compared to boarding schools, comparing rural schools to urban schools, analysing subject combinations, etc. In this vein, LPCA data are discussed in detail to guide research practitioners on how students’ performance and test item performance-related data are analysed.\n\nThe study describing the development of the LPCA tool and its implementation was published in Physics Education (PED)6 and the LPCA study instrument is available on protocols.io7 and Physport platform. The LPCA is a conceptual understanding test composed of 30 items addressing geometric and physical optics. It was designed based on students’ misconceptions related to the everyday understanding of light phenomena. The data connected to this tool are available in Underlying data8 and were listed and analysed in a Microsoft Excel file titled ‘Pre-Post-Test LPCA Data - Senior 5 Rwandan physics students’. This file contains three sheets; the first sheet presents the pre-test data, the second sheet presents the post-test data, while the third sheet contains filtered data (students who performed both the pre- and post-test). The data comprises various students’ backgrounds; rural and urban schools, boarding and day schools, and different subject combinations (see Table 1 in Methods section).\n\nNote: PCM: Physics-Chemistry-Mathematics, PCB: Physics-Chemistry-Biology, MPC: Mathematics-Physics-Computer science, MPG: Mathematics-Physics-Geography\n\nThe study describing the development and implementation of the GOCUT tool was published in the African Journal of research in Mathematics, Science and Technology education (AJRMSTE).3 The revised protocol where rote learning-related items where removed, is also available in.2 The GOCUT is a conceptual understanding test composed of 25 items of geometric optics. It was designed based on various existing inventories. The data connected to the GOCUT study are available in Underlying data9 and were listed and analysed in a Microsoft Excel file titled ‘Pre-Post-Test GOCUT Data - Senior 4 Rwandan physics students’. This file contains seven sheets; the first sheet introduces the data collected, while other sheets present pre-test and post-test data for three groups of instructional tools of intervention (control group, PhET simulations group, and YouTube videos group). The data comprises various students’ backgrounds; rural and urban schools, boarding and day schools, and different subject combinations (see Table 2 in Methods section).\n\nNote: PCM: Physics-Chemistry-Mathematics, PCB: Physics-Chemistry-Biology, MPC: Mathematics-Physics-Computer science, MPG: Mathematics-Physics-Geography\n\n\nMethods\n\nLPCA\n\nA total of eight Rwandan secondary schools were involved in the study. We selected two districts in Kigali city, and two districts in the rural Eastern Province. We listed the schools in those four districts, and chose two schools from each district that accommodated physics in their subject combinations. School characteristics, location, and type of school (School 1 to School 4 are from Kigali, while School 5 to a School 8 were from the eastern province, see Figure 1) were considered during the selection process. These school characteristics, location, and type of school were considered during the selection process so as to include a diverse group of students and to avoid any potential sources of bias.\n\nPCB: Physics-Chemistry-Biology, MPG: Mathematics-Physics-Geography, PCM: Physics-Chemistry-Mathematics, MPC: Mathematics-Physics-Chemistry.\n\nWe employed a pre- and post-test design10 to collect the data for measuring students conceptual understanding of optics-related concepts. The LPCA was administered twice to the students via paper form, before and after learning about the unit of light in senior-5.11 A total of 251 students from grade 11 or senior 5 (S5) were considered the final sample after removing those who sat for pre-test and missed post-test, and vice versa (see Table 1). The methods for the data coding are presented in the Analysis section. These students had no other teaching interventions offered apart from usual teaching.\n\nGOCUT\n\nThe boarding and day secondary schools chosen to be involved in the GOCUT were the same as for the LPCA (schools from rural areas were sampled from Eastern Province, while those from urban areas were sampled from Kigali). However, three schools were excluded due to ineffectiveness of implementing the designed intervention. Thus, researchers were not able to implement the intervention at these schools. Students were from grade 10 or senior 4 (S4), with various subject combinations. PCB: Physics-Chemistry-Biology, MPG: Mathematics-Physics-Geography, PCM: Physics-Chemistry-Mathematics. Table 2 displays characteristics of school and students in which the instructional tools were implemented and GOCUT was administered.\n\nTeaching interventions of PhET simulations and/or videos compiled on YouTube were offered (see Table 2) to the students. Details of the YouTube videos, including the names of any companies/institutions responsible for creating the materials are available in3 p. 257). GOCUT was administered twice to the students via paper form, before and after learning about geometric optics via the teaching interventions in senior-4.11 A total of 136 students from grade 10 or senior 4 (S5) were involved in the study (see Table 2).\n\nThe data were initially (pre-test) collected in January 2019 and finally (post-test) at the end of March 2019. The answer choices for GOCUT are A, B, C, and D. These choices measure the students’ conceptual understanding of optics, where one is stem (correct answer) while other three choices are distractors (wrong answers). Where the student did not answer, N is coded, while where the student answered more than one answer, T is coded. For the drawing question (item 13), C was coded for students who correctly drew, while W was coded for those who wrongly drew. For the explanatory question (item 9), the extended explanation was provided in the column after AH, after the drawing question.\n\nThis section presents the step-by-step analysis of the LPCA data. We took the case of the first inventory (light phenomena conceptual assessment, LPCA) to extend the description of analysis to help research practitioners in educational research get insight into performance and conceptual understanding test analysis. Please note that unlike the LPCA data file, the file for the GOCUT does not provide accumulated or detailed analysis. Nevertheless, LPCA and GOCUT are similar in manner; their data were recorded and arranged in the same way, so the explanation of how we analysed LPCA data may be used to analyse the GOCUT data.\n\nWe used Microsoft Excel 2016 to analyse the data. Since the LPCA test was a multiple-choice test (except for item 11 which requests a supporting explanation), each item has four choices—from A to D. We recorded this data in an Microsoft Excel sheet by putting an assigned letter to each item (A, B, C, or D). Where a student assigns more than one answer, we recorded “T” while where the student selects nothing or skips the question; we recorded “N.”\n\nThe first analysis was to use “COUNTIF” function to count the number of students who answered each letter; the sum should be the total number of students (see, for example, in pre- or post-test sheet, column F, row 4-10). The second analysis was to mark students by giving a score of “1” to everyone who answered each item correctly (who chose the right answer) and by giving a score of “0” to those who selected the wrong answer, did not answer, or selected more than one answer. We use “IF” and “EXACT” functions (see, for example, column AM, row 15). After computing these functions for each student, we summed the total scores for each student (see column BR) and the corresponding percentage scores (see column BS). These percentage scores show the students’ performance (scores received by every student over the whole LPCA test). A histogram was computed to check the normal distribution of the test scores (number of students in each assigned interval of scores, please see column BU-CG). The significance of performance before and after learning optics was computed in the filtered sheet (see column W-AA).\n\nThe third analysis was item analysis. See the bottom of “IF” and “EXACT” analysis on row 299 in pre-test sheet, for example. The sum of scores for each item of LPCA was computed to reveal the difficulty of the test. A graph was generated showing all 30 items; among them, some are difficult (performed by few students), and others are easy (performed by most of the students). In other words, it was more difficult to perform well in some of the items, and that these items were answered by fewer students. For this analysis, further analysis may generate a graph showing the answer choice for each item (please refer to the Underlying data.8 It shows the number of students who selected every letter for each item. It shows how the correct answer varies from alternative choices and analyses the students’ misconceptions. This figure is generated using the records of the first analysis (counted numbers of answers using “COUNTIF” function).\n\nIn the filtered sheet, we have filtered the students who sat for both pre- and post-test. This helps for side-by-side analysis of the results and helps to keep each student’s scores parallel so that the difference between both test scores is clear. It tracks the performance along with both tests, i.e., whether the students performed better in the post-test or the inverse. If it is inverse, analysis of misconceptions and a revisit of the instructions may be further studied (to understand why the student failed after learning, performing even more worse than he/she performed before learning). We have shown how Cohen’s D effect size and Normalised gains <g> are computed to measure the impact of instruction (see column W-AA, row 259-269). Effect size is computed by taking the difference of means of post-test and pre-test dividing by the average of standard deviations (see cell Y263). Cohen,12 Sawilowsky,13 and Mangnusson14 interpret “d” of 0.20 as small, 0.50 as a medium, and 0.80 as large. Normalised learning gain <g> is calculated by taking the difference of means of post-test and pre-test, dividing by the maximum mean. The maximum mean is the difference of 100% and the mean of pre-test scores (check out cell Y264). Hake15 interprets a <g> of <.3 as small, <g> of.3 to.6 as medium, and large and <g> of >.7 as large.\n\nThe data from both tools are valid and reliable as the tools underwent a rigorous validation and a test-rested reliability was checked before the official use. We first searched the literature for possible misconceptions that students had on the topic of optics and available tests to remedy them. We then drafted questions, using our experiences from the classroom, Rwandan textbooks (in case of LPCA), and existing tests, research articles and textbooks (in the case of GOCUT). We shared the survey questions with four university professors in physics education for content validation (i.e. to check that the questions were testing the real constructs/concepts we intend to evaluate) and to 38 students–selected from two schools from elsewhere, i.e. schools not included in this study—for face validation (i.e. to check the difficulty of questions so as to identify any confusion that may rise). The initial number of questions for each test was above 50 items, after improving them using suggestions from both validators, we reached 30 LPCA items and 25 GOCUT items.\n\n\nEthics statement\n\nThe study procedure was approved by the ethical committee in the University of Rwanda College of Education’s research unit and innovation (permit number: 01/P-CE/483/EN/gi/2018). Ethical clearance was provided after reviewing our research proposal. Our data collection involved secondary school students aged between 16 and 23 years old. Parental consent was not obtained for students under 18 (adult age in Rwanda); however, the study was considered low risk. We explained the purpose of our study to teachers and asked teachers, as well as the students, to sign an informed consent form before partaking in our tests and study. We assured them that the voluntary participation and publication of data would not reveal individual participants’ identities. Data were treated confidentially, and we have deleted the students’ names from our data to maintain their anonymity. Since the first protocol (LPCA) was fully designed by authors and the second protocol (GOCUT) was designed based on existing tests, there was no special approval obtained from developers, however, we fully credited their sources and works.\n\n\nData availability\n\nMendeley Data: Pre-Post-Test LPCA Data: Senior 5 Rwandan physics students. https://data.mendeley.com/datasets/dbvh59jg7j/1.8\n\nThis project contains the following underlying data:\n\n- LPCA.pdf (copy of the light phenomena conceptual assessment (LPCA), an inventory test of 30 items)\n\n- Pre-Post-Test LPCA Data - Senior 5 Rwandan physics students.xlsx (MS Excel file that contains the data)\n\nMendeley Data: Pre-Post-Test GOCUT Data: Senior 4 Rwandan physics students. https://data.mendeley.com/datasets/mmtpw5nvg3/1.9\n\nThis project contains the following underlying data:\n\n- GOCUT.pdf (copy of the geometric optics conceptual understanding test (GOCUT), an assessment test of 25 items)\n\n- Pre-Post-Test GOCUT Data - Senior 4 Rwandan physics students.xlsx (MS Excel file that contains the data)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThe LPCA and GOCUT were content validated by Prof Scott Franklin, Rochester Institute of Technology, NY, US, and Prof Eleanor Syre, Kansas State University, KS, US and face validated by students from GS Mukarange, Kayonza, Rwanda, and GS Saint Aloys, Rwamagana, Rwanda. This data article was commented on by Ms. Josiane Mukagihana and Ms. Celine Byukusenge.\n\n\nReferences\n\nNdihokubwayo K, Uwamahoro J, Ndayambaje I: Classroom observation data collected to document the implementation of physics competence-based curriculum in Rwanda. Data Br. 2021; vol. 36, no. June, p. 107055. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUwamahoro J, Ndihokubwayo K, Ralph M, et al.: Physics Students’ Conceptual Understanding of Geometric Optics: Revisited Analysis. J. Sci. Educ. Technol. 2021; 30(0123456789): 1–13. Publisher Full Text\n\nNdihokubwayo K, Uwamahoro J, Ndayambaje I: Effectiveness of PhET Simulations and YouTube Videos to Improve the Learning of Optics in Rwandan Secondary Schools. African J. Res. Math. Sci. Technol. Educ. 2020; 24(2): 253–265. Publisher Full Text\n\nNdihokubwayo K, Uwamahoro J, Ndayambaje I: Usability of Electronic Instructional Tools in the Physics Classroom. EURASIA J. Math. Sci. Technol. Educ. 2020; 16(11): 1–10. Publisher Full Text\n\nNdihokubwayo K, Uwamahoro J, Ndayambaje I: Implementation of the Competence-Based Learning in Rwandan Physics Classrooms: First Assessment Based on the Reformed Teaching Observation Protocol. EURASIA J. Math. Sci. Technol. Educ. 2020; 16(9): 1–8. Publisher Full Text\n\nNdihokubwayo K, Uwamahoro J, Ndayambaje I, et al.: Light phenomena conceptual assessment: an inventory tool for teachers. Phys. Educ. 2020; 55(3): 035009. Publisher Full Text\n\nNdihokubwayo K, Uwamahoro J, Ndayambaje I, et al.: LPCA. protocols.io. 2021. Publisher Full Text\n\nNdihokubwayo M, Kizito U, Jean N, et al.: Pre-Post-Test LPCA Data: Senior 5 Rwandan physics students. Mendeley Data. 2021. vol. V1. Publisher Full Text\n\nNdihokubwayo K, Uwamahoro J, Ndayambaje I: Pre-Post-Test GOCUT Data: Senior 4 Rwandan physics students. Mendeley Data. 2021; vol. 1. Publisher Full Text\n\nFraenkel JR, Wallen NE, Hyun HH: How to Design and Evaluate Research in Education. 8th ed. New York: McGraw Hill; 2012.\n\nREB: Advanced level Physics syllabus. Kigali: Ministry of Education; 2015.\n\nCohen J: Statistical Power Analysis for the Behavioral Sciences. 2nd ed. New York, NY: Lawrence Erlbaum Associates, Publishers; 1988.\n\nSawilowsky SS: Very large and huge effect sizes. J. Mod. Appl. Stat. Methods. 2009; 8(2):597–599. Publisher Full Text\n\nMagnusson K: Interpreting Cohen’s d Effect Size: An Interactive Visualization.2021. Reference Source\n\nHake RR: Interactive-engagement versus traditional methods: A six-thousand-student survey of mechanics test data for introductory physics courses. Am. J. Phys. 1998; 66(1): 64–74. Publisher Full Text"
}
|
[
{
"id": "101516",
"date": "09 Dec 2021",
"name": "Hassen Ghalila",
"expertise": [
"Reviewer Expertise Physics of plasma and spectroscopy"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nYour manuscript reports on the development and elaboration of a dataset for LPCA and GOCUT to help teachers and the educational system more generally to improve conceptual understanding of optics and associated light phenomena.\nMajor corrections\nIn my sense, a too great part of this manuscript is dedicated to the LPCA dataset. This is not necessary since you have already done this in your previous article (Ref.5). It would have been preferable to develop more analysis on the results obtained with the supplementary tools used in the GOCUT field. This discussion is totally absent in this manuscript, and I think will help to better address the dataset. Figures inside the excel files (only one for GOCUT?) could be used to help the comparison between the different tools employed with their associated results. It seems (after a very brief look at your data) that lessons using YouTube performed better than the other two? Also, it would be helpful to recall the ‘usual teaching’ (content and way of teaching) for the S4 students.\n\nYour samples are composed of four groups, one from the rural zones with boarding and day schools and another two from Kigali again with boarding and day schools. I didn’t see any discussion or comparison on the results obtained for these four groups. Does that mean that there is no difference between them?\n\nIn the dataset of LPCA, question 7 answers A and C are similar? Is it an error or something missing?\nMinor corrections\nIn the Introduction section: One of the two references 7 and 8 is too much and not necessary.\n\nIn the Methods section, GOCUT: The second to last paragraph, ‘A total of 136 students from grade 10 or senior 4 (S5) were involved in the study (see Table 2)’. Replace S5 with S4.\n\nIn the Ethics statement section: ‘Our data collection involved secondary school students aged between 16 and 23 years old.’. Is it 16 or 18 years old?\n\nIs the rationale for creating the dataset(s) clearly described? Partly\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": [
{
"c_id": "8180",
"date": "10 May 2022",
"name": "Kizito Ndihokubwayo",
"role": "Author Response",
"response": "Dear Reviewer, Thank you so much for your insightful comments and suggestions! Yes, LPCA was greatly discussed. Both LPCA and GOCUT datasets were described, and the methods used to collect related data were presented. We have clarified in the manuscript that both data sets are similar, although the participants, levels, and tests were different. The data entry was the same. That is why describing the analysis of all of them would be unnecessary. Thus, to avoid duplication of text, we opted to take LPCA as a reference and discuss its analysis procedures. So researchers who want to look at whether GOCUT can use the same analysis methods we presented for LPCA. The figure presented in the GOCUT dataset can be referred to as a plot of others in other sheets since MS Excel formulae are presented in corresponding cells. Regarding variables in our sample, the difference between them may be there or not, but this data note is not dedicated to presenting results, discussing, or drawing any conclusion; it just provides room for other researchers to reuse the data. Thus, the collection procedure and proposed data analysis are only presented. Regarding question 7 in the LPCA dataset, we could not find a mistake. If you mean answer choices in pre- and post-test, we found them different. Regarding the introduction section, since the link for LPCA protocol was provided in the text, reference 7 was deleted. Regrading the typo in the methods section, S5 was replaced by S4. Regarding the ethical statement section, it is 16 years old."
}
]
},
{
"id": "124417",
"date": "18 Mar 2022",
"name": "Imelda Kemeza",
"expertise": [
"Reviewer Expertise Educational Psychology with a bias to psychometrics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors’ manuscript created a dataset for LPCA and GOCUT for optimized conceptual understanding of light phenomena and also assessed instructional tools for active learning of optics in Physics.\nMajor concerns:\nIn my view, the manuscript authors punctuated the LPCA analysis with appropriate and relevant explanations. A similar treatment to GOCUT analysis would have informed comparisons and discussion of the dual analyses for a better-positioned dataset.\n\nIn the ethics statement: “Our data collection involved secondary school students aged between 16 and 23 years old. Parental consent was not obtained for students under 18 (adult age in Rwanda); however, the study was considered low risk.” Whether the study was considered low risk, research ethics are clear on what should be done when participants are under-aged. In this case, where some students were aged 16 and 17 years old, an assent and/or consent is deemed fit from the right population.\n\nMinor corrections:\nIn the introduction section, third paragraph, second sentence: “The revised protocol where rote learning-related items where removed, is also available in.” Replace the second 'where' with 'were'.\n\nIn the methods section, GOCUT in the second paragraph, the last sentence, change S5 to S4 for consistency in grade choice.\n\nIs the rationale for creating the dataset(s) clearly described? Partly\n\nAre the protocols appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and materials provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Partly",
"responses": [
{
"c_id": "8181",
"date": "10 May 2022",
"name": "Kizito Ndihokubwayo",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for the prodigious comments provided! We could not describe GOCUT analysis methods, but since GOCUT data and LPCA data are presented in similar ways and the same analysis discussed for LPCA would be appropriate for GOCUT. This was also highlighted in the manuscript. Actually, when you click on a cell, you can identify the formula used to compute a certain function. Thank you so much for the informative instruction on the ethics statement. Regarding the typo in the introduction section, “where” was replaced by “were.” Regarding the typo in the method section, S5 was replaced by S4."
}
]
}
] | 1
|
https://f1000research.com/articles/10-679
|
https://f1000research.com/articles/11-504/v1
|
09 May 22
|
{
"type": "Research Article",
"title": "Modulatory role of garlic (Allium sativum) extract against cisplatin- induced nephrotoxicity in female albino rats and their offspring",
"authors": [
"Abdelfattah Elbeltagy",
"Gamal Mohamed",
"Mohammed Akeel",
"Karoline Abdelaziz",
"Kadry Elbakry",
"Ahmed Elsayed",
"Gamal Mohamed",
"Mohammed Akeel",
"Karoline Abdelaziz",
"Kadry Elbakry",
"Ahmed Elsayed"
],
"abstract": "Background: Cisplatin (CP) is one of the chemotherapeutic drugs widely utilized in the treatment of several malignancies. However, recently; its use has been limited because of its hazardous health drawbacks. Previous researches confirmed that CP has severe deleterious side effects on pregnant mothers and their fetuses. Garlic (Allium sativum) extract has been claimed to exhibit potent antioxidative and free radical scavenging abilities. Aim: This work is mainly designed to evaluate the potential therapeutic role of garlic extract against CP-induced nephrotoxicity in pregnant rats and their offspring. Methods: 24 pregnant rats were used in the current study. They were randomly allocated into four groups (n=6): control, garlic, CP, and CP + garlic group. At the end of the weaning period, the mothers and the offsprings of all groups were sacrificed, the kidneys were immediately excised, and processed for histological and biochemical investigations. Also, blood samples were withdrawn and processed for estimation of the assigned biochemical parameters.\n\nResults: The renal histological sections from CP-treated mother rats displayed pronounced histopathological lesions however, their offspring showed mild renal histopathological lesions if compared with those of their mothers. The levels of renal tissue Superoxide dismutase, catalase, and glutathione peroxidase enzymes were significantly decreased. On the contrary, the levels of malondialdehyde, serum urea, and creatinine were significantly increased in CP-treated mother rats and their offspring as compared with control. The percentage value of caspase 3 activity was markedly elevated in the renal tissues of CP-treated mother rats and their offspring compared to the control group. Supplementation of garlic extract to the CP treated rats; the overall histological lesions, as well as biochemical parameters, were restored nearly to the control ones. It is concluded that garlic (Allium sativum) extract has a powerful ameliorative role against CP-induced nephrotoxicity in pregnant rats and their offspring.",
"keywords": [
"Cisplatin",
"nephrotoxicity",
"histopathology",
"garlic",
"antioxidants",
"caspase3"
],
"content": "Introduction\n\nCisplatin (CP), carboplatin, and oxaliplatin are platinum-based chemotherapeutic drugs.1 These drugs persist for a long time in the blood and bind to serum proteins, especially to the serum albumin.2 Generally, all these platinum drugs can induce nephrotoxicity through acute tubular necrosis of proximal tubular cells,3,4 but it is most commonly associated with CP.5\n\nCP is mostly used for treatment of solid cancers, like bladder cancer,6 head and neck cancers,7 cervical cancer,8 testicular cancer,9 ovarian cancer,10 and pulmonary cancers.11 Experimental studies on rats and mice revealed that CP leads to nephrotoxicity through formation of glutathione conjugates in blood stream.12 Other studies showed that CP binds to DNA leading to arrest of DNA synthesis and replication resulting in cell apoptosis.13,14 Moreover, Karasawa et al. stressed that, the nephrotoxicity induced by CP is mainly attributable to toxic generation of free radicals and binding to necessary cytoplasmic molecules, especially the anti-oxidant glutathione.15 CP also suppresses antioxidant enzymes like superoxide dismutase (SOD).16 Furthermore, the nephrotoxicity induced by CP is associated with elevated serum creatinine and urea, in addition, traces of glucose and protein may appear in urine.17 A specific study on humans revealed that CP has a high rate of placental transfer whereas the concentration of CP in the maternal blood is approximately equal to that found in the umbilical cord blood.18\n\nNatural products from plants and animals have been widely utilized all over the world either in the pure forms or crude extracts for protection from or treatment of various diseases.19 Allium sativum (Garlic) is one of the most famous plants that is widely used to combat several diseases because it contains more than 33 sulfur compounds, enzymes, minerals, amino acids, vitamins including A, B1 and C as well as fibers.20 The most vital active sulfur compounds in Allium sativum are allicin and alliin which are considered the main antioxidants and scavenging free radical compounds.21 Zaidi et al. declared, allicin and alliin can improve the hepatic functions via regulation of circulating liver enzymes.22 Also, garlic extract has a powerful role in lowering the levels of blood cholesterol, low density lipoprotein (LDL), triglycerides,23 urea as well as blood glucose levels in diabetic mice and rabbits.24\n\nGarlic extract is used to lessen abdominal discomfort, diarrhea and infections of respiratory tract,25 and for antimicrobial action.26 It can help to restrain some forms of cancers, heart disease, strokes and viral infections,27 coronary diseases,28 common cold,29 and prevention of neurotoxicity.30 Previous studies confirmed that CP can penetrate the placental barrier and induce congenital malformation in fetuses.31 On the other hand, placental transfer of garlic components was recorded by Saleh et al.32\n\nConsequently, the current investigation was designed to evaluate the therapeutic role of garlic extract on the nephrotoxicity induced by CP in pregnant female rats and their offsprings.\n\n\nMethods\n\nThe ARRIVE guidelines were followed,91 and a completed checklist is available at. All efforts were made to ameliorate the suffering of animals by keeping the animals inside clean conditions provided with suitable humidity, regular dark light cycle and gentle injection of cisplatin dose. This study was approved by the Bioethics Committee of Damanhur University, no. EA 23122, 2020. All experiments inclusive of animal handling and sacrifice were conducted as per the guidelines of the Bioethics Committee of Damanhur University.\n\nCP was obtained in from of commercial Egyptian Unistin Vial from Egyptian International Medical Company.\n\nOne kg of fresh garlic was obtained from the local market in Damanhur city, peeled and crushed by a blender and filtered through a strainer to obtain aqueous suspension. The obtained suspension was diluted in distilled water at 4 g/mL then centrifugated (Grant Instruments, LMC-3000 laboratory centrifuge, Cat.No. BIOSAN_22005) at 3000 ×g for ten min to separate the hard fibers.\n\nIn the current investigation, 24 females and 8 males of adult Wistar rats were obtained from the Hellwan Breeding Farm, Ministry of Health, Cairo, Egypt. The rats were housed in plastic cages in a well ventalated animal house under highly sterilized conditions at 25±2°C, appropriate humidity (50±10%) and regular cycle of 12 h light/12 h dark. They were fed on standard food and water ad libitum. After two weeks of acclimatization, the rats were mated in 8 special cages (1 male:3 females). After confirmation of pregnancy by investigation of vaginal smear for each female rat, the pregnant rats were isolated and randomly categorized into 4 groups (n=6) as follows:\n\nGroup I (control): The pregnant rats received 0.5 ml of distilled water daily through the oral route by a modified plastic syringe (intra-gastric tube).\n\nGroup II (Garlic extract): The pregnant rats received a daily oral dose of garlic extract (250 mg/kg) from the day-4 of gestation till the end of weaning.33\n\nGroup III (Cisplatin): The pregnant rats received a single intraperitoneal dose of CP (5 mg/kg b.w) at the 4th day of pregnancy, followed by 0.5 ml of distilled water daily through the oral route till the end of weaning.34\n\nGroup IV (CP and Garlic extract): They received a single I. P dose of CP as in group III followed by a daily oral dose of garlic extract (250 mg/kg b.w) till the end of weaning.\n\nAt the end of weaning (21st day post-natal), the mother rats and their 21 day old offspring were weighed and sacrificed by decapitation. The blood samples were immediately withdrawn by direct cardiac puncture and the serum was separated by centrifugation (Laboratory Centrifuges, R-8C) at 3000 rpm and stored frozen at -20oC for estimation of biochemical parameters.88 The rats were dissected through a midline abdominal incision and the kidneys were immediately excised and washed in normal saline. The right kidneys were longitudinally cut into two equal halves and kept in 10% neutral formalin for histological study. On the other hand, the left kidneys were homogenized using a Potter-Elvenhjem homogenizer in ice cold 1.15% potassium chloride (3mL per 1g of tissue) followed by centrifugation at 5000 rpm for 15 min and of the supernatant was separate and kept frozen for evaluation of antioxidants.\n\nInvestigated parameters\n\nHistological examination of kidneys\n\nThe right kidneys from mother rats and their 21 day old offspring were immediately fixed in 10% formalin for two days, dehydrated in ascending series of ethanol, cleared in xylol and put in melted paraffin wax. After cooling, the paraffin blocks were held in a Leica RM microtome (Minux®, S700 Rotary Microtome). 4-5 μm serial sections of renal tissues were cut and put on clean glass slides. The obtained sections were immersed in descending grades of alcohol and put in the oven to remove the wax using xylene. Finally, the sections were stained by hematoxylin and eosin (H&E) for investigation the histological architecture of kidneys using an Olympus BH-2 light, Cat. No. 6924 BH,) microscope fitted with digital camera (Canon EOS 6d mark II) to take photomicrographs.\n\nSerum analysis\n\nAssessment of creatinine and urea\n\nSerum creatinine and urea were estimated using criterion laboratory protocol and applying the commercially obtainable earmark kits by an auto analyzer (BT 300, Japan,Cat.No.NX-600-E210).35\n\nAssessment of sodium, potassium and magnesium\n\nThe levels of serum sodium and potassium were measured using Ireland E2A Na+/K+ reagent kits. Serum magnesium was determined by a spectrophotometer system using kits from BioMeriecux- France,Cat.No. 031 685858.\n\nAssessment of antioxidants and MDA in renal tissues\n\nMeasurment of MDA and antioxidant enzymes\n\nA part of the aliquots of the supernatant of left renal tissue homogenate was used to measure the levels of superoxide dismutase (SOD), catalase (CAT), Glutathione peroxidase (GPx) and malondialdehyde (MDA). The levels of MDA were assayed by measuring the level of thiobarbituric acid reactive substances (TBARS) that was used to evaluate the liberated MDA as a result of lipid peroxidation of cell membranes.36\n\nThe levels of SOD, CAT and GPx were detected by a colorimetric protocol using trade kits (Biodiagnostic, Cairo, Egypt, Cat No: E-BC-F006). The levels of SOD in the renal tissues homogenate were measured on basis of the ability of the SOD to supress the reduction of nitroblue tetrazolium (NBT).37 The levels of CAT enzyme were measured according to protocol evaluated by Aebi.38 GPx was detected in the kidney homogenates using commercial kits (Biodiagnostic, Cairo, Egypt, Cat.No. MBS744364) based on the industrial,s orders.39\n\nFlow cytometric detection of Caspase-3\n\nThe activity of caspase-3 was detected by flow cytometry technique in order to inspect the number of apoptotic cells in the renal tissues for groups 1, 3&4. This method is viable where the fluorochrome is immediately binded to the first antibody (Phycoerythrin (PE) and Fluorescein isothiocyanate (FITC) conjugate). The renal cell suspension was set to a density of 1 × 106 cell/ml with PBS/BSA buffer (phosphate buffered saline and 1% bovine serum albumin). Aliquot of 100μ L of renal cell suspension was placed test tubes as needed. The antibody (FITC rabbit anti-active caspase-3, solid as, material No.559341, catalog No. 554714, from BD Pharmingen) was added to 10μ L for each sample, mixed fully, and incubated at 25°C for 30 min. thereafter the cells were washed in 2 ml of PBS/BSA followed by centrifugation at 1500 rpm for 5 min and supernatant was removed. The cells were re-suspended in with 0.2 ml of 0.5% paraformaldehyde in PBS/BSA. The data was obtained by flow cytometry.89 This protocol was done in the Mansoura University Hospital using FACS Calibur Flow Cytometer (Becton Dickin-son, Catalog-4. A1 - Anesthesia Products Sunnyvale, CA, USA) equipped with a compact air-cooled low power 150 mW multi-line,4lines selecatble Argon ion laser beam, Cat. No. 58-472 (488 nm).\n\nData were expressed as mean ± standard error, (n=6 per group). Statistical analysis: one-way analysis of variance (ANOVA) followed by post hoc test. All statistical analysis was completed using the Analysis ToolPak in Microsoft Excel (Microsoft, Excel 2019) (RRID:SCR_016137). Means in the same row with different superscript (*) are significantly different (p > 0.05), *significant at p-value > 0.05, ** significant at p-value > 0.01 and ***significant at p-value > 0.001.\n\n\nResults\n\nThe obtained results revealed that, the mean body weights of CP injected mother rats and their offsprings were significantly lowered (p < 0.001) if compared with control. Following concomitant administration of CP and garlic extract, the mean body weight was markedly elevated (p < 0.001) if compared with CP group but still showing, a low significance, decrease for mothers and non-significant change for their offsprings if compared with the control values (Table 1 and Figure 1 A&A1).90\n\n* Significant at p-value ≤ 0.05,\n\n** Significant at p-value ≤ 0.01 and\n\n*** Significant at p-value ≤ 0.001.\n\nNote, a highly significant decrease in the mean body weight, blood sodium & potassium and a significant increase in the blood creatinine and urea among cisplatin induced in mother rats and their offspring. Following administration of cisplatin and garlic extract, the levels of blood creatinine in mother rats and their pups was still showing a significant increase (low significant and moderate significant respectively) with control while the level of urea and electrolytes are restored to the normal value as control. (The software used to edit the images and labels: Adobe photoshop CS 8me (Adobe, US) (RRID:SCR_014199) similar results can be achieved using Microsoft Paint).\n\nIn CP-treated mothers and their pups, the levels of serum creatinine and urea appeared significantly higher (p < 0.001) than control and garlic supplemented groups. Following administration of garlic extract to CP-treated group, the level of serum creatinine appeared significantly lowered (p < 0.001) in comparison with CP alone but still showing, a low significance increase for mothers and a moderately significant increase (p < 0.01) for their offspring if compared with the control group. On the other hand, the level of serum urea, more or less, simulated the values of the control group for both mothers and their offspring in group 4 (Table 1 and Figure 1 B-C1).\n\nThe results of our study revealed that the levels of serum sodium and potassium ions were significantly decreased (p < 0.001) in CP-treated mothers and their offspring while the levels of serum magnesium exihibited non-significant variation (p > 0.001) if compared with the control group. Following administration of CP and garlic extract, the levels of serum sodium and potassium were improved and showed non-significant change (p > 0.001) in comparison with the control (Table 1 and Figure 1 D-F1).\n\nIn control and garlic treated mother rats (Figure 2 A&B) and their offsprings (Figure 2 A1&B1) the renal cortex appeared with normal histological structure of renal tubules and renal corpuscles. The renal corpuscle consists of glomerulus (tufts of blood capillaries) that lies in Bowman’s space and surrounded by a tight Bowman’s capsule. The renal tubules are made of well-organized proximal tubules (PT), distal tubules (DT) and collecting ducts (CD). The PT has star-shaped lumen that lined with brush bordered endothelium. The DT has relatively rounded lumen that are surrounded by cubical epithelium with little microvilli. The CD has a relatively wide lumen compared to the PT and DT which is lined with short cubical epithelium.\n\n(A & A1: control, B & B1: garlic, C & C1 cisplatin and D & D1 Following concomitant administration of cisplatin and garlic extract.) Note: the renal cortex appears with normal histological structure of renal corpuscles and tubules in images A-B1, little and atrophied glomerulus (AG), damaged (arrowhead) and dilated tubules (stars) in image C & C1 and obvious amelioration in the histological structure of renal cortex in images D&D1. (The software used to edit the images and labels: Adobe photoshopCS8me similar results can be achieved using Microsoft Paint).\n\nAbbreviations: AG; Atrophied glomeruli, BC; Bowman's capsule, BS; Bowman's space, CD; Collecting duct, DT; Distal tubules, G; Glomerulus, PT; Proximal tubules, RC;Renal capsule × 400 (H&E).\n\nIn CP treated mother rats (Figure 2 C) and their offsprings (Figure 2 C1), the renal cortical sections dispalyed remarkable deleterious histological alterations but the severity of alteration was pronounced in mother rats. Such alterations included low density of renal corpuscles with a relativelly wide Bowman’s space, atrophied glomeruli, degenerative tubular cells and cortical tubular dilation. Following administration of CP and garlic extract, the renal cortical sections displayed remarkable amelioration in their architecture in spite of little degenerative tubules being present in some area of the renal cortical section of mothers (Figure 2 D&D1).\n\nThe level of SOD appeared significantly higher (p < 0.001) in the renal tissues of mothers that were supplemented with garlic extract alone while that of offspring appeared with non-significant change (p > 0.001) if compared with cotrol. In CP-treated mothers rats and their offspring, the level of SOD showed a remarkably significant decline (p < 0.001) if compared with the control and garlic groups. In CP-treated mother rats receiving garlic extract, the renal SOD significantly decreased if compared with CP-treated alone but still significantly lower than control; however, their offspring had with non-signifcant (p > 0.001) changes (Table 2 & Figure 3A&A1).\n\n* Significant at p-value ≤ 0.05,\n\n** Significant at p-value ≤ 0.01 and\n\n*** Significant at p-value ≤ 0.001.\n\nNote: a highly significant in the levels of SOD, CAT and GPx (with the exception of GPx in offspring) and significant increase in the level of MDA among CP treated group. Following administration of CP and garlic extract, the levels of SOD, CAT, GPx and MDA are restored near to the control values. (The software used to edit the images and labels: Adobe photoshopCS8me similar results can be achieved using Microsoft Paint).\n\nIn garlic extract treated mother rats and their offspring the level of renal tissues CAT appeared significantly higher than control (p < 0.001). However, a highly significant decline (p < 0.001) of this enzyme was noticed in the CP-injected mothers and their offspring. Concomitant administration of CP and garlic extract lessened such change in the CAT enzyme induced by CP, especially in offspring rather than mothers. Despite mothers still showing a significant decrease (p < 0.001) compared to the control (Table 2 & Figure 3 B&B1).\n\nIn CP-treated mothers, the renal content of GPx appeared significantly lower than the control (P<0.001). Post-treatment of CP-treated mother rats with garlic extract, the level of GPx enzyme showed significant elevation if compared with CP-treated group but still with a low significance decrease if compared with the control. The offspring of all studied groups appeared with non-significant changes from the control (Table 2 & Figure 3C&C1).\n\nIn garlic extract supplemented mother rats and their offsprings, the level of MDA in renal tissue homogenate appeared significantly lowered (p < 0.001) if compared with the control. In CP-treated mothers and their offspring the level of MDA showed highly a significant increase (p < 0.001) if compared with control. Following administration of CP and garlic extract, the level of MDA showed non-significant change (p > 0.001) compared with the control (Table 2 & Figure 3 D&D1).\n\nThe flow cytometric data, in the current research, displayed that the normal percentage value of apoptosis caused by caspase-3 in the renal tissues of control mother was lower than that of their offsprings (29.7% and 35.5%) respectively. However, the mean percentage value of apoptosis induced by activated caspase-3 was increased in CP-treated mother rats and their offsprings (63.6% and 48.5% respectively) if compared with control. Following administration of CP and garlic extract markedly declined the elevated percentage value of apoptosis caused by activation of caspase-3 to (31.7% and 33.6% in mothers and offspring respectively) (Table 3 & Figure 4).\n\nNote a highly % value of caspase3 activity in cisplatin (CP) induced mother rats and their offspring (63.6%, 48.5%) if compared with their control (29.7%, 35.5%) respectively. Following administration of CP and garlic extract, the mean % value of caspase-3 activity in the renal cells significantly lowered (mother rats =31.7%%, Offsprings =33.6%) if compared with CP-treated group. (The software used to edit the images and labels: Adobe photoshopCS8me similar results can be achieved using Microsoft Paint).\n\n\nDiscussion\n\nCP has severe deleterious side effects on pregnant mothers and their fetuses.40,41 On the other hand, it had been emphasized that carrot flavor like garlic and several other flavors are transmitted from the lacataing mother to her fetuses.42 Accordingly, the current work aimed to evaluate the modulatory role of garlic extract against CP-iduced nephrotoxicity in pregnant mother rats and their offsprings.\n\nThe obtained results of the current study revealed a remarkably significant decrease in the final body weight of CP-treated mother rats and their offspring if compared with a control. This result came in accordance with findings of previous studies43,44 who recorded a significant decrease in the body weight of CP-treated rats treated with a single dose (7.5 mg/kg). The declined Bwt in CP-treated rats might be attributed to the direct damage of CP on renal tubular cells resulting in decreased water and sodium reabsorption with subsequent polyuria, dehydration.45,46 Another study postulated that the decreased body weight in CP injected rats might be attributted to gastrointestinal toxicity resulting in lost appetite, ingestion and assimilation of food.48 The reduction in body weight of offspring which their mothers received CP may be attributed to excretion of CP metabolites in milk during breast feeding. On the other hand, an obvious increase of body weight was noticed postsupplementation garlic extract to CP treated -mother rats. Nasr and Saleh reported that garlic extract can help maintain body weight through regulation of renal and intestinal enzyme functions.33 Another study revealed that, if mothers consumed certain flavor compounds during the gestation and breastfeeding period, this would allow assimilation of carrot-flavored cereals to become available to their infants as infants are unable to digest this themselves.48 A further study assumed that, ingestion of garlic by pregnant women leads to longer breast attachment for their infants.49 In contrast to obtained result concerning body weight, Dixit and Joshi recorded a significant reduction in body weight after supplemattion with a garlic extract.50 Such conflicting results may be attributed to the difference in exposed dose of garlic as well as the conditions of experiment.\n\nDeleterious histological changes appeared in the renal cortex of CP-treated mother rats and their offspring. Such changes included atrophied glomeruli, dilatated Bowman’s space, necrosis and detachment of the proximal tubular cells, dilated tubular lumin of both proximal and distal tubules. This could be due to the cytotoxic effect of CP. Similar observations were recorded in rats treated with different doses of CP.51,52 Aydogan et al. postulated that CP causes direct cellular damage on the renal corpuscles and tubules structures through generation of reactive oxygen species (ROS).53 It had been reported that the nephrotoxicity induced by CP in childhood cancer therapy is accompanied with renal tubular damage, excess elimination of low molecular weight peptides and decreased excretion of some glycoprotein protein.54 Another study on CP revealed that about 25% of patients have a significant increase in the levels of blood nitrogen following 1-2 weeks of treatment which is considered as a main cause for glomerular and tubular damage.55 Pinta and Lippard suggested that the accumulation of platinum metabolites of CP inside the renal tubule is implicated in induction of nephrotoxicity.56 Moreover, frequent doses of CP can directly induce oxidative stress renal tubular and glomerular cells resulting in inflammation and apoptosis.57\n\nIn the present study, a remarkable improvement was recorded in the renal tissues of mother rats administrated with garlic after treatment with CP. Previous reports have demonstrated that garlic extract can prevent the oxidative stress and exerts amelioartive effect against various toxic agents through its vital antioxidant and free radical scavenger’s constituennts.58,59 Other studies revealed that garlic has a powerful cytoprotective effects on the cells of vital body organs.60,61\n\nSerum creatinine and urea levels are considered the major biomarkers that efficiently mark the glomerular filtration rate.46 In the current work, renal damage of CP was apparent from the increased levels of serum urea and creatinine in mother rats and their offspring. These observations agree with the previous, similar, reports.45,47 Motegi et al. reported that, use of CP by pregnant women can exhibit a reversible elevation of serum creatinine and urea of her neonates.62 Furthermore, the elevation in the serum levels of creatinine and urea might be attributed to renal disfunctions,58 tubular obstruction and cytotoxicity of the renal tubules cells.46 The disturbance in renal functions by CP is mainly due to its ability to supress protein synthesis by the renal tubular cells,63 or to promote lipid peroxidation and liberation free radicals in renal tubular cells.64 Aydogan et al. added that the significant elevation in the renal biomarkers is mainly attributed to the direct cytotoxic effect of CP on the glomerular and tubular structures through the excessive liberation of ROS.53\n\nIn the present study, administration of CP followed by garlic extract revealed obvious recovery in the levels of serum creatinine and urea that markedly elevated by treatment with CP alone. This could be attributed to a cytoprotective effect of garlic. Our findings are parallel to previous reports.33,58 Razo-Rodriguez et al. assured that garlic extract can maintain the levels of serum urea and creatinine through its organo-sulfur compounds.65 Moreover, these compounds could enhance the antioxidant effect and inhibit the levels of lipid peroxide through scavenging the free radicals and elevation of intracellular concentration of glutathione.\n\nThe present study revealed a significant decrease in the serum sodium and potassium in CP-treated mother rats and their offspring. Such results came in agreement with the findings of previous studies66,67 which showed excess elimination of potassium and sodium in patients treated with CP. An early study by Daugaard et al. confirmed that, CP metabolites can inhibit the mechanism involving electrolytes reabsorption especially in the distal segment of the nephron, resulting in hypokalemia and hyponatremia.68 Furthermore, CP can induce disturbance in both intestinal absorption and renal tubular reabsorption of potassium.66 Another study clarified that CPcan inhibit the activity of antidiurtic hormone leading to hypernatremia.69\n\nGarlic contains organo-sulfur compounds including S-Allylcysteine and allicin. These compounds had been reported to have a strong antioxidant role by elevation of GPx content in the cells as well as in scavenging of liberated free radicals.59,70,71 Other related studies revealed that, garlic extract can alleviate the cardiotoxicity induced by doxorubicin,72 Cd-induced toxicity52 and oxidative stress induced by acrylamide in different body organs.73 In the current work, treatment of mother rats with garlic extract alone or in combination with CP resulted in significant decline in the level of MDA and significant elevation of SOD, CAT and GPx activities in the kidney tissues. These findings support the antioxidant effects of garlic extract against CP-induced oxidative damage and lipid peroxidation. Lanzotti revealed that the thiosulfinates compounds of garlic play a major role in enhancing the antioxidants enzymes.74 Other constituents of garlic like S-allyl mercaptocyteine, and selenium have been reported to have potent antioxidant activity.59 Furthermore, S-allyl cysteine can inhibit the excessive liberation of lipid peroxidation and consequently stimulate potent antioxidant effects in both in vitro and in vivo experiments.75 In agreement with present study, significant elevation of CAT, SOD and GPx activities accompanied by marked decline in MDA was recorded in animals treated with garlic.76,77 The obtained results in the present work concerning the reduction in the activity of renal antioxidant enzymes; CAT, SOD and GPx and elevated lipid peroxidation (MDA) in CP treated mother rats are in line with the findings of previous reports.65,78 Sheikh-Hamad et al. declared that CP can liberate nitric oxide that is implicated in oxidative stress and nephrotoxicity.79 Kart et al. added that CP is implicated in excessive production of ROS in renal cell damage by promoting disturbance in membrane permeability.80 Elevation of the MDA enhanced lipid peroxidation and increased ROS generation leading to disturbance of membrane function and integrity.81 Moreover, the inhibitory effect of CP on CAT, SOD, and GPx was implicated in the pathogenesis renal tissues.\n\nCaspases are a family of proteases that play an important role in the regulation of apoptosis.82 In the current investigation, caspase-3 (strong apoptotic marker) has been shown to be increased in the renal tissues of CP-treated mother’s rats and their offspring. The obtained result agrees with work by previous researches.82,83 Sheikh-Hamad et al. reported that, CP can induce apoptosis through activation of tumor necrosis factor or messages form caspases 1, 2, 3 and 8 that activate caspase-3 in kidney.79 Razzaque et al. revealed that CP increased expression of both Fas and Fas ligand in human proximal tubular epithelial cells which accelearate tha activity of caspse-3.84 Other researchers reported that, CP can induce apoptosis in the renal tubular cells resulting in activation of caspase-9, which is a good promoter for the mitochondrial apoptotic pathway.83,85 Further studies explained that CP can induce apoptosis with progressive accumulation of DNA and inhibition of DNA repair pathways, through generation of reactive oxygen species.57,86\n\nGarlic was found to attenuate the increased caspase-3 levels induced by CP treatment. Previously, it was reported that, s-allyl cysteine in garlic can prevent the lipid peroxidation and the oxidative damage to DNA resulting in inhibition of apoptosis.33,87\n\n\nConclusions\n\nIn light of the demonstrated findings in this investigation, protective imprints of garlic extract against CP-induced deleterious histological and biochemical changes were found. Garlic extract has powerful ameliorative effects on CP-induced oxidative stress and renal damage through its antioxidant, anti-inflammatory and antiapoptotic properties through post-treatment with garlic extract. Eventually, further studies with different dose regimens and on larger number of animals over longer durations are recommended.\n\n\nData availability\n\nFigshare: Raw data for body weight and biochemical parameters. https://doi.org/10.6084/m9.figshare.19435616.v288\n\nThis project contains the following underlying data:\n\n- Raw data of biochemical parameters.xlsx (Raw data on rats body weight)\n\nFigshare: Data of Flow cytometry detection of caspase-3.xlsx https://doi.org/10.6084/m9.figshare.19435676.v489\n\nThis project contains the following uunderlying data:\n\n- Raw data of flow cytometric analysis for caspase-3.xlsx\n\nFigshare: Underlying data.pdf. https://doi.org/10.6084/m9.figshare.19435370.v190\n\nThis project contains the following underlying data:\n\n- Underlying data.pdf (Images/Figures used in the manuscript)\n\n\nReporting guidelines\n\nFigshare: Author Checklist – Full.pdf https://doi.org/10.6084/m9.figshare.19446926.v1.91 This project contains the following reporting guidelines:\n\n- Author Checklist – Full.pdf (ARRIVE checklist)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nThe underlying image data for this study are too large to share openly. The image files are predominately JPG files and approximately 198 MB in size. Considering the large size and multiple images (n=204), the image files will be shared on request to readers. Please contact the corresponding author beltagyaaa@yahoo.com, if you would like to request access to the image files. Representative images are shown in the figures and can be found in the Figshare repository.\n\n\nConsent to participate\n\nNot applicable.",
"appendix": "Acknowledgments\n\nThe authors would like to thank the biochemical research center in the Faculty of Science, Damanhour University, for providing facilities to bring to this work.\n\n\nReferences\n\nOun R, Moussa YE, Wheate NJ: The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans. 2018; 15;47(19): 6645–6653. PubMed Abstract | Publisher Full Text\n\nKato R, Sato T, Iwamoto A, et al.: Interaction of platinum agents, cisplatin, carboplatin and oxaliplatin against albumin in vivo rats and in vitro study using inductively coupled plasma-mass spectrometory. Biopharm. Drug Dispos. 2019; 40(7): 242–249. PubMed Abstract | Publisher Full Text\n\nOzkok A, Edelstein CL: Pathophysiology of cisplatin-induced acute kidney injury. Biomed. Res. Int. 2014; 2014: 967826.\n\nLudwig T, Riethmüller C, Gekle M, et al.: Nephrotoxicity of platinum complexes is related to basolateral organic cation transport. Kidney Int. 2004; 66(1): 196–202. PubMed Abstract | Publisher Full Text\n\nLandau SI, Guo X, Velazquez H, et al.: Regulated necrosis and failed repair in cisplatin-induced chronic kidney disease. Kidney Int. 2019; 95(4): 797–814. PubMed Abstract | Publisher Full Text\n\nTaber A, Christensen E, Lamy P, et al.: Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis. Nat. Commun. 2020; 11(1): 4858. PubMed Abstract | Publisher Full Text\n\nLee J, You JH, Shin D, et al.: Inhibition of Glutaredoxin 5 predisposes Cisplatin-resistant Head and Neck Cancer Cells to Ferroptosis. Theranostics. 2020; 10(17): 7775–7786. PubMed Abstract | Publisher Full Text\n\nYi SA, Kim GW, Yoo J, et al.: HP1gamma Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3. Int. J. Mol. Sci. 2020; 21(17): 5976. PubMed Abstract | Publisher Full Text\n\nde Vries G , Rosas-Plaza X, van Vugt MATM , et al.: Testicular cancer: Determinants of cisplatin sensitivity and novel therapeutic opportunities. Cancer Treat. Rev. 2020; 88: 102054. PubMed Abstract | Publisher Full Text\n\nGrabosch S, Bulatovic M, Zeng F, et al.: Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. Oncogene. 2019; 38(13): 2380–2393. PubMed Abstract | Publisher Full Text\n\nNguyen DJM, Theodoropoulos G, Li YY, et al.: Targeting the Kynurenine Pathway for the Treatment of Cisplatin-Resistant Lung Cancer. Mol. Cancer Res. 2019; 18(1): 105–117. PubMed Abstract | Publisher Full Text\n\nTownsend DM, Tew KD, He L, et al.: Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity. Biomed. Pharmacother. 2009; 63: 79–85. PubMed Abstract | Publisher Full Text\n\nWang D, Lippard SJ: Cellular processing of platinum anticancer drugs. Nat.Rev. Drug Discov. 2005; 4: 307–320. Publisher Full Text\n\nHolditch SJ, Brown CN, Lombardi AM, et al.: Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury. Int. J. Mol. Sci. 2019; 20(12): 3011. PubMed Abstract | Publisher Full Text\n\nKarasawa T, Sibrian-Vazquez M, Strongin RM, et al.: Identification of cisplatin-binding proteins using agarose conjugates of platinum compounds. PLoS One. 2013; 8: e66220. PubMed Abstract | Publisher Full Text\n\nSun L, Liu J, Yuan Y, et al.: Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity. Am. J. Physiol. Renal Physiol. 2018; 315(3): F469–F478. Publisher Full Text\n\nCheng TC, Hsu YW, Lu FJ, et al.: Nephroprotective effect of electrolyzed reduced water against cisplatin-induced kidney toxicity and oxidative damage in mice. J. Chin. Med. Assoc. 81(2): 119–126. PubMed Abstract | Publisher Full Text\n\nMarnitz S, Köhler C, Oppelt P, et al.: Cisplatin application in pregnancy:first in vivo analysis of 7 patients. Oncology 2018. 2010; 79: 72–77. Publisher Full Text\n\nParekh J, Chanda S: In vitro antimicrobial activity of Trapa natans L. Fruit rind extracted in different solvents. Afr. J. Biotechnol. 2007; 6(6): 766–770.\n\nJosling PA: The heart of garlic Nature’s aid to healing the human body. Chicago Illinois: HEC Publishing; 2005; 20.\n\nNasr AY: Protective effect of aged garlic extract against the oxidative stress induced by cisplatin on blood cells parameters and hepatic antioxidantenzymes in rats. Toxicol. Rep. 2014; 1(1): 682–691. Publisher Full Text\n\nZaidi SK, Ansari SA, Ashraf GH, et al.: Reno-protective effect of garlic extract against immobilization stress induced changes in rats. Asian Pac. J. Trop. Biomed. 2015; 5(5): 364–369. Publisher Full Text\n\nSumioka I, Hayama M, Shimokawa Y, et al.: Lipid-lowering effect of monascus garlic fermented extract (MGFE) in hyperlipidaemia subjects. Hiroshima J. Med. Sci. 2006; 55(2): 59–64. PubMed Abstract\n\nOhaeri OC: Effect of garlic oil on the levels of various enzymes in the serum and tissue of streptozotocin diabtic rats. Biosci. Rep. 2001; 21: 19–24. PubMed Abstract | Publisher Full Text\n\nJaber MA, Al-Mossawi A: Susceptibility of some multiple resistant bacteria to garlic extracts. Afr. J. Biotechnol. 2007; 6(6): 771–776.\n\nTimbo BB, Ross MP, McCarthy PV, et al.: Dietary supplements in a national survey: Prevalence of use and reports of adverse events. Am. Diet Assoc. 2006; 106(12): 1966–1974. PubMed Abstract | Publisher Full Text\n\nMansell P, Reckless J: Effects on serum lipids, blood pressure, coagulation, platelet aggregation and vasodilation. BMJ. 303: 379–380. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYeh GY, Davis RB, Phillips RS: Use of Complementary Therapies in Patients with Cardiovascular Disease. Am. J. Cardiol. 2006; 98(5): 673–680.\n\nJosling P: Preventing the common cold with a garlic supplement: a double-blind, placebo-controlled survey. Adv. Ther. 2001; 18: 189–193. PubMed Abstract | Publisher Full Text\n\nCapraz M, Dilek M, Akpolat T: Garlic. Hypertension and patient education. Int. J. Cardiol. 2006; 3: 15–19.\n\nMiyamoto S, Yamada M, Kasai Y, et al.: Anticancer drugs during pregnancy. Jpn. J. Clin. Oncol. 2016; 46(9): 795–804. Publisher Full Text\n\nSaleh HA, Abd El-Aziz GS, Mustafa HN, et al.: Protective effect of garlic extract against maternal and foetal cerebellar damage induced by lead administration during pregnancy in rats. Folia Morphol. (Warsz). 2018; 46(9): 795–804.\n\nNasr AY, Saleh HAM: Aged garlic extract protects against oxidative stress and renal changes in cisplatin-treated adult male rats. Cancer Cell Int. 2014; 14(92): 1–12.\n\nNaghizadeh B, Boroushaki MT, Vahdati Mashhadian N, et al.: Protective effects of crocin against cisplatin-induced acute renal failure and oxidative stress in rats. Iran. Biomed. J. 2008; 12(2): 93–100. PubMed Abstract\n\nDickey DT, Wu YJ, Muldoon LL, et al.: Protection against cisplatin induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J. Pharmacol Exp. Ther. 2005; 314(3): 1052–1058. Publisher Full Text\n\nOhkawa H, Ohishi N, Yagi K: Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 1979; 95: 351–358. PubMed Abstract | Publisher Full Text\n\nKakkar PS, Das B, Viswanathan PNA: Modified spectrophotometric assay of superoxide dismutase. Indian J. Biochem. Biophys. 21: 130–132. PubMed Abstract\n\nAebi H: Catalase in vitro. Methods Enzymol. 1984; 105: 121–126. Publisher Full Text\n\nPaglia DE, Valentine WN: Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med. 1967; 70: 158–169. PubMed Abstract\n\nSerkies K, Wdgrzynowicz E, Jassem J: Paclitaxel and cisplatin chemotherapy for ovarian cancer during pregnancy: case report and review of the literature. Arch. Gynecol. Obstet. 2011; 283(Suppl 1): 97–100. PubMed Abstract | Publisher Full Text\n\nGhaseminezhad K, Hejazi S: Teratogenic Effect of Cisplatin-Treatment in Mice Fetus. Cibtech J. Zool. 2015; 4(2): 25–30.\n\nMennella JA, Beauchamp GK: Experience with a flavor in mother’s milk modifies the infant’s acceptance of flavored cereal. Dev. Psychobiol. 1999; 35: 197–203. PubMed Abstract | Publisher Full Text\n\nAbdelmaguid EN, Hania NC, Noura SA: Protective effect of silymarin on cisplatin-induced nephrotoxicity in rats. Pak. J. Nutr. 2010; 9: 624–636. Publisher Full Text\n\nNasr AY: Effect of Misoprostol on Ultrastructural Changes of Renal Tissues in Cisplatin-Treated Adult Rats. J. Cytol. Histol. 2013; 4: 3.\n\nYao X, Panichpisal K, Kurtzman N, et al.: Cisplatin nephrotoxicity: A review. Am. J. Med. Sci. 2007; 334: 115–124. Publisher Full Text\n\nAzu OO, Francis IOD, Abraham AO, et al.: Protective Agent, Kigelia Africana Fruit Extract, Against Cisplatin-Induced Kidney Oxidant Injury in Sprague–Dawley Rats. Asian J. Pharm. Clin. Res. 2010; 3: 84–88.\n\nArhoghro EM, Kpomah DE, Uwakwe AA: Ocimum gratissimum aqueous extract enhances recovery in cisplatin - induced nephrotoxicity in albino wistar rats. Indian J. Drugs Diseases. 2012; 1(5): 129–142.\n\nMennella JA, Jagnow CP, Beauchamp GK: Prenatal and postnatal flavor learning by human infants. Pediatrics. 2001; 107: e88. Publisher Full Text\n\nMennella JA, Beauchamp GK: Maternal diet alters the sensory qualities of human milk and the nurslings’s behavior. Pediatrics. 1991; 88: 737–744. PubMed Abstract\n\nDixit VP, Joshi S: Effects of chronic administration of garlic (Allium sativum Linn) on testicular function. Indian J. Exp. Biol. 1982; 20: 534–536. PubMed Abstract\n\nAli BH, Al Moundhri MS: Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. Food Chem. Toxicol. 2006; 44: 1173–1183. Publisher Full Text\n\nLawal AO, Ellis EM: The chemopreventive effect of aged garlic extract against cadmium-induced toxicity. Environ. Toxicol. Pharmacol. 2011; 32: 266–274. PubMed Abstract | Publisher Full Text\n\nAydogan S, Yapislar H, Artis S, et al.: Impaired erythrocytes deformability in H2O2- induced oxidative stress: Protective effect of L carnosine. Clin. Hemorheol. Microcirc. 2008; 39: 93–98. PubMed Abstract | Publisher Full Text\n\nTakeda M, Komeyama T, Tsutsui T, et al.: Changes in urinary excretion of enclothelin-I-like immunoreactivity in patients with testicular cancer receiving high-dose cisplatin therapy. Ara. J. Kidney Dis. 1994; 24: 12–16. PubMed Abstract | Publisher Full Text\n\nKovach IS, Moertel CG, Schutt AJ, et al.: Phase II study of cis-diarnminedichloroplatinum (NSC-119875) in advanced carcinoma of the large bowel. Cancer Chemother. Rep. 1973; 57: 357–359. PubMed Abstract\n\nPinta AL, Lippard SI: Binding of the antitumor drug cis-diamminedichloroplatinum (II) (cisplatin) to DNA. Biochim. Biophys. Acta. 1985; 780: 167–180. Publisher Full Text\n\nAlhoshani AR, Hafez MM, Husain S, et al.: Protective effect of rutin supplementation against cisplatin-induced Nephrotoxicity in rats. BMC Nephrol. 2017; 15; 18(1): 1–10. Publisher Full Text\n\nAnusuya N, Durgadevi P, Dhinek A, et al.: Nephroprotective effect of ethanolic extract of garlic (Allium Sativum) on cisplatin induced nephrotoxicity in male Wistar Rats. Asian J. Pharm. Clin. Res. 2013; 6(Suppl 4): 97–100.\n\nCapasso A: Antioxidant action and therapeutic efficacy of allium sativum L. Molecules. 2013; 18(1): 690–700. PubMed Abstract | Publisher Full Text\n\nAssayed ME, Salem HA, Khalaf AA: Protective effects of garlic extract and vitamin C against cypermethrin reproductive toxicity in male rats. Res. J. Vet. Sci. 2008; 1: 1–15.\n\nHammami I, Amara S, Benahmed M, et al.: Chronic crude garlic-feeding modified adult male rat testicular markers: mechanisms of action. Reprod. Biol. Endocrinol. 2009; 24(7): 65.\n\nMotegi M, Takakura S, Takano H, et al.: Adjuvant chemotherapy in a pregnant woman with endodermal sinus tumor of the ovary. Obstet. Gynecol. 2007; 109: 537–540. Publisher Full Text\n\nAdejuwon AS, Femi-Akinlosotu O, Omirinde JO, et al.: Launaea taraxacifolia ameliorates cisplatin- induced hepato-renal injury. Eur. J. Medicinal Plants. 2014; 4(5): 528–541. Publisher Full Text\n\nSaad AA, Youssef MI, El-Shennawy LK: Cisplatin induced damage in kidney genomic DNA and nephrotoxicity in male rats: the protective effect of grape seed proanthocyanidin extract. Food Chem. Toxicol. 2009; 47(7): 1499–1506. PubMed Abstract | Publisher Full Text\n\nRazo-Rodríguez AC, Chirino YI, Sánchez-González DJ, et al.: Garlic powder ameliorates cisplatin-induced nephrotoxicity and oxidative stress. J. Med. Food. 2008; 11(3): 583–586.\n\nTamim H, Shadi L, Bassel J, et al.: Cisplatin-induced renal salt wasting syndrome. South. Med. J. 2010; 10; 103(8): 793–799. Publisher Full Text\n\nArunkumar PA, Viswanatha GL, Radheshyam N, et al.: Science behind cisplatin-induced nephrotoxicity in humans: a clinical study. Asian Pac. J. Trop. Biomed. 2012; 2(8): 640–644. PubMed Abstract | Publisher Full Text\n\nDaugaard G, Rossing N, Rorth M: Effects of high-dose cisplatin on glomerular function in the human kidney. Cancer Chemother. Pharmacol. 1988; 21: 163–167. PubMed Abstract\n\nSurinder A, Balamurugan N, Gunaseelan K, et al.: Adverse drug reaction profile of cisplatin-based chemotherapy regimen in a tertiary care hospital in India: An evaluative study. Indian J. Pharm. 2010; 42(1): 40–43.\n\nBongiorno PB, Fratellone PM, LoGiudice P: Potential health benefits of garlic (allium sativum): a narrative review. J. Complement Integr. Med. 2008; 5(1): 1–26. Publisher Full Text\n\nColin-Gonzalez AL, Santana RA, Silva-Islas CA, et al.: The antioxidant mechanisms underlying the aged garlic extract- and S- allylcysteine-induced protection. Oxidative Med. Cell. Longev. 2012; 2012: 1–16. PubMed Abstract | Publisher Full Text\n\nAlkreathy H, Zoheir AD, Nessar A, et al.: Aged garlic extract protects against doxorubicin-induced cardiotoxicity in rats. Food Chem. Toxicol. 2010; 48: 951–956. PubMed Abstract | Publisher Full Text\n\nAbd El-Halim SS, Mohamed MM: Garlic powder attenuates acrylamideinduced oxidative damage in multiple organs in Rat. J. Appl. Sci. Res. 2012; 8(1): 168–173.\n\nLanzotti V: The analysis of onion and garlic. J. Chromat. A. 2006; 12(1): 3–22.\n\nAlmaca G: Antioxidant effects of sulfur containing amino acids. Yonsei Med. J. 2004; 45(5): 776–788.\n\nGorinstein S, Leontowicz H, Leontowicz M, et al.: Raw and boiled garlic enhances plasma antioxidant activity and improves plasma lipid metabolism in cholesterol-fed rats. Life Sci. 2006; 78: 655–663. PubMed Abstract | Publisher Full Text\n\nAdaramoye A, Osaimoje DO, Akinsanya AM, et al.: Changes in antioxidant status and biochemical indices after acute administration of artemether, artemether-lumefantrine and halofantrine in rats. J. Compil. Basic Clin. Pharmacol. Toxicol. 2008; 102: 412–418. PubMed Abstract | Publisher Full Text\n\nAjith TA, Usha S, Nivitha V: Ascorbic acid and alpha tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study. Clin. Chim. Acta. 2007; 375: 82–86. PubMed Abstract | Publisher Full Text\n\nSheikh-Hamad D, Cacini W, Buckley AR, et al.: Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. Arch. Toxicol. 2004; 78: 147–155. PubMed Abstract | Publisher Full Text\n\nKart A, Yilmaz C, Musa K, et al.: Caffeic acid phenethylester (CAPE) ameliorates cisplatin-induced hepatotoxicity in rabbit. Exp. Toxicol. Pathol. 2010; 62: 45–52. PubMed Abstract | Publisher Full Text\n\nEstuo N: Lipid peroxidation: physiological levels and dual biological effects. Free Radic. Biol. Med. 2009; 47(5): 469–484. Publisher Full Text\n\nKaushal GP, Kaushal V, Hong X, et al.: Role and regulation of activation of caspases in cisplatin-induced injury to renal tubular epithelial cells. Kidney Int. 2001; 60: 1726–1736. PubMed Abstract | Publisher Full Text\n\nPark MS, De Leon M, Devarajan P: Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J. Am. Soc. Nephrol. 2002; 13: 858–865. PubMed Abstract | Publisher Full Text\n\nRazzaque MS, Koji T, Kumatori A, et al.: Cisplatin induced apoptosis in human proximal tubular epithelial cells is associated with the activation of the Fas/Fas ligand system. Histochem. Cell Biol. 1999; 111: 359–365. PubMed Abstract | Publisher Full Text\n\nBlatt NB, Glick GD: Signaling pathways and effector mechanisms pre programmed cell death. Bioorg. Med. Chem. 2001; 9: 1371–1384. PubMed Abstract | Publisher Full Text\n\nAvan A, Postma TJ, Ceresa C, et al.: Platinum induced neurotoxicity and preventive strategies: past, present, and future. Oncologist. 2015; 20: 411–432. PubMed Abstract | Publisher Full Text\n\nMikaili P, Maadirad S, Moloudizargari M, et al.: Therapeutic uses and pharmacological properties of garlic, shallot, and their biologically active compounds. Iran. J. Basic Med. Sci. 2013; 16: 1031–1048. PubMed Abstract\n\nElbeltagy A: Raw data for biochemical parameters.xlsx. figshare. [Dataset]. 2022. Publisher Full Text\n\nElbeltagy A: Raw data of flow cytometric analysis for caspse-3.xlsx. figshare. [Dataset]. 2022. Publisher Full Text\n\nElbeltagy A: Underlying Data.pdf. [Dataset]. Figure. 2022. Publisher Full Text\n\nElbeltagy A: Author Checklist - Full.pdf. figshare. [Dataset]. 2022. Publisher Full Text"
}
|
[
{
"id": "146986",
"date": "03 Oct 2022",
"name": "Fahmy G. Elsaid",
"expertise": [
"Reviewer Expertise Molecular physiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for your invitation to undergo the review of the article entitled: Modulatory role of garlic (Allium sativum) extract against cisplatin-induced nephrotoxicity in female albino rats and their offspring. The article aimed to evaluate the possible ameliorative role of garlic extract against nephrotoxicity induced by cisplatin (chemotherapeutic drug) in pregnant rats and the work is also extended to evaluate the complication on the offspring and attenuated the nephrotoxicity using a natural product. The authors focused on the investigation of renal histopathological and biochemical changes induced by cisplatin. The obtained results revealed that garlic extract successfully alleviated the deleterious renal histopathological and functional signs induced by cisplatin. The authors discussed that the sulfur and other phytochemical constituents of garlic extract play an essential role in the amelioration of renal structure and function.\nThe paper is interesting and suitable for publication in F1000Research after consideration of the following minor corrections.\nThe Histological sections of the control kidney mother need more resolution (Figure 2).\n\nThe authors need to explain the source of cisplatin and its concentration.\n\nHow do the authors detect the dose of garlic extract?\nAccordingly, I recommended this article be suitable for indexing.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "188352",
"date": "01 Aug 2023",
"name": "Stanila Stoeva",
"expertise": [
"Reviewer Expertise Isolation",
"HPLC analysis and in vivo assessment of plant extracts"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI find the work presented intriguing! On the one hand, cancers are discussed, which are one of the most common causes of mortality worldwide. On the other hand, the authors present the possibilities of conducting effective pharmacotherapy based on biologically active substances of natural origin. Anyway, I believe that answering the following questions will increase the quality of the scientific project and increase its publicity, respectively:\nPlease describe how and by whom the plant material used was botanically characterized.\n\nDid you define the algorithm of the extraction procedure or did you use someone else's protocol? If it is part of your laboratory's operating procedures, please explain the choice of conditions. If you have used a foreign protocol, please cite it in the manuscript. Add in the text at what temperature the extraction was carried out.\n\nHow is the plant extract used standardized? As you know, this is a key argument in justifying the observed biological effects. Perhaps the following article will give you guidance on the standardization procedure: A HPLC-UV Method for Analysis of Total Plant Extract and Catechin Fraction of Bancha Green Tea1?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "188353",
"date": "04 Aug 2023",
"name": "Joyce Trujillo",
"expertise": [
"Reviewer Expertise Renal pathophysiology and metabolic diseases"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors need to elaborate on how the decapitation method ensures minimal blood loss, followed by the successful execution of cardiac puncture without any significant blood volume loss.\nTo enhance clarity, the authors should standardize the axis titles and the labels for panels D and D1 of Figure 1. This consistency should extend to the specific electrolyte under evaluation. Furthermore, the description of Figure 1 would benefit from including CP and garlic extract doses. The authors should explain the absence of hypomagnesemia in the mother’s rats and their offspring, as this is a crucial aspect of this model that warrants discussion.\nFor a more streamlined presentation of data, consider consolidating weight, creatinine, and electrolyte results into a single format, such as a table or figures. Considering its representational value, I lean towards favoring figures. If both a table and a figure are to be retained, in the case of Figure 3 and Table 2, align the presentation of results in a consistent order.\nThe authors need to analyze whether the observed beneficial effects of garlic stem come directly from its antioxidant, anti-apoptotic, or anti-inflammatory properties, as suggested, and not by the possibility that these effects result from lowered serum levels of cisplatin via chelation or other chemical reactions.\nEmphasize the significance of incorporating a marker for renal tubular damage, particularly given that the filtration of CP is in the proximal tubules, such as Kim-1 or NAG. This tubular damage could be quantified subjectively through serum creatinine and urea level determinations.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-504
|
https://f1000research.com/articles/11-502/v1
|
09 May 22
|
{
"type": "Research Article",
"title": "ASEAN and the Frankenstein dilemma: Will ASEAN become a monster?",
"authors": [
"M Husni Syam",
"Eka An Aqimuddin",
"M Husni Syam"
],
"abstract": "Background: International organizations are pivotal as actors in international relations. Although its establishment represents a state, they have their objectives separate from their creators. The Association of Southeast Asian Nations [ASEAN] was created to handle cooperation and maintain peace and security in Southeast Asia. Although ASEAN was equipped with institutional organs to fulfil its purposes, member states' influence is unavoidable. This situation raises the Frankenstein dilemma in which creators cannot fully control its creature. This research aims to elaborate on ASEAN as a separate institution with independent objectives and how far member states can manage ASEAN as its creation. Methods: This study uses descriptive-analytical legal research as a method to examine ASEAN constitutional instruments and its first legal text to elaborate on its capacity as a legal person and its role in distinguishing interests between member states. The two ASEAN constitutional instruments are the Bangkok Declaration, 1967, and The ASEAN Charter, 2007, while the first legal instrument is the Treaty of Amity and Cooperation. All of the resources were gathered from ASEAN legal instruments database. Results: After carefully examining the documents, since its establishment ASEAN has kept member states at arms-length to realize their interests; the ASEAN position is only to legalize what its member state wants. Even after 40 years, this situation has not changed. While ASEAN has independent objectives and structures, its member states always made institutional designs to control ASEAN's capacity to act in the international forum. In this case, ASEAN is always under the authority of its member states and has never evolved like Frankenstein's creature. Conclusions: ASEAN will never turn into a monster as ASEAN never has sole interests that contradict its members. ASEAN member states always design ASEAN constitutional and legal instruments to restrict its role as an independent legal person in international forums.",
"keywords": [
"International organization",
"ASEAN",
"Frankenstein dilemma"
],
"content": "Introduction\n\nIn international law discourse, metaphors from fiction books are usually used to elaborate on concepts, theories, and doctrines. Some scholars (Klabbers, 2009, 2004; Guzman, 2013) use the Frankenstein metaphor to discuss the paradox in the development of international organizations [hereinafter IOs].\n\nSince 1945 (ICJ, 1949), IOs have been regarded as subjects of international law. This status gave IOs autonomous rights and obligations. Although they have autonomy, IOs are creatures created by states to strengthen their interests (Guzman, 2013). This condition brings out possibilities of conflict of interests between IOs as separate legal entities from their member states and the states themselves as a creator. Guzman predicts that IOs can become monsters like Frankenstein's creatures in Shelley's literary work (Guzman, 2013).\n\nThe Association of Southeast Asian Nations [ASEAN] (https://asean.org/) is an international organization established on August 8th, 1967, through the Bangkok Declaration (ASEAN, 1967). Significant changes to ASEAN emerged in 2007 after member states signed the ASEAN charter (ASEAN, 2017). This charter signifies tremendous changes within the institution because it explicitly expresses member states' desire to make ASEAN a separate legal subject under international law. Article 3 of the ASEAN charter confirms this issue by declaring that ASEAN has a capacity as a legal personality. Some scholars argue that ASEAN has been legitimate as a subject of international law since the ASEAN charter was concluded because it possesses a constituent instrument. The changes in instrument terms from ‘declaration’ to ‘charter’ signify a re-orientation of ASEAN to be a legal-based organization and reaffirm ASEAN's position as an international legal person. In practice, many terms are used for IOs constituent instruments such as treaties, charters, or declarations. However, the main point is the content that stipulates institutional structure and substantive rules linked to organizational objectives, whatever its name (Blokker, 2016). As the ASEAN charter has fulfilled these criteria, they believe ASEAN personality started in 2007.\n\nIn contrast, others consider that ASEAN had fulfilled its position as a subject of international law even before there was a charter. The Treaty of Amity and Cooperation [TAC] 1976 (ASEAN, 1976b), as the first legal instrument since ASEAN's establishment, was a sign for ASEAN to act as a separate legal entity from its member. They argue that ASEAN practices fulfil their capacity as international legal persons even though the Bangkok Declaration, as a constituent instrument, did not rule institutional design and objectives in detail (Chesterman, 2018).\n\nASEAN's status as the subject of international law means that ASEAN has separated rights and obligations from its member states. In contrast, ASEAN was established by its member states to enhance their interests. At this point, the Frankenstein dilemma possibly arises due to potential differences between the institutional and member states' objectives.\n\nBased on previous background, the primary purposes of this article are to examine ASEAN's role as a member state's tool to fulfil its objectives and the possibility that ASEAN has transformed into a monster with a conflict of interests from its creators. Furthermore, this paper also wants to look at how ASEAN member states overcame Frankenstein's dilemma.\n\n\nMethods\n\nThis article employed a descriptive-analytical legal research method. This research method is widely defined as positivist from a theoretical perspective as it only uses relevant legal sources or doctrine to answer research questions (Lieblich, 2020). The descriptive method is helpful to explain ASEAN's position as an international legal person based on three foundational legal instruments in ASEAN, namely the Bangkok Declaration 1967, TAC 1976, and ASEAN Charter 2007. These legal instruments were collected from the ASEAN legal instruments database (https://agreement.asean.org/) between 1-14 February 2022. After finding out ASEAN's status, the analytical method was applied to examine the consequences of ASEAN as a legal person that has the possibility cannot be controlled by its members or become a monster.\n\nThis research only examines three ASEAN legal instruments because its created the basic rules within ASEAN and represent an essential phase in the institution's development. The Bangkok declaration and ASEAN charter were the ASEAN constitutions, so it's necessary to look at these instruments' status, institutional design, and delegation within ASEAN. Although the TAC was not an ASEAN constituent instrument, this rule was vital because it was the first legal instrument successfully made by ASEAN and symbolized the evolution process from loosed-based to rules-based organization.\n\nThe structure to identify and examine three ASEAN instruments to answer the problem statements is conducted in the following steps. Firstly, every provision in the Bangkok Declaration, TAC, and ASEAN Charter was read and analyzed in the context of ASEAN legal capacity, delegation, and institution design. These categories are essential to identifying ASEAN as a separate legal subject and showing how member states design an institution to what they want. This step is vital to look at the nature of ASEAN since its establishment and how it has transformed until today.\n\nSecondly, after carefully reading and analyzing the three instruments, the analytical approach was applied by analyzing the norms in those instruments and comparing them to international institutional law (Collins, 2021). This step will clarify how ASEAN should be as an international legal person. Thirdly, the results from steps one and two were analyzed and used as a proposition to answer the possibility of ASEAN becoming a monster.\n\n\nResults\n\nFrankenstein's dilemma is a metaphor taken from classical literary works by Mary Shelley in 1818. The plot of Frankenstein began when his mother died when he was 17 years old (Shelley, 2010). The death of his mother caused deep grief in Frankenstein and, to kill his sorrow, Frankenstein starts to study seriously in a college. He was interested in natural sciences, especially chemistry, after meeting Professor. M. Waldman (Shelley, 2010).\n\nHe then buried himself in a laboratory to conduct experiments to create living things. The reasoning behind his experiment is trying to cheat death. He assumed that the creature he made could not die like his mother. Frankenstein finally succeeded in creating a living creature after trying several times to combine various materials from dead bodies.\n\nFrankenstein's assumption was wrong. The creature turned out to be a monster beyond his control. The beast starts to kill people and then hunts Frankenstein. He also begs Frankenstein to create another creature, in the form of a woman, to accompany him. Frankenstein rejected the request by saying that the creator could not be governed by his creation. However, the creature replies, “You are my creator, but I am your master; obey!” (Shelley, 2010).\n\nThe metaphor from Frankenstein is then taken to discuss developments in IOs. Guzman called it the Frankenstein dilemma when he explained the similar situation between the novel and the story of international institutional law. IOs that emerged as subjects of autonomous entities then created trade-offs carried out by the State as a creator. Between giving authority to organizations to fulfil their objectives with state control over the risk that international organizations did not turn into monsters (Guzman, 2013). In other words, when a group of states wants to establish IOs, they are aware of how much power or authority they wish to share with IOs. As much as the power State gives to IOs, it makes IOs more independent, and vice versa.\n\nTheoretically, two legal doctrines can be concluded from the International Court of Justice [ICJ] opinion on the ‘Reparation for Injuries’ case, namely Will Theory and Objective theory, to examine IOs as a subject of international law (Chesterman, 2018).\n\n‘Will theory’ is the most widely accepted Court opinion. If the member states of an IOs want to give their creation personality, then that is what it will receive. This theory strengthens the freely based consent of states (Chesterman, 2018). Furthermore, this theory is explicitly represented in IOs constituent instruments.\n\nSecond, ‘Objective theory’. IOs status as a legal personality cannot be deduced only from the will of the member states but also from possessing specific attributes (Chesterman, 2018). Even though it is not clearly stated in the constituent instrument that IOs have legal personalities, they are practically given the authority to carry out legal acts as subject to international law. This doctrine is known as implied power which means that when states assign a specific role to an IO, states automatically admit to giving the power to the institutions (Guzman and Landsidle, 2008).\n\nAmong various theories on international legal personality, Ian Brownlie has developed a three-part test to identify an entity that has possessed a legal character. The three attributes that must be included are:\n\n1. A permanent association of states, with lawful objects, equipped with organs or institutional structure;\n\n2. A distinction, in terms of legal powers and purposes, between the organization and the states;\n\n3. The existence of legal powers exercises that are available on the international plane and not solely within the national systems of one or more states (Brownlie, 1998).\n\nFrom the myriads theory of international legal personality, this article will employ ‘Will theory’ and the Brownlie test to examine the ASEAN personality. It is crucial to verify ASEAN's character since the status of IOs will be affected by the institution's independence.\n\nBy employing the Brownlie test, each attribute will be used to analyze ASEAN legal standing as an international legal person. ASEAN was deemed had fulfilled all features even before the ASEAN charter was formed in 2007. Since it was formed in 1967, ASEAN has intended to be a permanent organization, as seen in the preamble of the Bangkok Declaration, 1967 (ASEAN, 1967), which states the need to strengthen the bond of regional solidarity and cooperation. Before 1976, ASEAN only had a joint organ that functioned on behalf of its members. Later, after the agreement on the establishment of the ASEAN Secretariat was signed on February 24th, 1976, an autonomous organ separate from member states was fulfilled. The agreement indicates that ASEAN, as an international legal person, has the capacity to make an agreement or legal action with other legal persons, in this case with Indonesia as one of the ASEAN members. In other words, ASEAN exhibits its independence.\n\nDifferentiation between the IOs' and member states' interests has also been seen in the Bangkok Declaration, particularly the aims and purposes part. In this section, ASEAN has seven objectives to pursue: economic, social, peace, and security (ASEAN, 1967). ASEAN objectives explicitly indicate a distinction between member states and ASEAN interests. Finally, ASEAN has also fulfilled the element of power related to carrying out legal acts autonomously. In 1979, through its general secretary, ASEAN made an international agreement with Indonesia related to the immunity and privileges of the ASEAN Secretariat in Jakarta (ASEAN, 1979). Article II of the agreement stipulates that ASEAN can conclude contracts and legal proceedings. It demonstrates a legal person's rights under international law.\n\nHowever, there is still a problem with ASEAN treaty-making practices, mainly when ASEAN agrees with other legal persons. ASEAN rules on treaty-making power raise the question can ASEAN conclude treaties on behalf of its member states?. This issue is important because in several agreements, Secretary-General ASEAN conclude an agreement with third parties on behalf of member states. ASEAN legal instruments remain silent on this issue, even the ASEAN charter. However, theoretically, international law allowed IOs to act on behalf of their members, as stipulated in constituent instruments (Chen, 2014).\n\nBased on the legal doctrine abovementioned, several authors agree with Simon Chesterman that ASEAN had possessed status as a subject of international law even before ASEAN Charter was established. Article 3 of the ASEAN Charter states that ASEAN's legal personality only affirms what already exists.\n\nThe term ‘constitution’ refers to essential norms that regulate political institutions and define their competence, relations between the members and the community, lawmaking, conflict resolution, and law enforcement (Peters, 2009). Furthermore, a constitution has two possibilities meanings: substance (material) and institutional (organic). The latter explains the designation of organization and separation of powers; meanwhile, material aspects define essential legal principles for every one of the subjects belonging to the social community (Breau, 2008).\n\nThe similarity between the domestic legal system and international law is that both consider the constitution as a control device. The function of the constitution in domestic law is to put state objectives and structure, then give the division of power in each state organ so that there will be checks and balances between them. In the international law sense, the constitution becomes a control device because it consists of rules and principles that will guide international relations (Desierto, 2011).\n\nWhen states established IOs, they commonly formed treaties. Such treaties are widely-known as constitutions or constituent instruments. The content of the IOs constitution varies but generally has both institutional frameworks, rules, and substantive prescriptions for the organization's activity. There are unique characteristics of IOs constitutions. It's because every IOs have a different type of constitution for example, ASEAN. Both the Bangkok declaration and the ASEAN charter are different in terms of the status of ASEAN as a legal person. The latter explicitly stipulated it, while the previous was silent on the issue. As the ICJ stated in the ‘Legality of the Use by a State of Nuclear Weapons in Armed Conflict’ advisory opinion (I.C.J., 1996), the IOs constitution is unique because it creates new subjects with certain autonomy to fulfil common goals that member states have relied on the institution (Blokker, 2016).\n\nEven states are primary actors in international relations; they have limited resources to cope with the essential and challenging issues in the international community. To handle this problem, states need to share or delegate their authority to the new actor. In Bradley and Kelley (Guzman and Landsidle, 2008), international delegation is a grant of authority by two or more states to an international body to make decisions or take action. By this delegation, states consider having a risk to their sovereignty. IOs will have the authority to conduct on behalf of member states beyond their control. So that, when states make IO constitutions, they narrow the scope of authority delegated to the institutions. International delegation to IOs can be separated into delegations of legislative power, decision-making authority, and adjudicatory authority (Guzman and Landsidle, 2008).\n\nIn the IOs constituent instrument, member states usually decide what kind of authority that IOs can do. If member states consider giving legislative power, IOs can make rules that bind member states or third parties. In other cases, IOs have the ability to make a sole decision without the interference of member states. This act is purely a capacity that IOs have as a legal person to fulfil their objectives. When a dispute arises between member states or non-member states, sometimes IOs are given the power to settle disputes in a diplomatic or legal mode of settlement. Between these categories of international delegation into IOs, states are reluctant to provide the first category. It makes sense because it will compete with state sovereignty and authority as the primary actor in international relations. The standard type in which State likes to share its power is the IOs authority to adjudicate a dispute between states (Guzman and Landsidle, 2008).\n\nIn this research, the authors agree that the constituent instrument is a tool to distinguish between IOs and member states' interests. However, it also creates a control mechanism for IOs simultaneously. Guzman's categories will be adopted in the case of member states' delegation to the institution. The difference is that this feature will employ to analyze in the context of ASEAN, while previous research did not include ASEAN as a subject of study.\n\nThis paper will be divided into two parts based on time sequence to overlook the delegation process through constituent and legal instruments in the ASEAN. The first part is a pre-ASEAN charter, and the second is when the ASEAN charter exists. This partition is necessary to find if there is a differential allocation of power within ASEAN.\n\nPre-ASEAN Charter\n\nThe two crucial pre-legal instruments of the ASEAN Charter were the Bangkok Declaration, 1967 (ASEAN, 1967) and TAC 1976 (ASEAN, 1976b). Both are broad range topics cooperation instruments. While the Bangkok Declaration of 1967 set the foundation and objectives of ASEAN, TAC was the first legal instrument for ASEAN member states to fulfil its goal through cooperation in broad aspects, from economic to scientific, and handling disputes. These two instruments have standard norms that operate through member states' consultation and consensus, otherwise known as ‘the ASEAN way’ (Chesterman, 2018).\n\nThe 1967 ASEAN Bangkok Declaration was signed on August 8th in Bangkok, Thailand. It consists of narrow institutional machinery governed by the respective foreign ministers at the annual and special Meetings. Those foreign ministers' meetings were key for member states to fulfil ASEAN objectives and convened if required (ASEAN, 1967). Suppose the panel fails to be carried out. ASEAN will set up a semi-permanent administrative cycle of standing committees, ad hoc committees, and permanent committees of specialists to discuss specific issues within ASEAN. All of the committees, working alongside National Secretariats in the ASEAN Member States, which have a task to give services during foreign ministers' meetings (ASEAN, 1967).\n\nIn this first ASEAN constitution, member states explicitly wanted to create a new actor to fulfil ASEAN objectives. As a creature with a simple institutional framework, ASEAN was intentionally made to make cooperation in the region more effective and efficient. However, unlike the general constitution, the substances and institutional framework in the Bangkok Declaration were still modest. In terms of delegation, member states seem reluctant to delegate adjudicatory power but initially give decision-making and legislative authority in a limited manner.\n\nThe TAC was the first legal instrument in the sense of ‘hard law’ (Abbott and Snidal, 2000). ASEAN succeeded in regulating the framework of the closest intergovernmental cooperation on the broadest scale (ASEAN, 1976b). The cooperation in the TAC consists of economic, social, cultural, technical, scientific, administrative, and security issues in the Southeast Asian region. That cooperation is restricted by ASEAN's primary principles of mutual respect for independence, sovereignty, equality, territorial integrity, and national identity of all nations. Its existence is free from external interference, subversion or coercion, non-other means of interference in internal affairs, peaceful settlement, and practical cooperation (ASEAN, 1976b). These principles were part of ASEAN's unique characteristics, usually called ‘the ASEAN way’.\n\nAn essential aspect of the TAC is a provision of pacific settlement of disputes. When a dispute arises, it shall first settle through friendly negotiations at the ministerial level. Suppose negotiations fail and would like to progress within the ASEAN scheme. In that case, a party shall constitute the High Council, comprising of individuals at the ministerial level, to seek solutions (ASEAN, 1976b). In addition, the TAC also introduces another pacific means to settle a dispute through good offices, mediation, inquiry, conciliation, informal or ad hoc third party assistance of a fellow member state, or recourse to the modes of peaceful settlement of disputes under article 33 of the Charter of the United Nations (Charter, 1945; ASEAN, 1976b).\n\nThe first thing that should be noted is that the TAC was not the ASEAN constitution. Although it's made on institutional occasions, Bali Concord 1, the TAC was like other international agreements between states. Bali Concord 1 was the ASEAN important meeting to consolidate and enhance cooperation among member states (ASEAN 1976a).\n\nIt's important to discuss this factor because the TAC was the first legal instrument in terms of hard law for ASEAN. This treaty also shifts policy among ASEAN member states from loose-based intergovernmental organizations into more ‘legal-based’ institutions (Desierto, 2011). It is important to note that ASEAN member states also initiate to delegate some of their authority, particularly in adjudication.\n\nPost-ASEAN charter\n\nThe establishment of the ASEAN Charter in 2007 is a mere crystallization of the legal mindset of ASEAN member states. As clearly stipulated in Article 3 of the ASEAN charter (ASEAN, 2017), ASEAN member states intended to reshape ASEAN as a separate legal entity. Like Bagulaya argues, the constitutionalization of ASEAN under the charter allowed its member states to take advantage of a complete package of control (Bagulaya, 2019), particularly as stipulated in article 7 and 11 of the ASEAN charter that concerns the ASEAN summit and the authority of the Secretary-General.\n\nThe ASEAN Charter provides the Heads of State or governments of the member states with a vital power to decide in summit meetings. All matters within ASEAN will be referred to this forum, where it failed to settle in a lower structure, to get a final decision and decided by consultation and consensus mechanism. Furthermore, they can make relevant decisions in case of an emergency. Summit meetings also can command the relevant Ministers of Inter-Ministerial discussions and address the most significant international organization issues if it required to be tackled. Most importantly, they can raise the problems of realization of ASEAN objectives and other matters related to the interest of member states (ASEAN, 2017).\n\nNot only equipped with executive power, but the ASEAN summit also has judicial and legislative power. The judicial role played by the ASEAN summit can be used to settle disputes, but only those which are categorized as disputes that arise from the breach and interpretation of the charter. The legislative authority of the ASEAN summit can be seen in the provision to authorize the establishment and dissolution of Sectoral Ministerial Bodies and other ASEAN institutions (ASEAN, 2017).\n\nBagulaya (2019) noted that these ASEAN summit provisions act as the international organization's executive, legislative, and quasi-judicial centres. He adds that constitutional controls, in the sense of the separation of powers and checks and balances, are missing in the ASEAN Charter (Bagulaya, 2019).\n\nASEAN member states seem to have broadened delegation to ASEAN in the charter. It covers legislative, decision-making and adjudicative power. However, ASEAN still lacks to act independently as a legal entity because The Summit Meeting still has a crucial position to handle all issues within ASEAN.\n\nThe IOs constitution is a tool for member states to control the organization. The ASEAN Charter gave full authority to a summit meeting in the decision-making process based on ‘consultation and consensus’. This member state voice method brings complete control to states rather than the institution itself.\n\nIn the case of the appointment of the ASEAN secretary-general, the ASEAN Summit also appoints the individual in this role. The secretary-general of the ASEAN role is minimal, only meant to carry out official duties that mainly cover administrative tasks. While this role is presented as an ASEAN symbol in the international forum, the secretary-general should abide by policy guidelines already agreed by member states through summit or head of state/government decisions. Concerning dispute settlement, the ASEAN Secretary-General is given the power to “monitor compliance with findings, recommendations or decisions resulting from ASEAN dispute settlement mechanisms, and submit a report to the ASEAN Summit” (ASEAN, 2017).\n\nThe ASEAN Charter already accommodates an international delegation from member states to institutions. In addition, the authority to make laws, decisions, and adjudication is stipulated in the charter. The problem is that the powerful ASEAN summit hinders those authorities. Considering members of summit meetings are already heads of state or governments means that the given power to ASEAN is practically bounced back to member states. In other words, member states take back the authority after giving it to ASEAN through a constitution mechanism.\n\n\nDiscussion\n\nThe Bangkok Declaration and ASEAN Charter have determined the organization's scope. Suppose, at the beginning of the formation of organizational goals, more emphasis is placed on the regional security sector. In that case, the coverage is broadened by adopting the ASEAN community concept by expanding aspects to become social and political, economic, and social-cultural.\n\nIf we compare this to the Brownlie test (Brownlie, 1998), the Bangkok Declaration and ASEAN Charter clearly state that ASEAN has its own interests. This finding will strengthen ASEAN's position as an international legal personality.\n\nYet, expanding the scope makes the organization's concentration unfocused and has difficulties in working effectively. However, it seems that this is indeed what the member states want. Thus, state control over the organization will be more dominant. Compared to Guzman's opinion, which focuses on how institution design gets their decision, unanimity or voting will control the institution (Guzman and Landsidle, 2008; Guzman, 2013), ASEAN chooses the unanimity model, which gives power back to the member states.\n\nIf this is viewed from the side of the division of power, member states still hold control even though ASEAN has a legal personality of its own. Both pre-and post-ASEAN charter domination of member state power can be seen through the ASEAN Summit and how decisions are made by consultation and consensus methods (ASEAN, 2017). If a dispute occurs in case of breach or implementation, it will be taken to a head of state meeting to decide. Finally, the ASEAN Summit played the role of the executive, legislative, and quasi-judicial (Bagulaya, 2019). ASEAN can indeed agree with another international legal entity, but it is only for administrative purposes. Whereas discussion on the strategic issue, the secretary-general ASEAN on behalf of ASEAN as executive power, does not have authority to decide it. ASEAN seems only a facilitator for settling a dispute in the adjudicative process. When the party fails to resolve the conflicts, ASEAN member states have the dominant power to handle them through the ASEAN Summit forum. It further confirms that ASEAN has no autonomy in practice as a legal subject.\n\nConcerning the capacity of the ASEAN general secretariat, ASEAN Charter also limited its function. Ideally, as a representative of an institution, the secretary-general brings the institution's objective that possibly differs from member states. Unfortunately, when the ASEAN secretary-general plays its role, it shall be according to the policy given and mandate made by member states (ASEAN, 2017; Bagulaya, 2019).\n\nWhen looking at the ASEAN constituent instruments pre-ASEAN Charter and post, it seems that ASEAN is still under the control of the member states. Even in the ASEAN Charter, transfer of authority is explicitly stipulated, but the real power remains under ASEAN member states. Analogous to the Frankenstein metaphor, ASEAN does not turn into a monster.\n\n\nConclusion\n\nIn summary, it can be seen that ASEAN cannot become a monster outside of the creator's control, as in the Frankenstein dilemma. As seen through the ASEAN constituent and legal instruments, ASEAN member states have maintained their control of ASEAN by creating structures that hold its power from the very beginning of its formation. So the member states' control over ASEAN has its legitimacy because it gains through the rule of law. This research also contributes to how ASEAN can be more autonomous as an international legal person. This can happen by amending the ASEAN Charter, particularly on the decision-making process and role of secretary-general norms. It's essential to amend both standards to reduce member state control over the organization so ASEAN can fulfil its objectives without interference from member states.\n\nAs mentioned earlier, this research has limitations as it only analyses norms in the Bangkok Declaration, TAC, and ASEAN Charter to examine how ASEAN member states remain to have their power over the organization. This research tries to fill the gap from previous research, which only uses the ASEAN Charter to show that ASEAN was under its member's control. Further research can be conducted by adding other ASEAN legal instruments to this analysis to get broader coverage on the same issues to complement this research.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
"appendix": "Acknowledgement\n\nThe authors would like to express their deepest gratitude to the faculty for their supportive attitude and Universitas Islam Bandung [UNISBA] for fully funding this research.\n\n\nReferences\n\nAbbott KW, Snidal D: Hard and Soft Law in International Governance. International Organization. 2000; 54(3): 421–456. Publisher Full Text\n\nASEAN: THE ASEAN DECLARATION (Bangkok Declaration). 1967. Publisher Full Text\n\nASEAN: 1976 Declaration of ASEAN Concord.1976a; no. February: 1–6.\n\nASEAN: Treaty Of Amity and Cooperation. ASEAN Secretariat; 1976b. Reference Source\n\nASEAN: ASEAN Secretariat Agreement. 1979.\n\nASEAN The ASEAN Charter. ASEAN 50. ASEAN Secretariat; 2017.\n\nBagulaya JD: ASEAN as Wayang Kulit: A Critique of the Constitutional, Extra-Constitutional, and Practical Fetters of ASEAN. Asian Journal of International Law. 2019; 9(2): 275–297. Publisher Full Text\n\nBlokker N: Constituent Instruments. Oxford Handbook of International Organizations. Hurd I, Jacob IJ, Cogan K, editors. London: Oxford University Press; 2016; 943–961.\n\nBreau SC: The Constitutionalization of the International Legal Order. Leiden Journal of International Law. 2008; 21(2): 545–561. Publisher Full Text\n\nBrownlie I: Principles of Public International Law. Clarendon Press; 1998.\n\nCharter, UN: UN Charter 1945. 1945.\n\nChen Z: ASEAN and Its Problematic Treaty-Making Practice: Can International Organizations Conclude Treaties on Behalf of Their Member States?. Asian Journal of International Law. 2014; 4(2): 391–419. Publisher Full Text\n\nChesterman S: Does ASEAN Exist? The Association of Southeast Asian Nations as an International Legal Person. ASEAN. 2018; (May): 18–44. Publisher Full Text\n\nCollins R: How to Defend International Legal Method?. Research Methods in International Law: A Handbook. Deplano NTR, editor. Edward Elgar Publishing; 2021; 9–26.\n\nDesierto DA: ASEAN’S Constitutionalization of International Law: Challenges to Evolution under the New ASEAN Charter. Columbia Journal of Transnational Law. 2011; 49.\n\nGuzman A: International Organizations and the Frankenstein Problem. European Journal of International Law. 2013; 24(4): 999–1025. Publisher Full Text\n\nGuzman AT, Landsidle J: The Myth of International Delegation. California Law Review. 2008; 96(6): 1693–1723. Publisher Full Text\n\nI.C.J.: Legality of the Use by a State of Nuclear Weapons In Armed Conflict. I.C.J. Reports. 1996. 1996 (July); 6. Reference Source\n\nICJ: Reparations for Injuries Advisory Opinion.1949; 19.\n\nKlabbers J: Constitutionalism Lite. International Organization Law Review. 2004; 1: 31–58. Publisher Full Text\n\nKlabbers J: Introduction to International Institutional Law. Cambridge: CUP; 2009.\n\nLieblich E: How to Do Research in International Law? A Basic Guide for Beginners. SSRN Electron. J. 2020. Publisher Full Text\n\nPeters A: Indiana Journal of Global Legal Studies The Merits of Global Constitutionalism The Merits of Global Constitutionalism. Indiana Journal of Global Legal Studies. 2009; 16(2): 397–411. Publisher Full Text Reference Source\n\nShelley M: Frankenstein. London: Arcturus Publishing; 2010."
}
|
[
{
"id": "137128",
"date": "26 May 2022",
"name": "Tan Hsien-Li",
"expertise": [
"Reviewer Expertise Public international law",
"international organizations",
"ASEAN law and policy."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe theoretical and legal methodological framework sound good but unfortunately the thesis underdelivers as the content is too thin. My advice for the authors, if they wish retain to the research they've put in - which is fair, and sound - is to:\nOverhaul the research question along the lines of \"the enduring intergovernmental character of ASEAN\" and rewrite the thesis accordingly.\n\nAs ASEAN is an intergovernmental organization - not a supranational one - there will never be a Frankenstein moment. As such, discussion of the \"Frankenstein dilemma\" should not be the main focus of the article and should be removed\n\nExpand the ASEAN instruments examined -- the Bangkok Declaration and ASEAN Charter are of course compulsory. But to analyse only the TAC without looking at other important ASEAN instruments displays an obvious research lacuna. ASEAN has adopted hundreds of legal instruments so the focus on the TAC is highly questionable.\n\nA solid essay on ASEAN's intergovernmental character informing scholars and practitioners within and without the region would hold value.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "137845",
"date": "07 Jun 2022",
"name": "Koesrianti Koesrianti",
"expertise": [
"Reviewer Expertise International law",
"ASEAN law and International Dispute Resolution"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article addresses the Frankenstein dilemma for ASEAN, whether ASEAN will become a monster that has its objectives separate from the will of ASEAN Member States (AMS) as its creator. The authors use a legal research method of descriptive-analytical to examine the ASEAN constitutional instruments, namely, the ASEAN Declaration 1967, the ASEAN Charter 2007, and the Treaty of Amity and Cooperation 1976 (TAC). The author noted the TAC is not constituted as an ASEAN constitution, it is merely the first legal instrument of ASEAN hard law so that it is an important legal document for ASEAN. Basically, this article addresses an important topic and will become a complimentary idea of previous works on ASEAN as several articles have questioned the ASEAN as a rule-based organization after the ASEAN Charter entered into force in 2008.\nThis article only examines three ASEAN legal instruments, despite this limitation of the object of research, it should make an important contribution to the issue of ASEAN as a rule-based organization, especially the relationship between ASEAN as an organization and the AMS. In this context, the AMS indeed has created ASEAN as a new actor with a narrow scope of authority as basically, the AMS does not fully delegate their authority to ASEAN as AMS chooses the consensus for decision making.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-502
|
https://f1000research.com/articles/9-1200/v1
|
06 Oct 20
|
{
"type": "Research Article",
"title": "Thank Martin Luther that ciprofloxacin could cure your gonorrhoea? Ecological association between Protestantism and antimicrobial consumption in 30 European countries",
"authors": [
"Chris Kenyon",
"Geoffrey Fatti",
"Geoffrey Fatti"
],
"abstract": "Background: Higher consumption of antimicrobials plays an important role in driving the higher prevalence of antimicrobial resistance in Southern compared to Northern Europe. Poor controls on corruption (CoC), high uncertainty avoidance (UA) and performance vs. cooperation orientation (POCO) of societies have been found to explain much of this higher consumption in Southern European countries. We hypothesized that these predictors were in turn influenced by the Protestant Reformation in the 16th century onwards. Methods: We used structural equation modelling (SEM) to assess the relationships between country-level proportions being Protestant, CoC, UA, POCO and four markers of antimicrobial consumption in the community (all antibacterials, cephalosporin, macrolides and fluoroquinolones). Results: The proportion of a country that was Protestant was negatively correlated with the consumption of all antibacterials. SEM revealed that UA predicted all antibacterial consumption (direct effect coef. 0.15, 95% Confidence Interval [CI] 0.04-0.26). The proportion Protestant exerted an indirect effect on consumption (coef. -0.13, 95% CI -0.21- -0.05). This effect was mediated predominantly via its effect on UA (direct effect coef. 0.15, 95% CI 0.04-0.26). The model explained 37% of the variation in consumption. Similar results were obtained for each of the other three classes of antimicrobials investigated. Conclusions: Our results are compatible with the theory that contemporary differences in antimicrobial consumption in Europe stem in part from cultural differences that emerged in the Reformation. These findings may explain the differential efficacy of similar antibiotic stewardship campaigns in Northern and Southern European populations.",
"keywords": [
"antibiotic consumption",
"antimicrobial resistance",
"culture",
"Hofstede model",
"Protestant",
"Catholic",
"spandrel"
],
"content": "Introduction\n\nCountries in Southern Europe have been noted for some time to have a higher prevalence of antimicrobial resistance (AMR) than Northern European countries1,2. As an example, the prevalence of Neisseria gonorrhoeae resistance to ciprofloxacin varies over three fold between countries in Europe3.\n\nThe major determinant of these variations in AMR is the higher consumption of antimicrobials (AMC) in Southern European countries3,4. Fluoroquinolone consumption for example varies 6-fold between European countries and is associated with the prevalence of ciprofloxacin resistance in N. gonorrhoeae3. What is less clear is what the underlying reason is for the variations in AMC4,5.\n\nPrevious studies have found a range of cultural and structural factors underpin the large variations in the consumption of fluoroquinolone and other antibiotics between European countries and globally5–10. The act of prescribing an antimicrobial is highly social. Providing an antimicrobial represents the doctor’s concern for the patient, legitimizes the patient’s sick-role and reinforces the doctor’s claim to expert knowledge8,10–13. These vary between countries as do patients perceptions of the need for antimicrobials to treat infections8,11,13,14. One study compared a Dutch and Belgian city, 60km apart, both Dutch speaking but the two cities being historically Protestant and Catholic, respectively14. Where the Dutch labelled their upper respiratory tract infections (URTI) as ‘colds’ or ‘flu’ the Belgians labelled most episodes as ‘bronchitis’ and used more antimicrobials. In general, the researchers found that those from a Protestant background were more sceptical about using antimicrobials than those from Catholic backgrounds. This type of observation has led to some authors to speculate that there may be a negative association between the proportion of a country that is Protestant and antimicrobial consumption2,12,15. Others have contested this claim11, but no one has, to the best of our knowledge, formally tested this association. In this paper, we test the hypothesis that the proportion of a country’s population that are reported to be Protestant is negatively associated with AMC in Europe. Furthermore, we assess if the pathway through which this operates is via cultural and structural factors associated with Protestantism and AMC.\n\nTwo cultural dimensions have consistently been found to explain variations in AMC both within Europe and worldwide5–8,13,14,16. These are Hofstede’s uncertainty avoidance index (UA) and performance-orientation versus cooperation-orientation index (POCO)5–8,13,14,16. Both indices are negatively associated with both the proportion of a country that is Protestant17 and AMC5–8,16. The UA index is a measure of the extent to which a society feels threatened by ambiguous or unknown situations. In high UA cultures, individuals feel discomfort and stress in unstructured situations that are novel15. The POCO index (also termed the masculinity index) provides a measure of how performance-oriented cultures are. In high POCO cultures ego needs, assertiveness, targets and success are emphasized, whereas cooperation-oriented cultures place more focus on caring for all members of society, including the weak14. An important reason not to take an antibiotic for an illness such as an URTI is that this will select for AMR – an adverse effect for the population at large. It has been argued that this low-POCO populations are more receptive to this population-benefit message than high POCO-populations8,18.\n\nThe key structural factor found to be associated with AMC is control of corruption (CoC) at country and regional levels19,20. Countries with high levels of corruption (low CoC) have poorer institutional controls on prescribing practices and greater influence of pharmaceutical companies both of which can result in increased AMC12,19,20. Previous ecological studies have found associations between national level CoC, UA, POCO and the proportion of the country being Protestant7,8,13,16,21. Multivariate country-level studies from within Europe and elsewhere have also found that UA and POCO7,8,18,22 are predictors of AMC and an additional study has found that UA, POCO and CoC are independently associated with AMC16. In this ecological study we use structural equation modelling to assess the association between countries’ population proportions being protestant and AMC, modelling UA, POCO and CoC as potential mediating variables.\n\n\nMethods\n\nAntibiotic consumption. Data from the European Surveillance of Antimicrobial Consumption (ESAC) were used as a measure of national general population-level antimicrobial drug consumption23,24. ESAC reports antimicrobial consumption as the number of defined daily doses per 1000 inhabitants (DID) following the World Health Organization guidelines25. In our study, we used four measures of country-specific antimicrobial drug use in ambulatory care: Total antibacterials for systemic use (ATC group J01), Cephalosporins/other Beta lactams (ATC group J01D), fluoroquinolones (ATC group J01MA), macrolides, lincosamides and streptogramins (ATC group J01F). Data was available from 1998 to 2018 and we used this data to calculate the peak consumption of each of these four classes of antimicrobial over this time period. All countries with available data were used in all the analyses. This data is available from ESAC without restrictions: https://www.ecdc.europa.eu/en/antimicrobial-consumption/database/quality-indicators\n\nPercent protestant. The proportion of a national population that was protestant was sourced from the Pew Research Centre estimates for 2010: https://www.pewforum.org/2011/12/19/table-christian-population-as-percentages-of-total-population-by-country/\n\nUA and POCO. Individual scores for UA and POCO were obtained for each country from Hofstede Insights, freely available from (https://www.hofstede-insights.com/product/compare-countries/) is denoted as masculinity on the website.\n\nControl of corruption. The World Bank has provided indicators pertaining to six dimensions of governance since 1996. We used the dimension (control of corruption) that has been found to be most closely linked to AMC12,16,17: Control of corruption (CoC) is defined as the country-level extent to which public power is exercised for private gain, including both petty and grand forms of corruption, as well as the capture of the state by elites. The index provides each country's score in units of standard normal distribution, ranging from approximately -2.5 (low CoC) to 2.5 (high CoC). The values used are average scores for the years 2013 to 2015, which we calculated from the original data, which was obtained from the following site: http://datatopics.worldbank.org/world-development-indicators/.\n\nA correlation matrix was performed to investigate the relationship between the different variables hypothesized to be associated with AMC. This approach was complemented by scatterplots of the associations between percent Protestant and AMC. We used structural equation modelling (SEM) to analyse the factors predicting AMC. SEM provided a way to analyse and graphically represent the complex direct and indirect pathways between endogenous and exogenous variables. All variables were assessed for non-linearity. No transformation was necessary. The analyses were performed using the SEM-builder in STATA 16. A P-value of less than 0.05 was used as the threshold of statistical significance.\n\n\nResults\n\nComplete data was available for 29 of 30 countries with AMC data in the ESAC database (Table 1). Data for UA and POCO were missing for Cyprus. Peak total antibacterial consumption varied fourfold between 10.1 DID in the Netherlands and 40.4 DID in Greece (median 21.2 [IQR 16.7-23.9]; Table 2).\n\nSignificance levels are highlighted by * for P<0.05, ** for P<0.005. Abbreviations: All AB – All antibacterials, CoC – Control of Corruption; UA- Uncertainty Avoidance Index; POCO – Performance Oriented vs. Cooperation Oriented society.\n\nThe proportion of a country that was Protestant was negatively correlated with the consumption of all antibacterials (r= -0.38; P=0.041), cephalosporins (r= -0.59; P=0.001), macrolides (r= -0.50; P=0.005) and fluoroquinolones (r= -0.53; P=0.003) as well as UA (r= -0.69; P<0.001) and POCO (r= -0.46; P=0.012). It was also positively associated with CoC (r= 0.67; P<0.001; Table 2; Figure 1). UA was positively correlated with all four categories of AMC (all r≥ 0.55; P<0.005) and negatively associated with CoC (r= -0.62; P<0.001). POCO was correlated with three of four categories of AMC and also negatively associated with CoC (r= -0.37; P=0.049). CoC was negatively associated with all four categories of AMC (all r < -0.43; P<0.05).\n\nScatter diagrams of percent of a country that is Protestant and consumption (defined daily doses/ 1000 individuals/ day – DID) of all antibacterials (a), cephalosporins (b), macrolides (c) and fluoroquinolones (d) in 30 European countries.\n\nStructural equation modelling revealed that UA predicted community antimicrobial consumption (direct effect coef. 0.15, 95% Confidence Interval [CI] 0.04-0.26; Figure 2; Extended Data). The percent Protestant exerted only an indirect effect on consumption (coef. -0.13, 95% CI -0.21- -0.05; Extended Data). This effect was mediated predominantly via its effect on UA (direct effect coef. 0.15, 95% CI 0.04-0.26). The model explained 37% of the variation in consumption ().\n\nStructural equation modelling of predictors of consumption of total antibacterials (a), cephalosporins (b), macrolides (c) and fluoroquinolones. The numbers next to the arrows are coefficients and their significance is indicated as follows: * P<0.05, ** P<0.005 (Abbreviations: All AB – All Antibacterial consumption; Ceph – Cephalosporins, CoC – Control of Corruption, Macro – Macrolides; POCO – Performance Oriented vs. Cooperation Oriented Index; Quin – Fluoroquinolones; UA - Uncertainty Avoidance Index).\n\nThe SEM analysis found that the consumption of each class of antimicrobial was positively associated with UA and POCO (Figure 2; Extended Data). Only in the case of POCO predicting fluoroquinolone consumption was this association not statistically significant (Figure 2; Extended Data). Once again, the percent Protestant only exerted an indirect effect on AMC. This effect was mediated by UA and POCO both of which were negatively associated with percent Protestant. For each class of antimicrobial, the effect of UA explained the greatest proportion of variation in consumption (Extended Data). Overall the models explained 52% to 61% of the variation in consumption (Extended Data).\n\n\nDiscussion\n\nOur results recapitulate those from other studies that UA and, to a lesser extent, POCO mediate a considerable proportion of the variation of AMC in Europe6,8,10,16. Whilst percent Protestant has little to no direct effect on AMC, our analysis found it has an indirect effect via its negative association with UA and POCO. The fact that this effect was similar for all 4 categories of antimicrobials investigated makes this finding more robust.\n\nThese results are compatible with the theory that the profound rupture in European society in the 16th century induced by the Reformation may have had enduring effects that explain a portion of the contemporary variations in antimicrobial consumption between European countries. Our study provides evidence supportive of the thesis that this effect is mediated via Protestantism’s effect on two cultural variables – UA and POCO.\n\nThe reason that predominantly Catholic countries have higher UA and POCO scores is not clear, but may be related to factors such as the rituals and certainty-of-Faith that have characterized Catholicism11,14,17,26. It has been argued that Protestant teaching provided less certainty-of-Faith, encouraged more discussion, discouraged rituals, promoted austerity/simplicity and placed the locus of control less in the priest or church but in each individual12,17,26. Protestant populations may therefore be more tolerant of uncertainty, have less faith in quick fix solutions and be more amenable to discussions about therapeutic strategies not involving antibiotics12,17. Protestants have also been found to have more trust in the ‘self-healing power of the body’, which has in turn been found to be correlated with scepticism towards the use of antibiotics14. Both patients and doctors in historically Protestant, low-UA populations may therefore be more receptive to antibiotic stewardship messages that strongly discourage antibiotics for infections such as URTIs2. High-UA societies on the other hand, may be less receptive to stewardship messages due to the uncertainty of ‘what if the URTI is caused by a bacterial infection?’4,8,10.\n\nThere are a number of important limitations to this analysis. We should be extremely guarded about drawing causal inferences concerning processes hundreds of years ago based on contemporary data from a small selection of countries. We did not control for possible confounders in the association between proportion of the population Protestant and AMC. We did not control for socio-economic markers such as GDP/capita as previous analyses have found that these did not explain differences in AMC within Europe16,18. Our sample size was also too small to justify controlling for a large range of confounders. There are a number of fundamental problems with classifying countries by religion. To an important extent, countries have a fluid mix of particular religions and both the relative sizes of the religions and the nature of these religions vary over time26. There are also considerable differences within a religion such as differences between Catholicism in different countries and regions17. This problem is compounded by our percent-Protestant-variable which combines a heterologous group of Catholic, Orthodox and other groups into one non-Protestant category. This classification could, however, be defended since our hypothesis is that low AMC was a byproduct (spandrel) of the Protestant Reformation. This line of thought is strengthened by a European study that found that the percent of the population describing themselves as atheist as opposed to religious was strongly associated with lower AMC9. The study did not include a religious denomination variable but the authors noted evidence that secularization has been more pronounced in historically Protestant countries26 and concluded that the lower AMC in these countries may be indirectly related to Protestantism. We considered reverse causation unlikely, but this cannot be excluded. Finally, the various dimensions of Hofstede’s model have been criticized as being over-simplifications of cultural differences27.\n\nA spandrel is an architectural term referring to the tapering triangular space formed by the intersection of two rounded arches at right angles28. Gould argued that “evolutionary biology needs such an explicit term (spandrels) for features arising as by-products, rather than adaptations, whatever their subsequent exaptive utility…Causes of historical origin must always be separated from current utilities; their conflation has seriously hampered the evolutionary analysis of form in the history of life”28. Previous analyses have found evidence of a range of spandrels exerting their effects hundreds of years later29,30. One example comes from Southern Africa, where differential HIV prevalence by ethnic group has been linked to distant historical processes. A number of colonial policies that were imposed on indigenous ethnic groups practicing polygamous partnering resulted in dense sexual networks that facilitated the spread of HIV in these groups hundreds of years later29,31. In contrast, Southern African ethnic groups from European origin have low sexual network connectivity and HIV prevalence. This low connectivity stems primarily from historical processes in Europe many centuries prior that resulted in forms of monogamous partnering being normative29. Appreciating this historical connection has been shown to have three major benefits. Firstly, it provides an explanation as to how dramatic differences in behaviour and disease outcome can emerge. Secondly, it provides clues to the high HIV-prevalence populations as to how to tackle the underlying determinants of high prevalence. Thirdly, it does this in a non-judgemental way. Contemporary populations cannot be held responsible for events and processes occurring centuries prior29.\n\nSimilar arguments could be made as to the relevance of the current analysis. It provides a possible deep historical explanation for how differences in AMC have emerged in Europe. It suggests that the lower AMC in predominantly Protestant countries could be explained by cultural differences that emerged in a process starting centuries ago. If this is correct, then this insight should generate greater understanding for how much harder antibiotic stewardship work is in non-Protestant countries. This is not an argument that stewardship is impossible or should not be attempted, but rather that campaigns might need to be more intense to achieve the same outcomes. It also provides further evidence that stewardship efforts need to be adapted to the local cultural context6,7. A concrete example of this would be to incorporate rapid diagnostic tests (that can remove uncertainty about bacterial infections) as a part of stewardship campaigns in high UA populations7. If evidence were to come to light of ways to decrease uncertainty avoidance and favour cooperation- vs. performance-orientation these may also be considered as upstream interventions to reduce AMC.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nFigshare: Thank Martin Luther that ciprofloxacin could cure your gonorrhoea? Ecological association between Protestantism and antimicrobial consumption in 30 European countries, https://doi.org/10.6084/m9.figshare.12994439.v132.\n\nThis project contains the following extended data:\n\n- SEM models and estimates of Goodness of Fit\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nGoossens H, Ferech M, Vander Stichele R, et al.: Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005; 365(9459): 579–87. PubMed Abstract | Publisher Full Text\n\nBaquero F, Baquero-Artigao G, Canton R, et al.: Antibiotic consumption and resistance selection in Streptococcus pneumoniae. J Antimicrob Chemother. 2002; 50 Suppl S2: 27–37. PubMed Abstract | Publisher Full Text\n\nKenyon C, Buyze J, Spiteri G, et al.: Population-level antimicrobial consumption is associated with decreased antimicrobial susceptibility in Neisseria gonorrhoeae in 24 European countries: an ecological analysis. J Infect Dis. 2020; 221(7): 1107–1116. PubMed Abstract | Publisher Full Text\n\nBell BG, Schellevis F, Stobberingh E, et al.: A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect Dis. 2014; 14: 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBorg MA: National cultural dimensions as drivers of inappropriate ambulatory care consumption of antibiotics in Europe and their relevance to awareness campaigns. J Antimicrob Chemother. 2012; 67(3): 763–7. PubMed Abstract | Publisher Full Text\n\nBorg MA: Prolonged perioperative surgical prophylaxis within European hospitals: an exercise in uncertainty avoidance? J Antimicrob Chemother. 2014; 69(4): 1142–4. PubMed Abstract | Publisher Full Text\n\nBorg MA, Camilleri L: Broad-spectrum antibiotic use in Europe: more evidence of cultural influences on prescribing behaviour. J Antimicrob Chemother. 2019; 74(11): 3379–83. PubMed Abstract | Publisher Full Text\n\nDeschepper R, Grigoryan L, Lundborg CS, et al.: Are cultural dimensions relevant for explaining cross-national differences in antibiotic use in Europe? BMC Health Serv Res. 2008; 8: 123. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBlommaert A, Marais C, Hens N, et al.: Determinants of between-country differences in ambulatory antibiotic use and antibiotic resistance in Europe: a longitudinal observational study. J Antimicrob Chemother. 2014; 69(2): 535–47. PubMed Abstract | Publisher Full Text\n\nTouboul-Lundgren P, Jensen S, Drai J, et al.: Identification of cultural determinants of antibiotic use cited in primary care in Europe: a mixed research synthesis study of integrated design \"Culture is all around us\". BMC Public Health. 2015; 15: 908. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarbarth S, Monnet DL: Cultural and socioeconomic determinants of antibiotic use. Antibiotic policies: fighting resistance: Springe. 2008; 29–40. Publisher Full Text\n\nHulscher MEJL, Grol RPTM, van der Meer JWM: Antibiotic prescribing in hospitals: a social and behavioural scientific approach. Lancet Infect Dis. 2010; 10(3): 167–75. PubMed Abstract | Publisher Full Text\n\nHarbarth S, Albrich W, Brun-Buisson C: Outpatient antibiotic use and prevalence of antibiotic-resistant pneumococci in France and Germany: A sociocultural perspective. Emerg Infect Dis. 2002; 8(12): 1460–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeschepper R, Vander Stichele RH, Haaijer-Ruskamp FM: Cross-cultural differences in lay attitudes and utilisation of antibiotics in a Belgian and a Dutch city. Patient Educ Couns. 2002; 48(2): 161–9. PubMed Abstract | Publisher Full Text\n\nKooiker S, Van der Wijst L: Europeans and their medicines. Dongen, The Netherlands: Social and Cultural Planning Office of The Netherlands. 2003.\n\nGaygisiz U, Lajunen T, Gaygisiz E: Socio-economic factors, cultural values, national personality and antibiotics use: A cross-cultural study among European countries. J Infect Public Health. 2017; 10(6): 755–60. PubMed Abstract | Publisher Full Text\n\nHofstede G, Hofstede GJ, Minkov M: Cultures and organizations: Software of the mind. New York: McGraw Hill Professional; 2010. Reference Source\n\nKenyon C, Manoharan-Britto S: Cultural Drivers of Antibiotic Consumption in High-Income Countries - A Global Ecological Analysis. Microbial Drug Resis. In Press. Publisher Full Text\n\nRönnerstrand B, Lapuente V: Corruption and use of antibiotics in regions of Europe. Health Policy. 2017; 121(3): 250–6. PubMed Abstract | Publisher Full Text\n\nCollignon P, Athukorala PC, Senanayake S, et al.: Antimicrobial Resistance: The Major Contribution of Poor Governance and Corruption to This Growing Problem. PLoS One. 2015; 10(3): e0116746. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHusted BW: Wealth, culture, and corruption. J Int Bus Stud. 1999; 30(2): 339–59. Publisher Full Text\n\nMackenbach JP: Cultural values and population health: a quantitative analysis of variations in cultural values, health behaviours and health outcomes among 42 European countries. Health Place. 2014; 28: 116–32. PubMed Abstract | Publisher Full Text\n\nEuropean Centre for Disease Prevention and Control: Annual epidemiological report for 2015. Antimicrobial Consumption. Stockholm: ECDC. 2018. Reference Source\n\nVander Stichele RH, Elseviers MM, Ferech M, et al.: European surveillance of antimicrobial consumption (ESAC): data collection performance and methodological approach. Br J Clin Pharmacol. 2004; 58(4): 419–28. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO Collaborating Centre for Drug Statistics Methodology: Guidelines for ATC classification and DDD assignment 2020. Oslo, Norway: Norwegian Institute of Public Health. 2020. Reference Source\n\nDavie G: Religion in modern Europe: A memory mutates. OUP Oxford; 2000. Reference Source\n\nMcSweeney B: Hofstede’s model of national cultural differences and their consequences: A triumph of faith-a failure of analysis. Human relations. 2002; 55(1): 89–118. Publisher Full Text\n\nGould SJ, Lewontin RC: The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc R Soc Lond B Biol Sci. 1979; 205(1161): 581–98. PubMed Abstract | Publisher Full Text\n\nKenyon C, Zondo S: Why do some South African ethnic groups have very high HIV rates and others not? Afr J AIDS Res. 2011; 10(1): 51–62. PubMed Abstract | Publisher Full Text\n\nVoigtlander N, Voth HJ: Persecution Perpetuated: The Medieval Origins of Anti-Semitic Violence in Nazi Germany. Q J Econ. 2012; 127(3): 1339–92. Publisher Full Text\n\nDelius P, Glaser C: The myths of polygamy: a history of extra-marital and multi-partnership sex in South Africa. South African Historical Journal. 2004; 50(1): 84–114. Publisher Full Text\n\nKenyon C: Thank Martin Luther that ciprofloxacin could cure your gonorrhoea? Ecological association between Protestantism and antimicrobial consumption in 30 European countries. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.12994439.v1"
}
|
[
{
"id": "79088",
"date": "03 Mar 2021",
"name": "Christoph M. Tang",
"expertise": [
"Reviewer Expertise Microbial pathogenesis and virulence"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting and somewhat provocative paper that shows a relationship between events several hundred years ago and current use of antimicrobials.\nThe authors show a link between the consumption of antimicrobials in a given country and the prevalence of Protestantism.\nAs the authors correctly acknowledge in their discussion, studies of this nature cannot derive causal relationships (and only highlight associations) and they acknowledge that many potential confounding factors are likely to be at play. They did not control for socio-economic markers (eg GDP), reasoning that 'these did not explain differences in AMC within Europe'. Whilst this might be true when considering socioeconomic factors on their own, it does not mean that these factors would not impact findings when incorporated into a multivariate analysis. The authors also discuss the multiplicity of faiths within many individual countries (which report overall antibiotic consumption levels and not levels according to religion) and how the practice and teaching of the same religion can differ between countries (There are also considerable differences within a religion such as differences between Catholicism in different countries and regions).\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "76564",
"date": "04 May 2022",
"name": "Peter J Collignon",
"expertise": [
"Reviewer Expertise Microbiology",
"Infectious diseases",
"Antimicrobial resistance"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting paper with the thesis being that a Catholic tradition will result in higher use of antimicrobials than having a protestant background. While there appears to be an association using the limited parameters looked at in this study, that is very different from being able to infer any cause-and-effect relationship, however. The countries looked at that are “protestant” are generally colder as well. So maybe temperature has as big an effect. Or do those with a catholic tradition have more sexual encounters than those of a protestant background – especially as the focus is on gonococcus? But these and many other parameters were not measured to see what influence, if any, they might have in their correlation analysis. They only looked at a few parameters to assess the relationship with Antimicrobial consumption; poor controls on corruption (CoC), high uncertainty avoidance (UA) and performance vs. cooperation orientation (POCO) and proportion of a population that was protestant. These are not enough parameters given the complexities involved with antimicrobial resistance and consumption (e.g. many more parameters were looked at by Collignon P, Beggs JJ, Walsh TR, Gandra S, Laxminarayan R, in Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysis. Lancet Planet Health. 2018 https://www.sciencedirect.com/science/article/pii/S2542519618301864?via%3Dihub)1 It is important to note that even of the limited parameters they looked at, the percent Protestantism, was the least associated parameter with antimicrobial use. As they note “Once again, the percent Protestant only exerted an indirect effect on AMC. This effect was mediated by UA and POCO both of which were negatively associated with percent Protestant. For each class of antimicrobial, the effect of UA explained the greatest proportion of variation in consumption.” In a paper entitled “Corruption and use of antibiotics in regions of Europe” (their reference 19), Rönnerstrand, and Lapuente show that within countries in Europe, there are marked variations by regions and presumably not likely influenced by the percent of that country’s population that were protestant, as it also occurs within countries where there is little Protestantism e.g., Italy. What did correlate, however, were the local levels of corruption. This again is what these authors have shown in their data. So, in summary, the authors (Kenyon and Fatti) did show an association with Protestantism and antimicrobial consumption, but even though they only looked at limited parameters, their own data suggest religion itself plays little part in any cause and effect. It appears that lower consumption of antimicrobials is likely very much more associated with regions that have better governance and lower corruption rates, rate than their conclusion of cultural differences that emerged in the Reformation.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8194",
"date": "10 May 2022",
"name": "Chris Kenyon",
"role": "Author Response",
"response": "We thank the reviewer for their useful comments. We agree that we need to be very careful with the conclusions we draw from this study for all the reasons outlined by the reviewer. We acknowledge that the Collignon et al., paper referred to by the reviewer is one of the most definitive ecological analyses of the drivers of AMR globally. This is however different to our research questions which were: what are the determinants of antimicrobial consumption (AMC), is the percent of a countries population that is Protestant associated with AMC and if so is this association a direct or an indirect one (via UA, POCO or CoC)? As the reviewer notes, we find that there is a weak positive association and the effect is indirect- acting via UA and POCO. One parsimonious explanation for these findings is that an upstream determinant of UA and POCO is the percent of the population that is Protestant. As we note in the discussion, while we cannot prove that this is the causal pathway, this is at least a plausible way to interpret the data. To the best of our knowledge, this is the first time that statistical evidence has been produced to back up the percent Protestant-POCO/UA-AMC pathway. Once again we have endeavoured in our discussion to make it very clear that whilst we find some statistical support for this pathway, this does not constitute strong evidence that this pathway played any role in the genesis of differential levels of AMC in European countries. To address the reviewer's valid concerns, we have added the Collignon et al. reference and the following text in the discussion (4th paragraph): We also did not control for differences in environmental temperatures. Southern European countries tend to be both hotter and more Catholic than Northern European countries. A previous ecological study has found that environmental temperature is associated with the prevalence of certain types of antimicrobial resistance 33"
}
]
}
] | 1
|
https://f1000research.com/articles/9-1200
|
https://f1000research.com/articles/11-440/v1
|
20 Apr 22
|
{
"type": "Research Article",
"title": "Determinants of patient behavioural loyalty on primary health centres: Evidence from a cross-sectional study in Indonesia",
"authors": [
"Mardaleta Mardaleta",
"Abdul Rahman Lubis",
"Yossi Diantimala",
"Heru Fahlevi",
"Mardaleta Mardaleta",
"Abdul Rahman Lubis",
"Yossi Diantimala"
],
"abstract": "Background: Patients’ loyalty to visit and use the services provided by the primary health centers (PHCs) is an important requirement of a patient referral system in many countries. The aim of this study was to examine the influence of internal service factors (service provider, service process, and service environment) on service quality and behavioural loyalty of patients in Indonesian PHCs (Puskesmas). Methods: A cross-sectional study was conducted in 14 districts in Aceh Province, Indonesia between September and December 2020. Data were collected in 102 PHCs that were selected randomly from 137 PHCs that have an Inpatient Unit in the province. The demographic data, three components of internal service factors (service provider, service process, and service environment), the service quality and behavioural loyalty were assessed using a validated questionnaire. Hypothesis testing was conducted by using the structural equation model (SEM). Results: Our data suggested that two elements of internal service factors (service provider and service environment) had a positive and significant influence on service quality of the PHCs with p<0.001 and p=0.021, respectively. Service quality had a positive and significant influence of behavioural loyalty of patients to the PHCs (p=0.003). Service quality however did not serve as an intervening variable between internal service factors (service provider, service process, and service environment) and behavioural loyalty of patients, with p=0.091, p=0.230 and p=0.260, respectively. Conclusions: Service provider and service environment are two main factors that influence the service quality and the service quality directly influence the behavioural loyalty on PHC users. Therefore, to increase the patients’ loyalty to use the PHC services, the quality of the services should be improved by levelling up the quality of providers and both physical and social environments in the PHCs.",
"keywords": [
"Service provider",
"service process",
"service environment",
"quality of service",
"behavioural loyalty",
"health centre"
],
"content": "Introduction\n\nPatient intention to visit primary health centers (PHCs) is an important requirement of a patient referral system. In many countries, for instance Indonesia, individuals are encouraged to visit their local PHCs first and when it is required, they will be referred to public hospitals. As a gatekeeper to hospitals, facility of PHCs in Indonesia have already improved particularly after the implementation of universal coverage (Ekawati et al., 2017). However, some studies reported lack of intention to visit and revisit PHCs (Ulandari & Yudawati, 2019) and dissatisfaction to the PHCs service (Ekawati et al., 2017). Loyal patients that continue to visit the health care provider and follow medication procedures could improve health care services, patient referral system, and patient outcomes (Zhou et al., 2017). On the contrary, patients reluctant to visit PHCs may lead to unintended impact on the effectiveness of treatment and medication as they do not receive complete and continue medications, and thus, it may lead to low quality of community health.\n\nPrevious studies have documented a significant role of service quality on user loyalty. In health care setting, service quality is a crucial factor of an effective health care system (Mosadeghrad, 2014). Service quality of PHCs is very crucial for a health care system because PHCs are the main entrance and the provider of basic and promotional health care for the population. Failure to achieve expected service quality, means that people may be reluctant to visit or revisit PHCs and would prefer to visit public hospitals directly (Ulandari & Yudawati, 2019). As a result, the effectiveness of the health care sector would become deteriorated and continuous spikes of patient numbers in public hospitals cannot be avoided.\n\nDefining and measuring health service quality are challenging tasks as service quality is intangible and related to patient perception and expectation (Mosadeghrad, 2014). From the perspective of patients, service quality is determined and evaluated from their experiences and their interactions with the environment of a hospital or PHC, and interpersonal factors, such as the responsiveness and kindness of staff (Lam, 1997; Amin & Nasharuddin, 2013). Besides, service quality can potentially lead to the creation of patient behavioural loyalty, which is beneficial for both patient and PHC management. There is a body of literature on predictors of customer perceived service quality. However, similar studies in the context of health services are still scarce (Rose et al., 2004). Service quality in health care providers can be associated with two primary factors, namely, internal and external factors. Using patients as the respondents, Rose et al. (2004) found that interpersonal qualities or human dimension and physical environment quality play a significant role in the hospital service quality of Malaysian hospitals. Mosadeghrad (2014) revealed that the personality of physicians and the patients affect the health care service quality of Iranian hospitals. Meanwhile, Amin & Nasharuddin (2013) investigated the influence of admission, medical service, overall service, discharge, and social responsibility on hospital service quality. They found that the five variables which developed from the service quality (SERVQUAL) model has a significant relationship with hospital service quality.\n\nAlthough the literature on the impact of internal service factors, for instance, physician characters and hospital environment, regarding service quality is growing, studies on the relationship between service quality and behavioural loyalty are still limited, particularly in the context of primary health care and a developing country (Murti et al., 2013). Zhang & Yang (2018) note that determinants and mechanisms of patient loyalty in the health care industry still remain unexplored.\n\nSupriyanto et al. (2021) studied the influence of service quality on bank customer loyalty in Indonesia. They found that service quality had no significant effects on customer loyalty. On the contrary, Aladwan et al. (2021) documented a significant impact of service quality on patient loyalty and patient satisfaction in a Jordanian hospital. In addition, Krishna et al. (2016) investigated the relationship between health care service quality, patient satisfaction, and behavioural intentions in large hospitals in India. They found that from the five dimensions of SERVQUAL, only empathy affects the behavioural intention of the patients.\n\nAs research on the relationship between health care service and behavioural loyalty of patients is still limited, the present study aims to examine the influence of internal service factors (service provider, service process, service environment) on service quality and behavioural loyalty in Indonesian primary health centres. Further, the SERVQUAL dimensions have been validated in the Western world, and there is a possibility that the cultural differences of consumers will affect its applicability, particularly in the context of a public health care system (Amin & Nasharuddin, 2013).\n\nAs an emerging economy, Indonesia has a unique setting for its health care system, that reflects the important role of social insurance and a relatively strict patient referral system (Fahlevi et al., 2021; Handayani et al., 2018). Specifically, Indonesian PHCs are selected as research samples because, firstly, they play a crucial role in the Indonesian health care sector as a primary health care provider (Rawung & Sholihin, 2017) and, secondly, Indonesia adheres to the principle of tiered and systematic patient referrals, starting from the PHCs, as a first-level health service facility (Fahlevi, 2016). However, many patients prefer to directly visit public hospitals although Indonesian PHCs are able to deliver treatment for more than 144 types of diagnoses and are mostly free of charges. PHCs are often placed to obtain unnecessary referral permits to hospitals (Goniwala, 2017). As a result, there has been a surge in patient numbers in Indonesian public hospitals (Gasim, 2015).\n\nThis study contributes to the literature of service quality and behavioural loyalty in health care industries. Prior studies have mostly been conducted in hospital settings in developed countries, for instance the United States (US), the United Kingdom (UK), and Australia (Pai & Chary, 2011). There are only a few studies that were undertaken in developing and non-Western countries. Moreover, unlike prior studies that were mostly carried out in hospital settings, the present study was conducted in a unique setting, namely PHCs, known as Puskesmas in Bahasa Indonesia, as the frontline of the health care sector in most developing countries. Besides, this study tested the mediating role of service quality on the relationship between internal service factors and behavioural loyalty. The role of service quality as an intervening variable of the relations between internal factor services and behavioural loyalty is still unexplored.\n\n\nLiterature review\n\nPatients develop perceptions during the process of health care delivery and compare them to their expectations (Wu, 2011). The result of this process is service quality based on patient perspective. Therefore, service quality depends on the nature, context, and scope of the service expected (Fairchild et al., 1997). Service quality can also be defined as value, excellence, and conformity with the predetermined specifications and requirements of a service (Grönroos & Ojasalo, 2004; Mosadeghrad, 2014). The dimensions of SERVQUAL that are widely accepted are tangibility, empathy, reliability, responsiveness, and assurance which can be studied in order to understand their impact on service quality (Zeithaml et al., 2002). However, these dimensions need to be validated as culture and social dimensions may different from one country to another.\n\nPrevious studies classified quality dimensions into two parts, namely, technical quality and functional quality (Krishna et al., 2016). The former deals with medication technical accuracy in which the health care providers (doctors, nurses and other supporting medical staff) are the main actors. Technical quality is mirrored by the accuracy of diagnoses and procedures, as well as the effectiveness of medical protocols. Patients have limited knowledge and capacity to measure technical quality. The latter is related with the process of health care delivery. For instance, the interpersonal relationship between doctor and patient, the quality of the hospital environment, and the system. These factors are easily evaluated by patients. Therefore, marketing and business researchers focus more on functional quality.\n\nThe internal service factors that potentially contributes to service quality are service provider character, service process, and service environment. A service provider is a person that delivers health care services to patients (Paulus et al., 2016). Service providers are doctors, nurses, midwives, and other supporting workers in the hospital, or other health care providers. As they are human beings, they have different character and interpersonal skills that contribute to the way they deliver services.\n\nThe service process is the capacity of the health care provider in providing health services at the right time, whenever they are needed (Ferreira & Marques, 2019). The service process requires input, transformation processes, and results (Okoye & Obeta, 2015), and all are reflected by waiting time, atmosphere in the health care provider, and other dimensions.\n\nThe service environment is a condition that meets the convenience of service users such as location, parking, waiting rooms, examination rooms, and cleanliness, and has a variety of media and information centres that can please the service users (Lovelock & Wirtz, 2016; Meier & Krug, 2009). It also can be in the form of physical facilities such as infrastructure, medical equipment, hygiene of medical staff, and other important health conditions (Fatima et al., 2018). The service environment is also a medical facility that can attract many service users with high utility (Meesala & Paul, 2018).\n\nMeanwhile, behavioural loyalty is the result of repeated satisfaction of quality in a service provider (Fatima et al., 2018). Kumar et al. (2006) describes alternative forms of loyalty, namely, behavioural loyalty. Wu (2011) believes that behavioural intention is more suitable for measuring patient loyalty, but the other authors argue that loyalty should be viewed as attitude. Nevertheless, loyalty in every business industry has the same benefits (Wu, 2011), namely, improving visits and the use of services.\n\n\nHypothesis development\n\nThe service quality of the health care provider is a multi-dimensional concept (Ghahramanian et al., 2017) and providing high-quality service in the health care sector is the key to success in achieving better public health outcomes. From the perspective of patients, service providers can be the most influential factor of perceived service quality. Service providers are doctors, nurses, and other staff in hospitals or other health care organizations, and they interact directly with patients. Their interpersonal skill builds patient perception in the quality of health care and shapes the behavioural loyalty of the patients (Mosadeghrad, 2014; Fiaz et al., 2018).\n\nThe service provider plays a significant role in both technical and functional quality dimensions. The former refers to the technical precision of the medical diagnoses and treatments according to medical professional specifications and standards, while the latter deals with the way patients receive a health care service (Padma et al., 2010). Physicians are the main actors in diagnosing and deciding on the medical treatment to be delivered to patients and at the same time, they are the dominant person interacting with the patient. As a result, the service provider is among one of the most important determinants of service quality, and both are measured by patients and other stakeholders.\n\nPrevious studies have revealed that service provider character and personality affect service quality. For instance, Mosadeghrad (2014) investigated factors that contributed to health care quality in Iranian health care providers. They found that service quality was shaped by the character and personality of patients, doctors, and environmental factors. Moreover, (Atinga & Baku, 2013) studied determinants of service quality of antenatal care in Ghana. The study uncovered how physician attentiveness contributes to a positive impact on service quality. Based on the above discussion, the first hypothesis proposed is as follow:\n\nThe service process can be defined as the nature and characteristic of the process of delivering service. The indicators of a good service process can be how fast patients receive the medical treatment, since they register any interactions between patients and staff in the health care facility (Elleuch, 2008). The service process can also be measured by consistency in terms of quality and standards in health care provision.\n\nA good service process, for example, a shorter waiting list, will improve service quality (Atella et al., 2019). The service process affects service users, but it depends on several factors such as the nature, character of service users, and waiting times (Wood et al., 2009). Previous investigators found a relationship between service process and service quality. For instance, Elleuch (2008) studied Japanese patient satisfaction and found that it is determined by process character (patient-doctor interaction) and physical attributes (settings and appearance).\n\nThe service environment refers to the atmosphere of the health care provider that is created by both the physical environment and the social environment, that shape the patient impression. A good service environment is reflected by a comfortable condition, both outside and inside the building, with a friendly and informative social environment supported by various facilities, and infrastructure, based on policies to improve the quality of PHCs services (Meier & Krug, 2009).\n\nMoreover, the service environment also relates to social experiences gained by patients during their visits to the health care provider. This includes patient-friendly environment, responsiveness, and interaction between patient and health care providers. In their study in Pakistan, Fatima et al. (2018) revealed a positive association between health care service quality aspects, for instance, physical environment and customer-friendly environment, with patient loyalty through patient satisfaction.\n\nIn the health care sector, increasing access to hospitals through social insurance may lead to increasing patient interest and concern regarding the quality of health care services (Fatima et al., 2018). Notwithstanding, the rapid growth of private hospitals and private clinics provides alternatives for patients in selecting which hospital they want to visit. Thus, patient behaviour loyalty has become an important issue, both in a relatively strict referral system or a relatively less strict referral system. In this issue, service quality seems to be a key factor of the loyalty of patients.\n\nNgoma and Ntale (2019) believe that loyalty encourages users to repeat their use and provide positive feedback to the other members of the public, that would encourage actual and prospective users. Fatima et al. (2018) classified two types of loyalty, namely, attitudinal and behavioural loyalty. Attitudinal loyalty refers to loyalty created by distinctive sentiments of customers towards a product or service, while behavioural loyalty can be defined as repeating use of certain products or services from the same providers, expanding the use volume and promoting the product or service among other people (Fatima et al., 2018). The present study has a focus on behavioural loyalty.\n\nPatients normally use their prior service experience of using health care services to decide whether they would wish to, or not wish to, visit the health care service again. A body of literature has confirmed that the relationship between service quality and behavioural loyalty is emerging. Fatima et al. (2018) examines the influence of service quality on patients’ satisfaction and patients’ behavioural loyalty in six private hospitals in Pakistan. Those authors unveiled the fact that better quality of health care services may increase patient satisfaction and loyalty. Ambrose et al. (2016) undertook their study in the southern US, and examined the association between service quality and patients’ willingness to recommend a hospital to their relatives and friends. The study revealed that service quality has a positive influence on recommendation behaviour among patients.\n\nThe above literature review shows that the relationship between service quality and behavioural loyalty in health care industry is still relatively scanty. Most studies have been conducted in other sectors, for instance in banking industry. Besides, prior studies have been undertaken mostly in developed countries and in a hospital setting. Service quality and behavioural loyalty in the context of PHCs are still uncovered. Unlike hospitals, PHCs have different setting of organisation and limited offered services. For instance, PHCs only provides basic medication for their patients. However, it has an unreplaced role as a gatekeeper to hospital.\n\nReferring to the theoretical framework of the relationship between variables as described previously, the model to be tested in this study is depicted in Figure 1. This research aims to test the aforementioned hypotheses as well as to test the mediating role of service quality on the relationship between internal service factors (service provider, service process and service environment) and behavioural loyalty.\n\nH1–H4 indicate the hypotheses that are tested in this study.\n\n\nMethods\n\nA cross-sectional study, adhering to the STROBE guidelines (Mardaleta, 2022b), was conducted in 14 out of 23 districts in Aceh Province, Indonesia to assess the determinants of patient behavioural loyalty on PHCs. The PHC users, patients who received the services from PHCs, were interviewed directly. The questionnaire-assisted interviews were conducted by the authors after receiving the consent from the patients. The data collection was conducted between September and December 2020. The protocol of this study was approved by Komisi Program Studi Pendidikan Doktor Ilmu Manajemen, Universitas Syiah Kuala, Banda Aceh, Indonesia (No. B/359/UN11.1.1/DIM/TD.06/2020). The patients provided written consent prior to being included in this study. Due to the coronavirus disease 2019 (COVID-19) pandemic, some patients provided verbal consent only, and the interview was conducted in a social distancing manner. In such conditions, the investigators wrote the notes stating that the patients agreed to participate and signed the consent sheet. Such an approach was approved by the Indonesian ethical committee due to force majeure to avoid the transmission of the virus between patients and investigators.\n\nUsing purposive sampling method, 14 out of 23 districts in Aceh Province were selected based on regionalisation namely, the Central, South, West, and East region. In total, there are 137 PHCs (Puskesmas) that have Inpatient Unit in Aceh Province. The number of PHCs included in this study was determined using the Slovin minimum sample formula: (n=N1+N5%2), where n=1371+1375%2= 102 PHCs. Therefore, 102 PHCs were randomly selected using Randomizer, an online randomization tool. The patients who received the services from the selected 102 PHCs, were selected proportionally based on the annual number of inpatient patients of each PHC.\n\nTo assess the factors associated with behavioural loyalty of PHC users, this study assessed two main variables: exogeneous variable (internal service factors) and mediating variable. In this study, exogeneous variables are also called internal service factors since all the variables are part of the PHCs. The exogeneous variable has three main components: service provider, service process, and service environment. Detailed operational definition of each variable are provided in Table 1. In this study, we also examined the role of service quality as an intervening variable of the relationship between internal service factor and behavioural loyalty. Previous studies have shown a relationship between service quality and loyalty. For instance, Wu (2011) found a direct impact of service quality on re-visit intention of patients in Taiwanese hospitals. Krishna et al. (2016) demonstrated the indirect effect of one health care service quality, namely, empathy, to behavioural intention. Therefore, the role of service quality to mediate the impact of internal service factors on behavioural loyalty is supported by the previous literature.\n\n\n\n1. Social sensitivity\n\n2. Competence (knowledge and expertise)\n\n3. Motivation and satisfaction\n\n4. Professionalism\n\n\n\n1. Service speed\n\n2. Service standard\n\n3. Ease of receiving service information\n\n\n\n1. Physical environment\n\n2. Social environment\n\n\n\n1. Reliability\n\n2. Responsiveness\n\n3. Assurance\n\n4. Empathy\n\n5. Tangibles\n\n\n\n1. Positive impression\n\n2. Directing and suggesting\n\n3. Intention and commitment\n\n4. Treatment and follow-up care\n\nThe questionnaire was developed based on previous literature (Ahmed et al., 2017; Atella et al., 2019; Fairchild et al., 1997; Fatima et al., 2018; Ferreira & Marques, 2019; Fornara et al., 2006; Lovelock & Wirtz, 2016; Meier & Krug, 2009; Mosadeghrad, 2014; Okoye & Obeta, 2015; Parasuraman et al., 2005; Paulus et al., 2016; Zeithaml et al., 2002). The questionnaire consisted of four parts. The first part collected the demographic data while the last three parts assessed the exogeneous, mediating and endogenous variable domain (see the questionnaire in the Extended data (Mardaleta, 2022a)). For exogeneous, mediating and endogenous variables, the possible answers were provided in the Linkert-scale ranged from “Strongly disagree (score 1)” to “Strongly agree (score 5)”. The raw scores were used in the final analysis.\n\nThe convergent validity and discriminant validity tests were conducted to ensure the validity of the questionnaire. Based on previous literature, the validity of the questionnaires is confirmed if the loading factor at convergent validity is higher than 0.5 (Ghozali, 2014). Discriminant validity is verified if the cross loading at the construct is higher than another construct and average variance extracted (AVE) is higher than 0.5 (Ghozali, 2014). The reliability of the questionnaires is considering good if composite reliability (CR) value is higher than 0.5 and the value of Cronbach’s Alpha higher than 0.6 (Malhotra & Morris, 2009). Our validity tests showed that all questionnaires’ items were valid as p-value of convergent validity, discriminant validity and AVE were all > 0.50. All of the items were also reliable because the CR value was > 0.70 and Cronbach’s Alpha was > 0.60. Outer loading of each indicator of all variables ranged between 0.703 and 0.913. These indicated that the items within questionnaire are valid and reliable.\n\nThe multicollinearity possibility was assessed by using Tolerance dan Variance Inflation Factor (VIF). We found that the VIF value was smaller than 10 indicating no multicollinearity between the domains. To examine the data normality, critical ratio of skewness and kurtosis ± 2.58 were used. Hypothesis testing was carried out by using the structural equation model (SEM). This model was used because this model has several advantages. Firstly, SEM analysis is able to carry out complicated tests of decision-making processes in various public sector management and accounting sciences, and others. Secondly, SEM can be used to address both regressive and dimensional research questions, and it can measure the influence of theoretically existing relationships, including mediating relationships (Ferdinand, 2014, Holbert & Stephenson, 2003). Thirdly, SEM can analyse down to the level of indicators, or find the root of the problem, because it is not limited to latent variables. Therefore, SEM is the most appropriate method to solve complex and difficult problems, as SEM can distinguish empirical data and latent data that can be defined from the error value and loading factor. Lastly, SEM can perform regression analysis, factor analysis, and path analysis. The confirmatory factor analysis was used to determine the value of the loading factor. The initial measurement model was carried out to examine the goodness of fit value. All analyses were conducted using IBM SPSS Amos version 23.\n\n\nResults\n\nSince the COVID-19 pandemic, we were unable to interview the patients directly and therefore the questionnaires were provided to the patients and were then collected. The patients were provided with the phone number of the investigator and therefore were able to ask the questions to the investigators during completing the questionnaire. During the study, 402 questionnaires were distributed and all of them were returned. However only 389 respondents answered all the questions completely and were included in the final analysis (Mardaleta, 2022a). The characteristics of the respondents are provided in Table 2. More than half (59%) of the respondents were married and there was an equal gender proportion between male and female (49% vs 51%). Most on the patients were aged between 18 and 54 years old and almost half of them (48%) completed the senior high school. Based on the type of occupation, only 5% of respondents were working as civil servant while the rest were working in non-civil servant sector (Table 2).\n\nOur assessment of criteria measurement of SEM indicated that the data were normal and there were no outliers indicating the data could be used to test our SEM structural model and the hypotheses. An evaluation of the goodness of fit criteria of a model with several index suitability criteria and a cut off value was conducted in order to ensure whether a model can be accepted or rejected. Our SEM model had a p-value > 0.05, chi-square fit statistics/degree of freedom was less than 2 goodness-of-fit index (GFI), root mean square error of approximation < 0.08, Tucker Lewis index and normed fit index were both > 0.90, parsimonious goodness-of-fit index <1.0 and GFI > 0.90. These suggested that our SEM model was acceptable.\n\nThe SEM test was assessed the influence between variables; if the variable has a probability value p < 0.05, the hypothesis is accepted. The results of the SEM analysis are provided in Table 3. It can be clearly seen that not all of the hypotheses are supported by the study. Two components of internal service factors, service provider and service environment, had a positive and significant influence on service quality of the PHCs with p < 0.001 and p = 0.021, respectively. The service process has a positive, but insignificant, impact on service quality. Our data also suggested that service quality, indeed, was a determinant of behavioural loyalty of patients to the PHCs (p = 0.003) (Table 3).\n\nWe also assessed the intervening role of service quality. Here, we assessed its role as mediator variable that influences the relationship between the independent variable (internal service factors) and the dependent variable (behavioural loyalty). Our data suggested that service quality did not serve as an intervening variable between internal service factors (service provider, service process, and service environment) and behavioural loyalty of the patients, with p = 0.091, p = 0.230 and 0.260, respectively (Table 4).\n\n\nDiscussion\n\nThis study confirms the influence of two internal service factors (service provider and service environment) on service quality. This is consistent with the study conducted in Iranian hospitals (Mosadeghrad, 2014). Those authors found that service quality was shaped by the character and personality of doctors (service provider) as well as environmental factors, for instance, resources and facilities owned by the hospital. It is also consistent with the findings of Atinga & Baku (2013), which revealed that physician attentiveness has a significant and positive impact on service quality. However, the present study does not provide empirical proof on the relationship between service process and service quality of PHCs. The dimensions of service process are service speed and service standard. Thus, this finding is not in line with Elleuch's (2008) in the Japanese hospital setting, and it was found that service quality is determined by process character (patient-doctor interaction) and physical attributes (setting and appearance).\n\nFurthermore, the result of this study confirms a positive and significant impact of quality service on patient behavioural loyalty. This is consistent with prior studies, for instance, Fatima et al. (2018) in Pakistan and Rehman (2012) in Pakistan, United Arab Emirates, and the UK, Aladwan et al. (2021) in the Jordanian hospital setting, and Krishna et al. (2016) in India. Fatima et al. (2018) found that service quality, reflected by costing, process quality, interaction, and environment quality, affected patient loyalty. Rehman (2012) revealed that service quality of health care service was shaped by patient loyalty, which was mediated through patient satisfaction. In their research, service quality was proxied by privacy and safety, patient-friendly environment, responsiveness, physical environment, and communication.\n\nHowever, the present study does not confirm the relationship between internal service factors and patient behaviour loyalty through service quality. Thus, the results are not in line with some previous research, for example, Lee (2021) found that the service provider with good communication skills has a positive effect on the cognitive trust of service users that leads to patient loyalty. Moreover, this research finding is also not consistent with research from other sector settings. For instance, Boonlertvanich (2019) studied the impact of customer-perceived service quality on the behavioural loyalty of customers of a large commercial bank in Thailand. This study confirms an intervening role of satisfaction and trust in the relationship between service quality and behavioural loyalty.\n\nThe present study suggests that management of PHCs should focus on the improvement of internal service factors, particularly service provider and service environment, as these factors contribute positively to service quality. In doing so, management can ensure that doctors, nurses, and other supporting staff are having good interpersonal skills, motivation, and professionalism in order to provide the best health service to patients. PHCs management should focus on recruiting good personality of service providers. Moreover, PHCs need to maintain both a physical and social environment that shape good perceptions of patients on the service provided by the PHCs. PHCs should invest in improving both medical and supporting facilities, as well as creating a caring social environment. Finally, this study confirms the influence of service quality in behavioural loyalty of patients. Thus, each PHC needs to improve service quality to attract more patients and motivate existing patient to re-visit the PHC. As a result of improved patient loyalty, patients will follow the referral system properly and, thus, public hospitals in Indonesia can have ideal patient numbers.\n\nThis study is not free from limitations. Firstly, only PHCs in Aceh province were included in this study. Therefore, the generalisation of results is limited. Secondly, this study did not take into account patient characteristics as independent variables that may contribute to the different perception of service quality. Therefore, this study suggests a wider research scope for further research. Qualitative-based research is also suggested to explore patient perception in service quality, particularly in the current pandemic situation. Lastly, it is suggested for further study to compare determinants of service quality between PHCs and private clinics, to gain a more comprehensive understanding of service quality from the perspective of health care users.\n\n\nConclusions\n\nIn a health care system where competition among providers is limited and the patient referral system is a crucial component, patient loyalty is very important. Indonesian public hospitals have been mostly over capacity as the referral system is not working properly. One of the reasons is the service quality of PHCs as the main entrance of the patient referral system. This study found that behavioural loyalty of PHCs patients is determined by quality service, while quality service is shaped by internal service factors, namely, service provider and service environment. Thus, the findings of this study can be used to improve the service quality and behavioural loyalty of the patients and, hence, it will lead to the decline in the number of hospital patient visits.\n\n\nData availability\n\nFigshare: ‘Determinants of patient behavioural loyalty on primary health centres: evidence from Indonesia’, https://doi.org/10.6084/m9.figshare.19326731 (Mardaleta, 2022a).\n\nThis project contains the following underlying data:\n\n• R_Master Data.xlsx [Table containing the raw data of the study].\n\nFigshare: ‘Determinants of patient behavioural loyalty on primary health centres: evidence from Indonesia’, https://doi.org/10.6084/m9.figshare.19326731 (Mardaleta, 2022a).\n\nThis project contains the following extended data:\n\n• Study Quesionnaire.pdf [Questionnaire used to collect the data during the study]\n\n\nReporting guidelines\n\nFigshare: STROBE checklist for “Determinants of patient behavioural loyalty on primary health centres: evidence from Indonesia”, https://doi.org/10.6084/m9.figshare.19326845 (Mardaleta, 2022b).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAbdul Rehman A: Customer satisfaction and service quality in Islamic banking: A comparative study in Pakistan, United Arab Emirates and United Kingdom. Qual. Res. Financ. Mark. 2012; 4(2–3): 165–175. Publisher Full Text\n\nAhmed S, Tarique KM, Arif I: Service Quality, Patient Satisfaction and Loyalty in the Bangladesh Healthcare Sector. Int. J. Health Care Qual. Assur. 2017; 30(5): 477–488. PubMed Abstract | Publisher Full Text\n\nAladwan MA, Salleh HS, Anuar MM, et al.: The relationship among service quality, patient satisfaction and patient loyalty: case study in Jordan Mafraq Hospital. Linguistics and Culture Review. 2021; 5(April): 27–40. Publisher Full Text\n\nAmbrose BW, Sanders AB, Yavas A: Servicers and Mortgage-Backed Securities Default: Theory and Evidence. Real Estate Econ. 2016; 44(2): 462–489. Publisher Full Text\n\nAmin M, Nasharuddin SZ: Hospital service quality and its effects on patient satisfaction and behavioural intention. Clin. Gov. 2013; 18(3): 238–254. Publisher Full Text\n\nAtella V, Belotti F, Bojke C, et al.: How Health Policy Shapes Healthcare Sector Productivity? Evidence from Italy and UK. Health Policy. 2019; 123(1): 27–36. PubMed Abstract | Publisher Full Text\n\nAtinga RA, Baku AA: Determinants of antenatal care quality in Ghana. Int. J. Soc. Econ. 2013; 40(10): 852–865. Publisher Full Text\n\nBoonlertvanich K: Service quality, satisfaction, trust, and loyalty: the moderating role of main-bank and wealth status. Int. J. Bank Mark. 2019; 37(1): 278–302. Publisher Full Text\n\nEkawati FM, Claramita M, Hort K, et al.: Patients’ experience of using primary care services in the context of Indonesian universal health coverage reforms. Asia Pac. Fam. Med. 2017; 16(1): 4–10. PubMed Abstract | Publisher Full Text\n\nElleuch A: Patient satisfaction in Japan. Int. J. Health Care Qual. Assur. 2008; 21(7): 692–705. Publisher Full Text\n\nFahlevi H: Understanding why the role of accounting is unchanged in Indonesian public hospitals. J. Account. Organ. Change. 2016; 12(2): 203–222. Publisher Full Text\n\nFahlevi H, Irsyadillah I, Indriani M, et al.: DRG-based payment system and management accounting changes in an Indonesian public hospital: exploring potential roles of big data analytics. J. Account. Organ. Change. 2021; 18: 325–345. Publisher Full Text\n\nFairchild DG, Mcloughlin KS, Gharib S, et al.: Productivity, Quality, and Patient Satisfaction. J. Gen. Intern. Med. 1997; 12(1): 663–667.\n\nFatima T, Malik SA, Shabbir A: Hospital healthcare service quality, patient satisfaction and loyalty: An investigation in context of private healthcare systems. Int. J. Qual. Reliab. Manag. 2018; 35(6): 1195–1214. Publisher Full Text\n\nFerdinand A: Structural Equation Modelling Dalam Penelitian Manajemen: Aplikasi Model-Model Rumit Dalam Penelitian Untuk Tesis Magister dan Disertasi Doktor. Undip Press; 2014.\n\nFerreira DC, Marques RC: Do quality and access to hospital services impact on their technical efficiency?. Omega (United Kingdom). 2019; 86: 218–236. Publisher Full Text\n\nFiaz M, Ikram A, Ilyas A: Enterprise Resource Planning Systems: Digitization of Healthcare Service Quality. Adm. Sci. 2018; 8(3): 38. Publisher Full Text\n\nFornara F, Bonaiuto M, Bonnes M: Perceived Hospital Environment Quality Indicators: A Study of Orthopaedic Units. J. Environ. Psychol. 2006; 26(4): 321–334. Publisher Full Text\n\nGasim H: Optimalisasi Pelayanan Kesehatan Terhadap Masyarakat Miskin di Provinsi Gorontalo. Publik (Jurnal Ilmu Administrasi). 2015; 4(1): 1–8. Reference Source\n\nGhahramanian A, Rezaei T, Abdullahzadeh F, et al.: Quality of healthcare services and its relationship with patient safety culture and nurse-physician professional communication. Health Promot. Perspect. 2017; 7(3): 168–174. PubMed Abstract | Publisher Full Text\n\nGhozali I: SEM Metode Alternatif dengan menggunakan Partial Least Squares. Badan Penerbit Universitas Diponegoro; 2014.\n\nGoniwala G: Gambaran Pelaksanaan Rujukan Peserta BPJS Kesehatan di Puskesmas Tikala Baru dan Puskesmas Teling Atas di Kota Manado. Universitas Sam Ratulangi; 2017.\n\nGrönroos C, Ojasalo K: Service productivity - Towards a conceptualization of the transformation of inputs into economic results in services. J. Bus. Res. 2004; 57(4): 414–423. Publisher Full Text\n\nHandayani PW, Meigasari DA, Pinem AA, et al.: Critical success factors for mobile health implementation in Indonesia. Heliyon. 2018; 4(11): e00981. PubMed Abstract | Publisher Full Text\n\nHolbert RL, Stephenson MT: The Importance of Indirect Effects in Media Effects Research: Testing for Mediation in Structural Equation Modeling. J. Broadcast. Electron. Media. 2003; 47(4): 556–572. Publisher Full Text\n\nKrishna R, Jandavath N, Byram A: Healthcare service quality effect on patient satisfaction and behavioural intentions in corporate hospitals in India. Int. J. Pharm. Healthc. Mark. 2016; 10(1): 48–74. Publisher Full Text\n\nKumar V, Shah D, Venkatesan R: Managing retailer profitability-one customer at a time!. J. Retail. 2006; 82(4): 277–294. Publisher Full Text\n\nLam SSK: SERVQUAL: A tool for measuring patients’ opinions of hospital service quality in Hong Kong. Total Qual. Manag. 1997; 8(4): 145–152. Publisher Full Text\n\nLee C: Patient loyalty to health services: The role of communication skills and cognitive trust. Int. J. Healthc. Manag. 2021; 14(4): 1254–1264. Publisher Full Text\n\nLovelock C, Wirtz J: Service marketing, people, technology, strategy (Eight). World Scientific; 2016.\n\nMalhotra N, Morris T: Heterogeneity in professional service firms. J. Manag. Stud. 2009; 46(6): 895–922. Publisher Full Text\n\nMardaleta M: Determinants of patient behavioural loyalty on primary health centres: evidence from Indonesia. figshare. [Dataset]. Journal Contribution. 2022a. Publisher Full Text\n\nMardaleta M: Determinants of patient behavioural loyalty on primary health centres: evidence from Indonesia. figshare. Journal Contribution. 2022b. Publisher Full Text\n\nMeesala A, Paul J: Service quality, consumer satisfaction and loyalty in hospitals: Thinking for the future. J. Retail. Consum. Serv. 2018; 40(July 2016): 261–269. Publisher Full Text\n\nMeier H, Krug CM: Standardization of Service Delivery in Industrial Product-Service Systems. The 19th CIRP Design Conference–Competitive Design.2009.\n\nMosadeghrad AM: Original Article Factors influencing healthcare service quality.2014; 3(2): 77–89. Publisher Full Text\n\nMurti A, Deshpande A, Srivastava N: Service Quality, Customer (Patient) Satisfaction and Behavioural Intention in Health Care Services: Exploring the Indian Perspective. J. Health Manag. 2013; 15(1): 29–44. Publisher Full Text\n\nNachtigall C, Kroehne U, Funke F, et al.: (Why) Should we use SEM?. Methods of Psychological Research. 2003; 8(2): 1–22.\n\nNgoma M, Ntale PD: Word of mouth communication: A mediator of relationship marketing and customer loyalty. Cogent Bus. Manag. 2019; 6(1). Publisher Full Text\n\nOkoye I-MNH, Obeta CE: Examining the Relationship between Service Environment and Costumer Satisfaction in Service Encounters in Selected Superstores in Enugu, South East Nigeria. Eur. J. Manag. Bus. Econ. 2015; 7(29): 77–84.\n\nPadma P, Rajendran C, Lokachari PS: Service quality and its impact on customer satisfaction in Indian hospitals: Perspectives of patients and their attendants. Benchmarking. 2010; 17(6): 807–841. Publisher Full Text\n\nPai YP, Chary ST: Dimensions of hospital service quality: a critical review Perspective of patients from global studies. Int. J. Health Care Qual. Assur. 2011; 26(4): 308–340. PubMed Abstract | Publisher Full Text\n\nParasuraman A, Zeithaml VA, Malhotra A: E-S-QUAL a multiple-item scale for assessing electronic service quality. J. Serv. Res. 2005; 7(3): 213–233. Publisher Full Text\n\nPaulus FW, Ohmann S, Popow C: Practitioner Review: School-based interventions in child mental health. Journal of Child Psychology and Psychiatry and Allied Disciplines. 2016; 57(12): 1337–1359. PubMed Abstract | Publisher Full Text\n\nRawung LC, Sholihin M: Does extended autonomy of public service agency lead to a better performance? A case of Indonesian community health centers. Jurnal Dinamika Akuntansi Dan Bisnis. 2017; 4(2): 231–248. Publisher Full Text\n\nRose RC, Uli J, Abdul M, et al.: Hospital service quality: a managerial challenge. Int. J. Health Care Qual. Assur. 2004; 17(3): 146–159. PubMed Abstract | Publisher Full Text\n\nSupriyanto A, Wiyono BB, Burhanuddin B: Effects of service quality and customer satisfaction on loyalty of bank customers. Cogent Bus. Manag. 2021; 8(1). Publisher Full Text\n\nUlandari S, Yudawati S: Analisis Kualitas Pelayanan, Sarana Prasarana Dan Lingkungan Terhadap Kepuasan Pasien. Care: Jurnal Ilmiah Ilmu Kesehatan. 2019; 7(2): 39. Publisher Full Text\n\nWood GC, Spahr R, Gerdes J, et al.: Patient satisfaction and physician productivity: Complementary or mutually exclusive?. Am. J. Med. Qual. 2009; 24(6): 498–504. Publisher Full Text\n\nWu C: The impact of hospital brand image on service quality, patient satisfaction and loyalty. Afr. J. Bus. Manag. 2011; 5(12): 4873–4882. Publisher Full Text\n\nZeithaml VA, Parasuraman A, Malhotra A: Service quality delivery through web sites: A critical review of extant knowledge. J. Acad. Mark. Sci. 2002; 30(4): 362–375. Publisher Full Text\n\nZhang Y, Yang MM: Hospital service quality and patient loyalty: the mediation effect of empathy. J. Bus. Ind. Mark. 2018; 33(8): 1176–1186. Publisher Full Text\n\nZhou WJ, Wan QQ, Liu CY, et al.: Determinants of patient loyalty to healthcare providers: An integrative review. Int. J. Qual. Health Care. 2017; 29(4): 442–449. Publisher Full Text"
}
|
[
{
"id": "135575",
"date": "26 Apr 2022",
"name": "Abram L. Wagner",
"expertise": [
"Reviewer Expertise Epidemiology",
"public health",
"vaccination services"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe relationship between patients and health care workers is key to working in medicine and public health. Physicians and other health care workers provide direct clinical care and make recommendations about behavioral changes. Within Indonesia, health care workers within primary health centers, or Puskesmas, are also available to refer patients to specialists, within the Indonesian system of health care coverage.\nHow the patient-physician relationship operates is key. A stable relationship can lead to better and more sustained health outcomes in the individual and community. The study by Mardaleta et al. examines this relationship within the dimension of loyalty. They developed a model of how service providers, service processes, and service environments can lead to behavioral loyalty through the intermediate variable of service quality.\nOverall, this was a well-written and well-analyzed study. My one major contention that I would want the authors to respond to would be about treating health care as a business. I think there are certain analogies between health care and business, so discussing loyalty is relevant. However, health care isn't a business in the sense that patients are not consumers exactly. Health care providers have larger ethical and professional obligations beyond a typical commercial business. This doesn't negate the analysis, but the introduction or discussion could contextualize what is or isn't transferable from businesses. For example, there is literature on how you can be concerned about providing good patient-centered care but also not treat patients as consumers (e.g. Gusmano et al., 20191).\nThe study sampling frame relied on primary health centers. I assume patterns of loyalty might differ between those who do or do not regularly attend clinics. This could be a limitation.\nMinor issues:\nI would remove the sentence, \"Supriyanto et al. (2021) studied the influence of service quality on bank customer loyalty in Indonesia. They found that service quality had no significant effects on customer loyalty.\" - I understand the reason for it, but I think health care is generally different enough from other industries that making cross-industry comparisons could be problematic.\n\nLikewise, I would delete, \"The service process can be defined as the nature and characteristic of the process of delivering service.\" - it's a bit of a tautology.\n\nI believe Slovin's minimum sample formula is sort of a back-of-the-envelope calculation for figuring out how many people to sample into a study, whereas you are using it to sample the cluster. I would just state that explicitly.\n\nYou mention that you selected the number of inpatient patients in each Puskesmas proportionally - can you provide a range in the methods or results?\n\nWhen you mention SEM analyses, you state, \"Thirdly, SEM can analyse down to the level of indicators, or find the root of the problem, because it is not limited to latent variables.\" - I believe here you mean \"not limited to observed variables\" because isn't the benefit of SEM that you can measure latent constructs?\n\nCould you better explain the importance of behavioral loyalty? I see that it could represent trust in health care providers and recommendations they provide, willingness to engage within the system, adherence to treatments or willingness to get screened/get vaccinated, etc.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8189",
"date": "06 May 2022",
"name": "Heru Fahlevi",
"role": "Author Response",
"response": "Thank you for reviewing our manuscript. We believe the comments and suggestions improve the quality of our current manuscript We have removed the sentence: “Supriyanto et al. (2021) studied the influence of service quality on bank customer loyalty in Indonesia. They found that service quality had no significant effects on customer loyalty”. We have removed the sentence: “The service process can be defined as the nature and characteristic of the process of delivering service” from the literature review. Thank you for your suggestion. We have provided a brief explanation of the use of Slovin's formula. The range of the included patients from each PHC has been added in the “Sample and sampling method” section. Thank you for catching this error. We have revised this. We have corrected an error on the third advantage of the SEM analysis. We have provided more explanation of the important of the behavioral loyalty at the end of the discussion including its importance in the context of the COVID-19 pandemic."
}
]
},
{
"id": "135573",
"date": "03 May 2022",
"name": "Morteza Arab-Zozani",
"expertise": [
"Reviewer Expertise Health policy"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear respectable authors,\nThank you for considering a great area of research related to determinants of patient behavioral loyalty on primary health centers in Indonesia. The focus of this cross-sectional study is investigating the effects of internal service factors on service quality and behavioral loyalty of patients in PHCs in Indonesia. Based on the results, the service provider and service environment are two main factors that influence the service quality, and service quality directly influences the behavioral loyalty of PHC users. Your manuscript is well-written but needs some minor revisions as follows:\nPlease include \"internal service factors\" and \"service quality\" in your title to make it clearer and more complete.\n\nAbstract: Please add the sample size in the methods section. It is not clear enough to me.\n\nWhat is the basis for developing the hypotheses of this study? Give a brief explanation.\n\nHow is the informed consent form obtained from the patients?\n\nAre the samples selected in equal proportions from all regions? Otherwise, there is a possibility of sampling error/selection bias.\n\nPlease remove the lines 1- 5 at the start of the results section. These details are not related to the results. Please add these details in the methods section and also in the limitations of the study.\nCheers.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "8188",
"date": "06 May 2022",
"name": "Heru Fahlevi",
"role": "Author Response",
"response": "We would like to thank you for the suggestion for the change of the title but we prefer our current title since this would be clearer for the readers rather than \"internal service factors\" which might less common. We have provided the information on the sampling of the respondents and the sample size used in the present study in the abstract. Thank you for the suggestion. We have provided an explanation of how each hypothesis was developed. Please read the text under the subheading of each hypothesis where the basis for developing the hypothesis is provided. We have provided the information on how the informed consent was obtained. It could be seen under the Research design. We wrote: “The questionnaire-assisted interviews were conducted by the authors after receiving the consent from the patients. …The patients provided written consent prior to being included in this study. Due to the coronavirus disease 2019 (COVID-19) pandemic, some patients provided verbal consent only, and the interview was conducted in a social distancing manner. In such conditions, the investigators wrote the notes stating that the patients agreed to participate and signed the consent sheet. Such an approach was approved by the Indonesian ethical committee due to force majeure to avoid the transmission of the virus between patients and investigators.\" Thank you for your suggestion. We have removed some texts about the issue that we faced during the data collection due to the COVID-19 pandemic and moved them to methods and limitations."
}
]
}
] | 1
|
https://f1000research.com/articles/11-440
|
https://f1000research.com/articles/11-500/v1
|
05 May 22
|
{
"type": "Case Study",
"title": "Data protection record of processing activities and privacy notice generator toolkit by EMBL’s European Bioinformatics Institute",
"authors": [
"Montserrat González Ferreiro",
"Steven Newhouse",
"Steven Newhouse"
],
"abstract": "EMBL-EBI, Europe's biomolecular data hub, is a world leader in managing and analysing big data in biology and making it freely available to scientists worldwide. Researchers can access the open data resources and related services of EMBL-EBI by submitting minimal personal data. In May 2018, following the enforcement of the European Data Protection Regulation (GDPR), EMBL adopted the EMBL Internal Policy no. 68 on General Data Protection. It reflects European data protection principles while remaining within the bounds of EMBL's international legal status. As a result of GDPR and EMBL's Internal Policy No. 68 coming into force, 190 EMBL-EBI user-facing services that processed personal data in 2018 were required to have Records of Processing Activities (RoPA) and Privacy Notices (PN). EMBL-EBI's solution was to develop a Data Protection Engine (DPE) that automatically generates RoPA and PN when a service owner answers a series of questions. In addition to maintaining a centrally located database for RoPAs and PNs, the DPE tracks changes to the documents, as well as providing versioning and time-stamped updates. It is the aim of this article to share the EMBL-EBI IT department’s experience with designing and implementing the DPE and providing a toolkit to let others develop a similar solution and benefit from our experience. Implementation steps, benefits, challenges, opportunities, and practices are discussed and critically analysed.",
"keywords": [
"Data protection",
"personal data",
"GDPR",
"research infrastructures",
"intergovernmental organisations",
"privacy notice",
"record of processing activities."
],
"content": "Introduction\n\nThe European Molecular Biology Laboratory (EMBL) is the leading intergovernmental laboratory for life science research in Europe. Aimed at advancing the study and understanding of molecular biology, training young scientists and fostering innovation in science and technology alike. It has six sites in five host nations - one of which is EMBL’s European Bioinformatics Institute (EMBL-EBI).\n\nEMBL is an intergovernmental organisation, subject to international public law, entrusted with a number of privileges and immunities necessary for its functions. Accordingly, it has the power to self-regulate data protection. Such self-regulation is necessary to take account of EMBL’s status as an intergovernmental organisation, and its focus on scientific research beyond national borders.1 The EMBL Internal Policy no. 68 on General Data Protection defines EMBL's self-regulation in response to the requirements of the European General Data Protection Regulation (GDPR), which came into force in May 2018.2\n\nAs a result of GDPR and the coming EMBL Internal Policy no. 68 requirements, EMBL-EBI had to prepare nearly 200 Records of Processing Activities (RoPA) and Privacy Notices (PN) for data processing activities, including scientific and IT services, within less than four months. To expedite and automate this process, EMBL-EBI developed the Data Protection Engine (DPE), which uses a set of questions and templates to automatically generate all the required documents.\n\n\nSteps to design the Data Protection Engine\n\nTo simplify the design of the DPE, we used a form to collect the necessary information from Service Owners regarding their data processing activities in order to generate RoPAs and PNs automatically. The information collected in the form is used to complete templates for RoPAs and PNs.\n\nWith the templates and questionnaire ready, we defined the DPE workflow to facilitate collaboration between staff, service owners, and data protection specialists.\n\nAs soon as the workflow design was complete, the implementation began, and notifications were added to improve workflow management.\n\n\nCreating the templates for Records of Processing Activities\n\nThe RoPAs are inventories of the personal data that is being processed and how it is being processed. In our analysis, we determined that we needed at least two RoPA templates: one for EMBL-EBI to use as a data controller, the other for EMBL-EBI to use as a data processor. On occasion, EMBL-EBI acts as a joint data controller, but these cases are not as common. In such cases, EMBL-EBI will share the data controller RoPA template with other controllers so they can use it to jointly define the content and shape.\n\nThe template for EMBL-EBI as a data controller reflects that it is processing the personal data and determines the purposes and means of the processing of personal data (see Template 1, Extended data3). There are three main sections in the template: data controller information, data processor information, and data protection impact assessment.\n\nThe template for EMBL-EBI as a data processor reflects that it is processing the personal data on behalf of a data controller, and the purposes and means of the processing of personal data defined by the data controller (see Template 2, Extended data3). There are two main sections in the template: data processor information, and data protection impact assessment.\n\nThe information required to fill out the RoPA templates has been identified, and different scenarios have been considered. The options included in the templates also reflect some of the most common scenarios, such as the types of personal data processed and their purposes.\n\n\nCreating the templates for Privacy Notices\n\nThe PN offers data subjects (in our case service users) information about how an organisation processes personal data and complies with data protection principles. Two PN templates were created. The first PN template is for use by EMBL-EBI when it is a data controller, and it collects personal data directly from data subjects. The second template is to be used when EMBL-EBI is a data controller and it collects personal data indirectly, such as when another organisation provides the data. When EMBL-EBI performs the function of a joint data controller, it shares the PN template with other controllers in order to define content and structure jointly.\n\nThe PN template for a data controller who obtains personal data directly from data subjects (see Template 3, Extended data3) and the PN template for a data controller who does not obtain personal data directly from data subjects (see Template 4, Extended data3) have the same structure. Both include seven sections: who controls the personal data and how to contact them, the lawful basis for processing personal data, how personal data is collected and used, who has access to the personal data, data transfers to third parties or international organisations, data retention, and data subject rights.\n\nDifferent cases have been analysed to determine what information is needed to fill out the PN templates. The options included in the templates also reflect some of the most common scenarios, like who will have access to the personal data.\n\n\nSummary of the documents to be generated by the DPE\n\nIn different scenarios, different results will be generated by the DPE. Mainly, we have to consider where the personal data comes from in addition to the freedom to decide how the data is to be processed. Documents generated by the DPE are summarised in Table 1.\n\nIn the case of EMBL-EBI being a Joint data controller with other organisations, both the RoPA and the PN will be created using the DPE manual mode, a mode developed to create tailored documents.\n\n\nCreating the Data Protection Engine questionnaire\n\nThe questionnaire includes all questions necessary to obtain the information that can be used to complete the templates, as well as some information that is useful for monitoring purposes or to communicate with an appropriate contact.\n\nBecause the DPE was created when the GDPR was to come into force and there was a high level of uncertainty regarding the exact requirements, we wanted a comprehensive questionnaire to allow us to expand the RoPAs and PNs as needed.\n\nThe questionnaire (see Template 5, Extended data3) includes nine main sections that include data on the data processor or data controller, basic information on the service that processes the personal data, sources of personal data, personal data processing responsibilities, time limits for erasure of personal data, technical and security measures used to protect personal data, a short data protection impact assessment, and the lawful basis for processing personal data.\n\nThe questions are written considering EMBL and EMBL-EBI, however they can be easily adapted to request information about the processing of personal data by other organisations, as can the templates.\n\n\nDesigning the EMBL-EBI Data Protection Engine workflow\n\nThe key aim of the DPE is to facilitate the creation and review of RoPAs and PNs and to coordinate the interactions of the many roles involved: service owner, team leader and data protection administrator (DP Admin). The service owner is the operational contact for the service. A service owner reports to the team leader, who is ultimately responsible for the service processing personal data. Data protection administrators provide support to the service owner and team lead on all data protection questions and review the information they provide in the DPE.\n\nThe following workflow shows how to use the DPE, from reading the user guidelines to publishing the RoPA and PN with the automatic mode, when the questionnaire generates the RoPA, and when the content needs to be customised (Figure 1).\n\nThe workflow involves actions by Data Protection Administrator (DP Admin), Service Owner and Group Team Leader (GTL) among others. This figure is an original figure produced by the authors for this review article.\n\nThe process for manual and automatic creation is nearly identical, with only one difference: the second step for manual creation already requires the involvement of the data protection specialist, who holds the role of DP Admin, and reviews all responses to the questionnaire, called the DPE record. When the manual mode is selected, there is a warning displayed to the users saying “Manual mode will freeze all the answers to the questionnaire not being able to be modified later and keep all the selected values. Only the Data Protection administrator can edit the Record of Processing Activities and Privacy Notice manually”.\n\nManual creation also has the disadvantage that any changes to the RoPA and PN will have to be made manually. Automatic creation, on the other hand, only requires updating relevant fields in the questionnaire to generate new versions of these documents.\n\nThere are notifications going to the Service Owner, Team Leader, and Data Protection Administrators, as we can see from the workflow. To ensure that there is always someone available to assist DPE users, the notifications to the Data Protection Administrators can include a list of people.\n\n\nData Protection Engine current status and future work\n\nIn January 2022, we had 259 Records of Processing Activities and Privacy Notices, of which 10 were customised. Overall, the DPE has proved its usefulness with the vast majority of data processing activities following common patterns. Our decision to provide a manual option for the few uncommon cases that cannot be covered with the automatic approach appears justified.\n\nIn the near future, we intend to improve notifications and send reminders to the data protection support team if requests aren't handled after one day. Additionally, we would like to make the options provided by the questionnaire regarding personal data retention periods more specific.\n\nIt will also be necessary to review the templates with the EMBL Data Protection Officer in the long term, since the requirements of EMBL IP 68 and GDPR are clearer today.\n\nIn the future, the DPE could be expanded as a data protection service hub by designating Data Protection Assessment as a separate entity from RoPA and PN, including links to documentation and training for EMBL staff, on demand video training for new joiners, and gathering together all the guidelines and instructions for implementation that we have collected over the years.\n\n\nConclusion\n\nThe toolkit includes the questionnaire to collect information from service owners and store it in a central repository, the templates to generate RoPA and PN, a recommendation to offer the possibility to create manual RoPAs and PN if they need to be tailored, for example if a specific format or look and feel is required, and the workflow designed to develop the DPE. This project saved EMBL-EBI considerable time and helped standardise data protection practices, and we are confident that it can help other organisations as well.\n\n\nData availability\n\nNo underlying data are associated with this article.\n\nOpen Science Framework: Supplementary materials for the Data Protection Record of Processing Activities and Privacy Notice generator toolkit by EMBL’s European Bioinformatics Institute. https://doi.org/10.17605/OSF.IO/S856G.3\n\nThis project contains the following extended data:\n\n- 01-DP-Article-Template1-RoPA-Data Controller.docx\n\n- 02-DP-Article-Template2-RoPA-DataProcessor.docx\n\n- 03-DP-Article-Template3-PN-DataFromDataSubject.docx\n\n- 04-DP-Article-Template4-PN-DataNotFromDataSubject.docx\n\n- 05-DP-Article-Questionnaire.docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nJoseph Rossetto and Liang Shen, along with other team members of the EMBL-EBI Web Development team, contributed intellectually to the development of the EMBL-EBI's Data Protection Engine in 2018. We would also like to thank Daniel Gant for reviewing this article's grammar. An earlier version of this article can be found on OSF preprints (DOI: 10.31219/osf.io/3wbez).\n\n\nReferences\n\nEMBL: EMBL Internal Policy no. 68 on General Data Protection.2018. Reference source\n\nRegulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation). http\n\nGonzalez-Ferreiro M: Supplementary materials for the Data Protection Record of Processing Activities and Privacy Notice generator toolkit by EMBL’s European Bioinformatics Institute. [Dataset].2022. Publisher Full Text"
}
|
[
{
"id": "137469",
"date": "12 May 2022",
"name": "Mikael Linden",
"expertise": [
"Reviewer Expertise GDPR"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nHaving the documentation required by GDPR, such as Privacy Notice (PN) and Records of Processing Activities (RoPA), is a non-trivial task in an organisation like EMBL-EBI which has hundreds of personal data filing systems. The paper describes a tool and process that EBI's IT department developed to collect the information from their service owners and publish it. The results may be interesting and useful for other organisations with similar challenges.\nTo make the paper easier to read, it deserves more description of the context it relates to. Does the personal data processing covered in the paper refer to, for example:\nSamples deposited at EBI (some of them qualifying as their donors' personal data)? Logs of the use of EBI's services, identifying the researcher using EBI's services? Systems containing EBI's staff's personal data (such as HR or IT service logs)?\nThe paper only lightly touches on the substance of data protection, i.e. how do the EBI services comply with their data protection obligations (that are described in PN and RoPA). The contribution of this paper is more on how to manage the process of collecting and maintaining information from hundreds of service owners in the organisation and how it can be supported by a tool. Do you think the process and tool could be applied also in a context other than PN and RoPA (for instance, for managing general service documentation, for managing information security documents such as a disaster recovery plan)?\nThe paper describes how the (initial) information is collected from the service owners. How do you manage the process of keeping the collected information up-to-date over time?\nThe paper mentions there are around 200 RoPAs and PNs for different personal data filing systems. Have you considered bundling them together for their easier management? For instance, services that are similar enough could share RoPA and PN.\nIn the bottom left cell of Table 1: If EBI is a data processor, it shouldn't publish a PN as it is the responsibility of the data controller.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? Yes",
"responses": []
},
{
"id": "170480",
"date": "09 May 2023",
"name": "Harshvardhan Pandit",
"expertise": [
"Reviewer Expertise Data Protection",
"Semantics",
"Data Governance"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article describes a case study where an organisation has fulfilled its obligation to manage ROPA and Privacy Notices based on the GDPR. The use of document templates to manage collection and approval processes within the organisation is described, and examples are provided as supplementary data. The case study is sufficiently described to present the information and its benefits, as well as outline how ROPA and Privacy Notices are managed internally. This topic has received little attention in literature and therefore the article provides valuable insight to the state of the art.\nIn terms of limitations, the article lacks adding references to existing work for GDPR, more specifically regarding ROPA and Privacy Notices. Please see article1 which presents ROPA requirements from an analysis of GDPR and all EU DPAs. The article contains further insight into the literature surrounding ROPA. Article2 also describes ROPA management processes.\nAnother limitation is comparison of ROPAs to other similar organisations, for example EDPS publishes its ROPA as public documents. Is the EMBL's ROPA also managed similarly in terms of data, structure, documents? Or are the organisational processes and information different enough that the solution described here is of limited use and must be adapted to use it elsewhere?\nFor the ROPA templates used, it is mentioned that joint-controller cases use the same template as controllers, with shared editing of the records. However, under GDPR a joint-controller ROPA must also specify who is responsible for implementing the processing whereas a (non-joint) controller ROPA will not have this information field. So the templates would be different for the two use-cases. Please clarify this in the article, whether the controller ROPA was extended with the additional field or the controller ROPA also contained a field that is only necessary in cases of joint-controllers.\nWhere relevant, please provide references to GDPR articles. For example, Article 30 defines the required fields for ROPA, and Articles 13 and 14 provide some of the requirements for Privacy Notices. These are important as they show where the requirements were collected from (and to assess whether these are complete) and also to link the fields back to their source (in GDPR).\nPlease provide information on the technologies used to collect information (e.g. web forms, spreadsheets), manage it (a database if used, formats), and tools used to generate ROPA and PNs. Were there any processes to verify all required information has been provided, or that it is complete/correct, and if there was any process to use or facilitate querying e.g. find all ROPAs for a given data source or service, or also to collate information from documents such as to create a combined list of all data categories being processed. If this information is not available, it would be a good candidate for future work.\nAs this is a case study, areas where difficulties or challenges were encountered would be welcome to identify areas of improvement. For example, as discussed above - what are the areas where technologies and tools can assist and make the process more efficient? Article1 works with a similar motivation as the case study, and tries to argue for a common specification for ROPA based on legal requirements. Would such work improve the EMBL's processes, e.g. by providing the form and management to take information, ensure it is correct, and to enable its use in document templates (as provided).\nDisclaimer: I (Harshvardhan Pandit) am one of the authors of the article1 mentioned in the review. I believe the self-promotion is justified as I believe the article is of importance to the work described here and there are no other examples that could be used instead.\n\nIs the background of the case’s history and progression described in sufficient detail? Yes\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Not applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes\n\nIs the case presented with sufficient detail to be useful for teaching or other practitioners? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-500
|
https://f1000research.com/articles/11-185/v1
|
14 Feb 22
|
{
"type": "Research Article",
"title": "Modelling sociodemographic factors that affect malaria prevalence in Sussundenga, Mozambique: a cross-sectional study.",
"authors": [
"Joao Ferrao",
"Dominique Earland",
"Anisio Novela",
"Roberto Mendes",
"Marcos Ballat",
"Alberto Tungadza",
"Kelly Searle",
"Dominique Earland",
"Anisio Novela",
"Roberto Mendes",
"Marcos Ballat",
"Alberto Tungadza",
"Kelly Searle"
],
"abstract": "Background: Malaria is still one of the leading causes of mortality and morbidity in Mozambique with little progress in malaria control over the past 20 years. Sussundenga is one of most affected areas. Malaria transmission has a strong association with environmental and sociodemographic factors. The knowledge of sociodemographic factors that affects malaria, may be used to improve the strategic planning for its control. Currently such studies have not been performed in Sussundenga. Thus, the objective of this study is to model the relationship between malaria and sociodemographic factors in Sussundenga, Mozambique. Methods: Houses in the study area were digitalized and enumerated using Google Earth Pro version 7.3. In this study 100 houses were randomly selected to conduct a community survey of Plasmodium falciparum parasite prevalence using rapid diagnostic test (RDT). During the survey, a questionnaire was conducted to assess the sociodemographic factors of the participants. Descriptive statistics were analyzed and backward stepwise logistic regression was performed establishing a relationship between positive cases and the factors. The analysis was carried out using SPSS version 20 package. Results: The overall P. falciparum prevalence was 31.6%. Half of the malaria positive cases occurred in age group 5 to 14 years. Previous malaria treatment, population density and age group were significant predictors for the model. The model explained 13.5% of the variance in malaria positive cases and sensitivity of the final model was 73.3%. Conclusion: In this area the highest burden of P. falciparum infection was among those aged 5–14 years old. Malaria infection was related to sociodemographic factors. Targeting malaria control at community level can combat the disease more effectively than waiting for cases at health centers. These finding can be used to guide more effective interventions in this region.",
"keywords": [
"sociodemographic",
"social determinants of health",
"malaria",
"prevalence",
"Sussundenga"
],
"content": "Background\n\nMalaria is a serious and sometimes fatal disease caused by a Plasmodium spp. parasite that commonly infects Anopheles spp. mosquitos which feed on humans. Although malaria can be a deadly disease, infection and death can be prevented.1 Almost half of the world’s population lives in areas at risk of malaria transmission. Six countries account for more than half of all malaria cases worldwide and Mozambique is among them.2\n\nIn Mozambique, a country in Sub-Saharan Africa, with a population of over 30 million, malaria is one of the leading causes of mortality and morbidity. In 2018, Mozambique recorded the third largest number of malaria cases in the world, accounting for 5% of all cases.3\n\nThe country has made little progress in malaria control. Indoor residual spraying (IRS), insecticide treated bed nets (ITNs), and parasitological diagnosis in health facilities using rapid diagnostic test (RDTs) with effective artemisinin combination therapy (ACT) are the forms of malaria intervention currently being used. The entire country uses RDTs with ACT as the standard of care in public health facilities and ITNs are only available at antenatal clinics, indicated for pregnant women and children under five.4\n\nManica Province in central Mozambique has the second highest number of malaria incidences in the country. In the first quarter of 2020, there were 1,039,283 recorded cases with an incidence of 371 per 1000 inhabitants.5 Sussundenga village, in Manica Province is one of most affected areas, with 31,397 malaria cases reported in 2019.\n\nMalaria risk, disease severity, and clinical outcome depend on environmental, sociodemographic, economic, and behavioral factors.6–9 A study in Chimoio, the provincial capital of Manica, close to Sussundenga Village, modelled the influence of climate on malaria occurrence. The study indicated that selected environmental characteristics accounted for 72.5% of malaria incidences, implying that non-environmental factors such as sociodemographic, economic, cultural and behavioral traits would account for the rest.10\n\nWhile Mozambique is a country with one of the highest incidences and prevalence of malaria in the region and, it accounts for nearly half of childhood deaths, little is known about the epidemiology to inform appropriate and effective interventions. This is one of two major barriers to expanding control measures in the country with the other being limited funding.\n\nIn the country, malaria transmission occurs all year round and, the knowledge of sociodemographic factors that affect malaria is crucial for informing the implementation of the most appropriate and effective malaria interventions to achieve control. In Sussundenga no studies are known in this field. Therefore, the objective of this study was to model the relationship between malaria and sociodemographic factors in Sussundenga’s rural municipality.\n\n\nMethods\n\nThe village of Sussundenga is a rural, agrarian community 40 km from the Zimbabwe border, and is 40 km from the provincial capital of Chimoio (Figure 1).\n\nA. Map of Mozambique, Manica province and Sussundenga district: adapted from National Cartography and Remote Sensing Centre (CENACARTA).11 B. Sampled site in Sussundenga village: adapted from CENACARTA.\n\nSussundenga has an estimated population of 31,429 inhabitants, 47% males and 53% females. The age distribution is: 19.5% from 0 to 4 years old, 29.9% from 5 to 14-years-old, 20.5% from 15 to 24 years old and 30.1% with over 24 years old. The village is divided administratively in 17 residential areas (neighborhoods).11\n\nThe climate is tropical with an average annual precipitation of 1,200 mm. The rainy season occurs from November to April. The average minimum temperature is 6.3°C in the month of July and the average maximum temperature is 38.9°C in the month of January and the annual average is 21.2°C.12\n\nGoogleEarth ProTM Google Earth Pro version 7.3 (Google, Amphitheatre Pkwy, Mountain View, CA, USA). satellite imagery was used to digitize and enumerate all household structures in the village of Sussundenga (Figure 2). This was a pilot study to determine malaria prevalence, risk factors, and health seeking behaviors. The sample size was determined by feasibility for the study team and study design of the community based cross-sectional survey. All households in the study area were digitized and enumerated using Google Earth Pro. With the aim of enrolling 100, a random sample of 125 households was taken, as backup for refusals and errors in the digitizing process (misclassified non-household structures).\n\nCoordinates of the households were extracted using a GPS device and maps of the selected households to conduct study visits. The study involved two visits to the selected households. The first was a notification visit where the study team introduced themselves to the head of the household and explained the objectives and procedures of the study. It is customary for the head of household to provide permission to the study team before any activities take place at the household involving other household members. Once the head of household gave permission, the study team conducted a household census with the head of household and begin the process of individual written informed consent with the household residents, for all adult (18+ years) residents and parental permission and consent from minors.\n\nAfter obtaining consent from the household residents, the study team informed participants when they would return the following day to conduct the study activities. The only eligibility requirement was that the residents live in the household full time. Data collectors verbally administered a questionnaire to collect the basic demographics. The field study was carried out from December 2019 to January 2020.\n\nThe study nurse collected current malaria specific symptoms by self-report and took participant’s temperature using a digital thermometer (GP-300, RoHS:ISO 9000). They then collected a finger prick blood sample to administer a Rapid Diagnostic Test (RDT), RightSign BiotestR (Biotest, Hangzhou Biotest Biotech Co, China, Ref.No:IMPF – C51S). According to the manufacture, this test captures the HRP2 antigen on the strip and has a sensitivity is >99.0%. The results were recorded and, in the event, that a participant was positive for malaria, the study nurse referred them to the Sussundenga rural health center (RHC) for diagnosis confirmation and treatment. The questionnaire was conducted using tablet computers with the REDCap a secure, web-based data capture tool. Study data were collected and managed using REDCap electronic data capture tools hosted at University of Minnesota13 downloaded to an Excel sheet for analysis.42 REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources.\n\nThis study was a cross-sectional community-based survey. The analyses were conducted on datasets downloaded from REDCap to an Excel spread sheet. A binary variable was used to represent the dependent variable, malaria infection, to show whether malaria was present (positive) to RDT or absent (negative) was used.\n\nThe explanatory variables analyzed were the following sociodemographic factors: age, if the person was an adult or child, age category, sex, history of malaria treatment, paid employment, cell phone ownership, education level, population density, location (neighborhood), household category and household size.\n\nThe malaria prevalence, was calculated by dividing positive cases of malaria by the study population tested at the time multiplied by 100.14\n\nChi-square for proportion of age group and sex was tested. To establish the relationship between malaria prevalence and sociodemographic factors, logistic backward stepwise logistic regression was used with the following model:\n\nWhere: G (Pi) = link function\n\nPi = likelihood of response for the -ith factor\n\nßo = intercept\n\nß1 = coefficient\n\nxi = independent variable.\n\nThis method starts with a full (saturated) model and each step gradually eliminates variables that do not contribute. Allowing for a reduced model that best explains the data. This method is useful since, it reduces the number of predictors, reducing multicollinearity and resolves overfitting.15\n\nTo evaluate potential confounders and, effect modifiers between the final model variables, the Hosmer–Lemeshow (1989) test was performed.16 To build the final model, the independent variables p<0.05 were included. Outcomes such as scores statistic’s, regression coefficient’s, significance levels of variable coefficients and, overall classification accuracy were performed.\n\nThe sensitivity (conditional probability of a positive test given that the patient has malaria) of the final model measures the proportion of positive that were correctly identified and, was calculated using14:\n\nThe specificity (conditional probability of a negative test given that the patient is well) of the final model measures the proportion of negative case correctly identified and was calculated using17:\n\nPositive predictive value (PPV) that is, the conditional probability, whether the screened people who tested positive do or do not actually have malaria was calculated using17:\n\nNegative predicted value (NPV) that is, the conditional probability that an individual with a test indicative of no malaria infection is actually disease free, was calculated using17:\n\nAll tests were carried out using SPSS IBM version 20 (IBM Corporation, Armonk, New York, USA) (RRID: SCR_002865).\n\n\nResults\n\nFrom 125 selected households 100 were visited Figure 3 presents the positive and negative cases per visited site. Of the 358 participants tested and, interviewed 108 (31.6%) tested positive for malaria. There was an equal distribution of the enrolled participants among sex, 55% were female and 45% males, Chi-squared = 0.081, P = 0.8872, Degree of freedom (DF) = 1.\n\nThe age of participants varied from 1 to 80 years old, with a median of 17 years and an average of 21 standard deviation (SD), 16.2 years old. The participants’ education level varied, where 35.1% had no education or less than primary (5 grades), 47.4% had primary or basic school (grades 5 to 10) and 17.5% had secondary and higher education.\n\nFigure 4 presents the malaria positivity results for age categories. Half of the malaria positive cases occurred among those 5 to 14 years age category. This category comprises has 32.7% of the Sussundenga population according to the National Institute of Statistics (INE). The age category of over 24 years presented 17.6% of the malaria cases, this age category comprises 30.4% of the Sussundenga population according to the INE. There was a statistically significant difference in positive malaria cases among groups, chi-square = 17.527, P = 0.0075, Df = 6.\n\nThe backward stepwise regression selection of predictors into the binary logistic model produced a series of models and, in this study, we only present the relevant, initial models and other outputs can be found in appendix 1.\n\nTable 1 presents the backward stepwise (Wald) model summary and the Nagelkerke’s R2 in final step is 0.135. This suggests that presence of malaria variation shown in the dependent variable of this model is approximately 13.5%.\n\na Estimation terminated at iteration number 5 because parameter estimates changed by less than .001.\n\nb Estimation terminated at iteration number 4 because parameter estimates changed by less than .001.\n\nTable 2 presents the Hosmer and Lemeshow test, indicating that this model fit the data.\n\nTable 3 presents the classification table of the final model, that is, the models capability to predict malaria positive cases, indicating a model accuracy of 71.6%. The sensitivity of the final model in classifying malaria positive cases is 73.3% and specificity of the final model to classify malaria negative cases is 93.3%. The positive predictive value is 66% and, the negative predictive value is 72.5% meaning that, the final model is able to predict 66% of malaria positive tests and, 72.5% negative malaria tests.\n\na The cut-off value is .500.\n\nTable 4 presents the Wald’s test of significance and the odds ratio predictors variables in the final model. From the results, pervious malaria treatment (p=0.15), population density (p=0.05), and age group (p=0.00) were significant predictors while, household category did not add significantly to the model. The table indicates that the age category 0 to 4 years old as almost three times more likely to test positive for malaria (OR 2.829, 95% CI 1.153–6.944), 3.6 times (OR 3.61, 95% CI 1.952 – 6.755) for age group 5 to 14 years and, 1.6 times for the age group of 15 or older (OR 1.603, 95% CI 0.824 – 3.117).\n\na Variable(s) entered on step 1: Adult or child, Sex, Previous malaria treatment, Employment, Age, Cell phone, Education, Population density, Household size, HH category, Age category, Location.\n\nThe built model is:\n\n\nDiscussion\n\nIn this study, malaria prevalence was 31.6% for Sussundenga Village, much higher than the prevalence recorded in Chimoio city (20.1%).18 In the neighboring Zimbabwe, malaria prevalence was 19.5% in Mutare and 50.9% in Mutasa districts in 2016.19 In southern Zambia a study in 2020, reported parasite prevalence between 0.7 and 1.8%20 and, 34% in Malawi in 2016.21\n\nNo significant difference was found between different sexes in this study. Similar results were reported in Chimoio, Mozambique in 2018,18 in Malawi in 202022 and in Zimbabwe23 in 2021.\n\nThis study recorded half of the malaria prevalence in the 5 to 14 years age category and, an odds ratio of 3.61. In Ghana this age groups accounted for 43.3% and, in Rwanda the odds of infection by malaria were reported to be 1.817 times for this age category.24,25 Studies in Kenya indicated that highest malaria prevalence occurs in children between ages of 11 to 14 and, children from 5 to 18 years as the most at-risk age category.26,27 Contrarily, in Chimoio, Mozambique it was reported 52% of malaria cases are found in children under five,18 this discrepancy may due to the fact that the present study was carried out at community level while, the Chimoio study was carried out from health center data.\n\nThis study suggests that recent diagnosis and treatment for malaria infection reduces the odds of subsequent infection approximately by 54.5%. Similar results were reported in Mozambique, Ghana, Comoros, Kenya, Indonesia and India.28–34 This reduction in odds is likely due to prophylactic effect of ACT. It provides protection from 2 weeks to 1 month after completion. After repeated infections, the individual develops a certain degree of immunity. Also, when re-infected, patients tend to present a mild form of the diseases without symptoms and, natural active immunity is established after ten or more P. falciparum infections, which can be sufficient to suppress symptoms and clinical signs.35\n\nDifferent results were reported in Angola where women who had a previous malaria infection during pregnancy also had a higher risk to contract malaria.36 This is likely because pregnant women may take sulfadoxine-pyrimethamine rather than ACT.\n\nIn this study population density was found as a significant predictor for an individual to test positive for malaria. Similar results were reported in Chimoio18 in 2016, in a study in 14 endemic African countries37 in 2017 and in Ethiopia38 in 2015.\n\nThe variables age, if the person was an adult or child, sex, paid employment, cell phone ownership, education level, location (Bairro) and household size were removed from the model due to redundancy and for not adding significance to the model.\n\nThe age category is a good proxy for age group and, household size for household category. Paid employment and cell phone ownership variables were included in this study, as rural wealth indicators. These were not found significant predictors contrary to a study in Mozambique that indicated that, children from higher income families (58%) tend to be at lower risk for malaria compared to children from lower income families (43%).39 Another study in sub-Saharan Africa40 showed that, malaria prevalence increases with a decrease in income in 2018.\n\nEducation level was not finding significant predictor in this study. Similar results were reported in Malawi in 2018,41 Indonesia and India.33,34 There were conflicting results reported in Mozambique39 in 2011, in Ghana in 2014 and in Sub-Saharan Africa40 in 2018.\n\nIn this study it is suggested that approximately 13.5% of the variation in malaria infection can be attributed to sociodemographic and economic traits. A previous study modelled the influence of climate on malaria occurrence in Chimoio and indicated that environmental traits accounted for 72.5% of malaria occurrences.7 This implies that non-environmental factors such as sociodemographic, economic, cultural and behavioral traits could partially account for the remaining percentage, consistent with the present study.\n\nThe capability model using social, economic, and demographic variables to predict malaria positive cases (model accuracy), was 72.3% in this study. A logistic regression model analyzing hematological parameter and age in Ghana reported 77.4%.24 The sensitivity of the final model in classifying malaria positive cases was 73.3% and the final model was able to predict 66% (PPV) meaning that the model is very effective in predicting malaria infection using sociodemographic characteristics. In Iran a model predicting malaria re-introduction reported 81.8% positive predictive value41 and 52.72% in Ghana in a model analyzing hematological parameter and age.27\n\nData collection for this study was conducted in December and January during the rainy and wet season which is also the peak malaria transmission season. Because of this, it is likely that we detected a large number of infections and results reflect this season and my not be representative of malaria dynamics in the dry season. The RightSign Biotest R test detects the histidine rich protein 2 antigen of the P. falciparum parasite which can last over a month in the blood among patients recently treated with malaria.\n\n\nConclusion\n\nThis study evaluated the sociodemographic factors that affect malaria prevalence in Sussundenga Village, Mozambique. Recent diagnosis and treatment, population density and age category were found to be significant predictors. The model accuracy was 72.3% implying that the model is robust. Targeting malaria control at the community level can contribute to decreased transmission that may be more impactful than passive case detection and treatment alone. This model indicates that 13.5% of malaria cases can be attributed to sociodemographic factors while previous studied indicated that environmental conditions are attributed to approximately 73% of malaria cases. Further studies are needed especially in the dry season and in other areas of the district to fully understand the malaria transmission dynamics in this region and inform efficient control measures.\n\n\nData availability\n\nHarvard Dataverse: Replication Data for: Modelling sociodemographic factors that affect malaria prevalence in Sussundenga, Mozambique: a cross-sectional study. https://doi.org/10.7910/DVN/BUMDEM.42\n\nThis project contains the following underlying data:\n\n- [Aditional file -F1000Research.tab] (raw data from questionnaires).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nEthical consideration\n\nThis study is part of the Malaria Risk, Prevention, and Health Seeking Behaviors in Sussundenga, Mozambique Project. All participants, or the guardians provided informed written assent and consent prior to participation. Ethical review and approval for the study was completed by the Institutional Review Board (IRB) at the University of Minnesota [STUDY00007184] and from A Comissão Nacional de Bioética em Saúde (CNBS) at the Ministry of Health of Mozambique [IRB00002657]. The images taken from google and other sites were properly cited and referenced.",
"appendix": "Acknowledgments\n\nWe would like to thank the provincial and district directorates of health to grant permission to carry out this study especially the Dr. Firmino Jaqueta, Dr. Serafina Benesse, Dr. Filipe Murgorgo and Mrs. Elsa Trabuco. We also thank Mr. Gabriel Viegas for editing figures. A preprint version of this article can be found on Research Square (DOI: 10.21203/rs.3.rs-614728/v1).\n\n\nReferences\n\nCenters for Disease Control and Prevention: About Malaria-Biology. Centers for Disease Control and Prevention; 2012. Accessed July 14, 2020. Reference Source\n\nWorld Health Organization: The World malaria report 2018. WHO; 2018. Accessed July 27, 2020. Reference Source\n\nWorld Health Organization: Making strides against malaria in Mozambique: Control, prevention and treatment in action. WHO; 2020. Accessed July 14, 2020. Reference Source\n\nWorld Health Organization: Mozambique 2018. WHO; 2018. Accessed July 14, 2020. Reference Source\n\nDPS: Relatório Do Primeiro Semestre Do Ano 2020. Governo da Provincia de Manica; 2020.\n\nChuang TW, Soble A, Ntshalintshali N, et al.: Assessment of climate-driven variations in malaria incidence in Swaziland: toward malaria elimination. Malar. J. 2017; 16: 232. PubMed Abstract | Publisher Full Text\n\nManh BH, Clements ACA, Thieu NQ, et al.: Social and environmental determinants of malaria in space and time in Viet Nam. Int. J. Parasitol. 2011; 41: 109–116. PubMed Abstract | Publisher Full Text\n\nInstituto Nacional de Estatística: Inquérito Demográfico e de Saúde. INE; 2011. Accessed July 14, 2020. Reference Source\n\nEdwin P, Msengwa A: Prevalence and socio-demographic factors associated with malaria infection among children under five years in Tanzania. Jour. Pub. Helt. Epid. 2018; 10: 387–394. Publisher Full Text\n\nFerrão JL, Mendes JM, Painho M: Modelling the influence of climate on malaria occurrence in Chimoio Municipality, Mozambique. Parasit. Vectors. 2017; 10: 260. PubMed Abstract | Publisher Full Text\n\nCENACARTA. Uso Cobertura Solo: Accessed July 16, 2020. INE; 2016. Reference Source\n\nMinistério da Administração Estatal: Perfil Do Distrito De Sussundenga. INE; 2005. Accessed July 12, 2020. Reference Source\n\nHarris PA, Taylor R, Thielke R, et al.: Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 2009 Apr; 42(2): 377–381. PubMed Abstract | Publisher Full Text\n\nCenter for Disease Control: Principles of Epidemiology in Public Health Practice, Third Edition: An Introduction. CDC editor. CDC; Third2006. Reference Source\n\nde Oliveira EC , dos Santos ES , Zeilhofer P, et al.: Geographic information systems and logistic regression for high-resolution malaria risk mapping in a rural settlement of the southern Brazilian Amazon. Malar. J. 2013; 12. PubMed Abstract | Publisher Full Text\n\nLaerd Statistics: Binomial Logistic Regression using SPSS Statistics.Reference Source\n\nTrevethan R: Sensitivity, Specificity, and Predictive Values: Foundations, Pliabilities, and Pitfalls in Research and Practice Front. Public Health. 2017; 5. PubMed Abstract | Publisher Full Text\n\nFerrão JL, Mendes JM, Painho M, et al.: Spatio-temporal variation and socio-demographic characters of malaria in Chimoio municipality, Mozambique. Malar. J. 2016; 15: 329. PubMed Abstract | Publisher Full Text\n\nSande S, Zimba M, Chinwada P, et al.: A review of new challenges and prospects for malaria elimination in Mutare and Mutasa Districts, Zimbabwe. Malar. J. 2016; 15: 360. PubMed Abstract | Publisher Full Text\n\nBhondoekhan FRP, Searle KM, Hamapumbu H, et al.: Improving the efficiency of reactive case detection for malaria elimination in southern Zambia: A cross-sectional study. Malar. J. 2020; 19: 175. PubMed Abstract | Publisher Full Text\n\nMathanga DP, Tembo AK, Mzilahowa T, et al.: Patterns and determinants of malaria risk in urban and peri-urban areas of Blantyre, Malawi. Malar. J. 2016; 15: 590. PubMed Abstract | Publisher Full Text\n\nChilanga E, Collin-Vézina D, MacIntosh H, et al.: Prevalence and determinants of malaria infection among children of local farmers in Central Malawi. Malar. J. 2020; 19: 308. PubMed Abstract | Publisher Full Text\n\nMundagowa P, Chimberengwa PT: Poor housing construction is associated with contracting malaria in a rural area south of Zimbabwe: A Case-control Study. Malar. J. Publisher Full Text\n\nPaintsil EK, Omari-Sasu AY, Addo MGBM: Analysis of Haematological Parameters as Predictors of Malaria Infection Using a Logistic Regression Model: A Case Study of a Hospital in the Ashanti Region of Ghana 2019. Malar. Res. Treat. 2019; 2019: 1–7. PubMed Abstract | Publisher Full Text\n\nZeleke GT, Egide H, Francois T: Application of Logistic Regression Model to Identify Potential Risk Factors of Malaria in Rwanda using 2010 Demographic and Health Survey. IJASM. 2015; 2(3): 50–54. Reference Source\n\nSultana M, Sheikh N, Mahumud RA, et al.: Prevalence and associated determinants of malaria parasites among Kenyan children. Trop Med Health. 2017 Oct 23; 45: 25. PubMed Abstract | Publisher Full Text\n\nNankabirwa J, Brooker SJ, Clarke SE, et al.: Malaria in school-age children in Africa: an increasingly important challenge. Tropical Med. Int. Health. 2014 Nov; 19(11): 1294–1309. PubMed Abstract | Publisher Full Text\n\nWorld Bank: Inquérito Nacional sobre Indicadores de Malária 2018.2019. Reference Source\n\nDi Gennaro F, Marotta C, Pizzol D, et al.: Prevalence and predictors of malaria in human immunodeficiency virus infected patients in beira, mozambique. Int. J. Environ. Res. Public Health. 2018; 15(9): 2032. PubMed Abstract | Publisher Full Text\n\nNdong IC, Okyere D, Enos JY, et al.: Prevalence of asymptomatic malaria parasitaemia following mass testing and treatment in Pakro sub-district of Ghana. BMC Public Health. 2019; 19: 1622. PubMed Abstract | Publisher Full Text\n\nArtadji A: Recul et persistance du paludisme en Union des Comores: une approche géographique pour déterminer l’importance des facteurs environnementaux et sociaux dans son maintien. Géographie Univ la Réunion. 2019. Reference Source\n\nErnst KC, Lindblade KA, Koech D, et al.: Environmental, socio-demographic and behavioural determinants of malaria risk in the western Kenyan highlands: A case-control study. Tropical Med. Int. Health. 2009; 14(10): 1258–1265. PubMed Abstract | Publisher Full Text\n\nHasyim H, Dale P, Groneberg DA, et al.: Social determinants of malaria in an endemic area of Indonesia. Malar. J. 2019; 18(1): 134. PubMed Abstract | Publisher Full Text\n\nRanjbar M, Shoghli A, Kolifarhood G, et al.: Predicting factors for malaria re-introduction: An applied model in an elimination setting to prevent malaria outbreaks. Malar. J. 2016; 15(1): 138. PubMed Abstract | Publisher Full Text\n\nMioto LD, Ligia Carla Faccin Galhardi MKA: Aspectos parasitológicos e imunológicos da malária. Bios. 2012; 14(1): 42–55. Reference Source\n\nCampos PA, Valente B, Campos RB, et al.: Plasmodium falciparum infection in pregnant women attending antenatal care in Luanda. Angola. Rev Soc Bras Med Trop. 2012; 45(3): 369–374. PubMed Abstract | Publisher Full Text\n\nBouma MJ, SantosVega M, Yeshiwondim AK, et al.: Temperature and population density determine reservoir regions of seasonal persistence in highland malaria. Proc. R. Soc. B. 2015; 282: 20151383. Publisher Full Text\n\nThe impact of urbanization and population density on childhood Plasmodium falciparum parasite prevalence rates in Africa Caroline W. Kabaria1,2*, Marius Gilbert3,4, Abdisalan M. Noor2,5, Robert W. Snow2,5 and Catherine Linard3,6.\n\nInstituto Nacional de Estatistica Inqueriro Sociodemografico e de Saude 2011. INE; 2012. Reference Source\n\nDegarege A, Fennie K, Degarege D, et al.: Improving socioeconomic status may reduce the burden of malaria in sub–Saharan Africa: A systematic review and meta-analysis. PLoS One. 2019; 14(1): e0211205. PubMed Abstract | Publisher Full Text\n\nKabaghe AN, Chipeta MG, Gowelo S, et al.: Fine-scale spatial and temporal variation of clinical malaria incidence and associated factors in children in rural Malawi: a longitudinal study. Parasit. Vectors. 2018; 11: 129. PubMed Abstract | Publisher Full Text\n\nFerrao J: 2021. Replication Data for: Modelling sociodemographic factors that affect malaria prevalence in Sussundenga, Mozambique: a cross-sectional study. Harvard Dataverse, V1, UNF:6:AOiZHf6kq1bQfKIDHoh+MA== [fileUNF].Publisher Full Text"
}
|
[
{
"id": "127464",
"date": "01 Apr 2022",
"name": "Ewan Cameron",
"expertise": [
"Reviewer Expertise Malaria risk stratification",
"statistics",
"mechanistic disease modelling",
"model calibration"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn the manuscript entitled, \"Modelling sociodemographic factors that affect malaria prevalence in Sussundenga, Mozambique: a cross-sectional study\", the authors present the results of a survey and statistical analysis designed to uncover predictors of positive parasite status by rapid diagnostic test in this area of endemic malaria transmission. Malaria is a significant contributor to disease burden in Mozambique, so this topic is of high importance. In my report below I raise a number of questions for the authors regarding aspects of the analysis that were unclear to me (i.e., perhaps where the clarity of presentation could be improved) or where I felt that further analysis might strengthen the conclusions.\nContext and Aims:\nThe framing of the study in terms of context and aims as it currently stands deserves considerable review. Owing precisely to its status as one of the most malarious countries in the world, Mozambique has attracted a great deal of attention from malaria researchers over many decades and there have been many studies investigating environmental and socio-demographic factors behind malaria transmission in the country. For example, Temu et al. (Plos One, 2012)1 identified IRS use, pig-keeping, and house construction as key factors influencing malaria risk in Zambezia province. See also, Brentlinger et al. (Am J Trop Med Hyg, 2007)2. Likewise, there are many studies examining factors related to explanatory factors for malaria prevalence such as treatment seeking (Cassy et al. Mal J, 2019)3 and ITN use (Moon et al., Mal J, 2016)4. Factors shaping malaria risk in Mozambique have also recently been studied in the context of measuring the impact of malaria control strategies in Mozambique by Galatas et al. (Plos Medicine, 2020)5.\n\nThis wealth of prior research and understanding contrasts strikingly with the authors' proposition that \"little is known about the epidemiology to inform appropriate and effective interventions\". Importantly, it also raises the question of why information on two well-known factors shaping malaria transmission in Mozambique, namely IRS and ITN use, do not seem to have been captured or included in this study? Another key known factor, household construction, may have been included but there is no detail that I could see in the manuscript to illuminate the meaning of the \"household category\" variable used in the model?\n\nRegarding the statement \"ITNs are only available at antenatal clinics, indicated for pregnant women and children under five\": I'm not sure that this is well phrased, since the WHO recommends universal net use in high transmission areas. While ITN distribution campaigns focus on the highest risk groups of young children and pregnant women these are not the only groups who should be advised to use bed nets; likewise, ITNs would generally be available commercially at markets. (See e.g. Scott et al. Mal J, 2021)6.\n\nStatistical Analysis:\nThe statistical analysis method used to derive the primary results of this study, namely the identification of key factors behind malaria prevalence in the study area, is a stepwise logistic regression, which is indeed appropriate for this objective. Some minor details require clarification or revision:\n\n(i) there are some minor formatting errors in the equations: e.g. on page 5, equation 2 uses lower case g and then an upper case G for seemingly the same function, and betai should have a subscript i as in beta_i; on page 8 the last equation should have 1.289 \"x\" Age category (5 to 14 years) instead of \"+\"\n(ii) \"To evaluate potential confounders and, effect modifiers between the final model variables, the Hosmer–Lemeshow (1989) test was performed.\" This doesn't make sense to me: the HM test is for model specification / acceptable fit, rather than for breaking variables down into their roles in the causal hierarchy.\n(iii) I was confused by the chi square test reports in some places: for the distribution by sex the chi-squared statistic of 0.081 doesn't sound like the right order of magnitude and in fact I get 0.081 as the p-value for a binomial exact test on this sample so perhaps this is a typo?; for the tests by age category, since this is a four x two table I would have thought we're looking at 3 degrees of freedom rather than 6?\n(iv) The population density variable must have a large dynamic range because it is assigned a slope (\"constant\"?) of 0.000 in table 8: could this be rescaled so that we can see its slope within the 3 decimal places?\n(v) I was confused why the age categories changed from four in the earlier discussion to three in Table 4? Also, it would help to nominate one age group as the reference group so that the odds ratios can be understood as relative to that group.\n(vi) I'm confused by the focus on understanding the predictive accuracy of the model in terms of specificity and sensitivity(*), which are appropriate for a diagnostic tool, but which may not be particularly relevant to the use of a risk factor model such as this one for field epidemiology. I.e., if the end use is to prioritise the delivery of a particular intervention such as seasonal malaria chemopraxis then identifying that a certain age group has twice the parasite prevalence of another could be of substantial value even where the sensitivity was low because prevalence itself was very low across both strata. This comes back to the context and aims of the study, in the sense that the value of the fitted model (or more precisely the knowledge discovered through it) is ultimately something that exists only relative to the way in which it is intended to be used.\n(*also: are these defined according to a thresholding of the predictive prevalence above and below 50%?)\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "8168",
"date": "12 May 2022",
"name": "Joao Ferrao",
"role": "Author Response",
"response": "Dear Reviewer. thank you very much for your precious comments. They are very useful and they were used to improve the manuscript. In the manuscript entitled, \"Modelling sociodemographic factors that affect malaria prevalence in Sussundenga, Mozambique: a cross-sectional study\", the authors present the results of a survey and statistical analysis designed to uncover predictors of positive parasite status by rapid diagnostic test in this area of endemic malaria transmission. Malaria is a significant contributor to disease burden in Mozambique, so this topic is of high importance. Response: Thank you very much for the comment. In my report below, I raise a number of questions for the authors regarding aspects of the analysis that were unclear to me (i.e., perhaps where the clarity of presentation could be improved) or where I felt that further analysis might strengthen the conclusions. Response: Thank you very much. All comments will be taken in consideration accordingly. Context and Aims: The framing of the study in terms of context and aims as it currently stands deserves considerable review. Response: Thank you very much for the comment. The review will be done according to the reviewer's suggestions. Owing precisely to its status as one of the most malarious countries in the world, Mozambique has attracted a great deal of attention from malaria researchers over many decades and there have been many studies investigating environmental and socio-demographic factors behind malaria transmission in the country. For example, Temu et al. (Plos One, 2012)1 identified IRS use, pig-keeping, and house construction as key factors influencing malaria risk in Zambezia province. See also. Response: Thank you very much for the comment. These studies were considered in our discussion. Considering the size of the country 800,000 Km2, more than 2,700 Km long, its heterogeneity in terms of landscape, sociodemographic and culture and poor resources, I would consider that the number of studies “investigating environmental and socio-demographic factors behind malaria transmission in the country” very few for local programmatic decisions making policies. See also Brentlinger et al. (Am J Trop Med Hyg, 2007). Response: Thanks for the recommendation. We find two studies from the recommended authors. However, we feel that they are specific for HIV patients and are outdated. Likewise, there are many studies examining factors related to explanatory factors for malaria prevalence such as treatment seeking (Cassy et al. Mal J, 2019) and ITN use (Moon et al., Mal J, 2016). Response: Thanks very much for the observations. Two articles (2019 and 2022 on care seeking were found and include in our discussion. As stated in the paper “This study is part of the Malaria Risk, Prevention, and Health Seeking Behaviors in Sussundenga, Mozambique Project”. There is another study dealing specifically with this issue. Factors shaping malaria risk in Mozambique have also recently been studied in the context of measuring the impact of malaria control strategies in Mozambique by Galatas et al. (Plos Medicine, 2020)5. Response: Thank you very much for the comment. The studies were considered in our discussion. This wealth of prior research and understanding contrasts strikingly with the authors' proposition that \"little is known about the epidemiology to inform appropriate and effective interventions\". Importantly, it also raises the question of why information on two well-known factors shaping malaria transmission in Mozambique, namely IRS and ITN use, do not seem to have been captured or included in this study? Response: Thank you very much for rising a very important issue of IRS and ITN use. We do consider IRS and ITN use suiting better as “health seeking behaviors” and due to its high relevance, a separate paper was produced: https://www.researchgate.net/publication/357008627_P_Falciparum_Community_Prevalence_and_Health_Seeking_Behaviors_in_Rural_Sussundenga_District_Mozambique Another key known factor, household construction, may have been included but there is no detail that I could see in the manuscript to illuminate the meaning of the \"household category\" variable used in the model? Response: Thank you very much for the question. Household size and household construction are very important variables. In the methodology we rephrase the variables and their meaning. We hope that now is clear that household category means type of house or type of construction. In this study, household category or household construction was found as a predictor variable. Regarding the statement \"ITNs are only available at antenatal clinics, indicated for pregnant women and children under five\": I'm not sure that this is well phrased, since the WHO recommends universal net use in high transmission areas. While ITN distribution campaigns focus on the highest risk groups of young children and pregnant women these are not the only groups who should be advised to use bed nets; likewise, ITNs would generally be available commercially at markets. (See e.g. Scott et al. Mal J, 2021)6. Response: Thank you for the comment. We do agree that “young children and pregnant women are not the only groups who should be advised to use bed nets; Indeed, recent studies are indicating an age shift in Malaria due this situation. As for the statement: “likewise, ITNs would generally be available commercially at markets. We would agree in a “normal” market driven country. For the Mozambican case where, most people are living bellow the poverty line, buying a mosquito net for prevention can be a luxury. For example, in 2021, a mosquito factory in Chimoio, Manica closed it is doors and the major reason was lack of clients to purchase the nets. We added this useful contribution in our discussion. Statistical Analysis: The statistical analysis method used to derive the primary results of this study, namely the identification of key factors behind malaria prevalence in the study area, is a stepwise logistic regression, which is indeed appropriate for this objective. Some minor details require clarification or revision: Response: Thank you very much for the observation. there are some minor formatting errors in the equations: e.g. on page 5, equation 2 uses lower case g and then an upper-case G for seemingly the same function, Response: Thank you very much for observation. This was corrected. and betai should have a subscript i as in beta_i; Response: Thank you for the observation. Correction was made. on page 8 the last equation should have 1.289 \"x\" Age category (5 to 14 years) instead of \"+\" Response: Thank you for the observation. \"To evaluate potential confounders and, effect modifiers between the final model variables, the Hosmer–Lemeshow (1989) test was performed.\" This doesn't make sense to me: the HM test is for model specification / acceptable fit, rather than for breaking variables down into their roles in the causal hierarchy. Response: Thanks for a very good observation We agree, to avoid confusing we rephrased the sentence. (iii) I was confused by the chi square test reports in some places: for the distribution by sex the chi-squared statistic of 0.081 doesn't sound like the right order of magnitude and in fact I get 0.081 as the p-value for a binomial exact test on this sample so perhaps this is a typo?; Response: Thank you for the observation. As stated in the methodology, “Sussundenga has an estimated population of 31,429 inhabitants, 47% males and 53% females”. In the present study, the enrolled participants among sex, 55% were female and 45% males. Using the Biostat 5.3 software we find the following out put The table was corrected. For the tests by age category, since this is a four x two table I would have thought we're looking at degrees of freedom rather than 6? Response: Thanks for the observation. We believe that is more appropriate to check the age category compared also to sample results and National Institute of Statistics projections for accuracy, giving us a 4 x 4 contingency table. The following recalculations are presented and were corrected in the manuscript. The table was corrected. The population density variable must have a large dynamic range because it is assigned a slope (\"constant\"?) of 0.000 in table 8: could this be rescaled so that we can see its slope within the 3 decimal places? Response: This was very important observation. We increased one decimal place and we rewrite the equation. I was confused why the age categories changed from four in the earlier discussion to three in Table 4? Response: Thank you for your valuable observation. We stated four age categories, 0 to 4, 5 to 14, 14 to 24 and > 24 (Additional file 1). The software did not find difference between age categories 14 to 24 and > 24 and grouped them as the same category. This seems to be right. Also, it would help to nominate one age group as the reference group so that the odds ratios can be understood as relative to that group. Response: Thank you for the observation. We fill that a priori, it would be difficult to select a reference age group. I'm confused by the focus on understanding the predictive accuracy of the model in terms of specificity and sensitivity(*), which are appropriate for a diagnostic tool, but which may not be particularly relevant to the use of a risk factor model such as this one for field epidemiology. I.e., if the end use is to prioritise the delivery of a particular intervention such as seasonal malaria chemopraxis then identifying that a certain age group has twice the parasite prevalence of another could be of substantial value even where the sensitivity was low because prevalence itself was very low across both strata. This comes back to the context and aims of the study, in the sense that the value of the fitted model (or more precisely the knowledge discovered through it) is ultimately something that exists only relative to the way in which it is intended to be used. Response: Thanks for the observation. Since sensitivity and specificity are measures of performance of a binary model, is pertinent to access them in the logistic model. We included an explanation in the methodology and we also discussed the results. (*also: are these defined according to a thresholding of the predictive prevalence above and below 50%?) Response: Yes"
}
]
},
{
"id": "129856",
"date": "14 Apr 2022",
"name": "Gabriel Zorello Laporta",
"expertise": [
"Reviewer Expertise Epidemiology of vector-borne diseases"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nFerrao et al. provide us with a cross-sectional study aimed at estimation of malaria falciparum prevalence in Mozambique, Africa. The study is well written and has good data, but some parts are not clear enough, as follows:\nStudy sample size and figure 2. Please specify the randomization process to select 125 households in the study area. What is the statistical power of the selection of 100 houses? If the study area’s landscape is heterogenous in terms of risk of malaria infection, is a random selection the best approach for selection? Should a stratified sample selection approach be used instead?\n\nTo estimate sensitivity and specificity, it is essential to have a training dataset and a testing dataset. The training dataset is to build a statistical model and the testing dataset is to evaluate the fitted model. Please specify the training and the testing data.\n\nThe built model shows that access to treatment and age are the only important predictors. Please explain the lack of importance of social and economic predictors in the built model. The built model shows a coefficient (1.289) lacking a variable. Please revise.\n\nRDT based on HRP2 has issues to detect falciparum lacking HRP2 genes. This is an important limitation and indicates that the estimates of prevalence may be underestimated.\n\nIn data source, please include labels to the variables’ levels per variable, i.e., 1=, 0=.\n\nConclusions have several issues:\n“Recent diagnosis and treatment, population density and age category were found to be significant predictors”. Issue: pop density was not significant predictor.\n“The model accuracy was 72.3% implying that the model is robust”. Issue: it depends on the approach that it was calculated.\n“This model indicates that 13.5% of malaria cases can be attributed to sociodemographic factors while previous studied indicated that environmental conditions are attributed to approximately 73% of malaria cases”. Issue: be specific of which sociodemographic factor, and environmental conditions were not studied in this study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "8167",
"date": "12 May 2022",
"name": "Joao Ferrao",
"role": "Author Response",
"response": "Dear Reviewer. thank you very much for your precious comments. They are very useful and they were used to improve the manuscript. Ferrao et al. provide us with a cross-sectional study aimed at estimation of malaria falciparum prevalence in Mozambique, Africa. The study is well written and has good data, but some parts are not clear enough, as follows: Study sample size and figure 2. Please specify the randomization process to select 125 households in the study area., what is the statistical power of the selection of 100 houses? If the study area’s landscape is heterogenous in terms of risk of malaria infection, is a random selection the best approach for selection? Should a stratified sample selection approach be used instead? Response: Thanks for the important question raised. Indeed, this was a pilot study to determine malaria prevalence, risk factors, and health seeking behaviors. The sample size was determined by feasibility for the study team and study design of the community based cross-sectional survey. All households in the study area were digitized and enumerated using Google Earth Pro. A random sample of 125 households was taken, with the aim of enrolling 100 to account for errors in the digitizing process. The village is relatively small (156.9 Km2) and we added the area of the village in the test. The Sussundenga village is within an area of 156.9 Km2. To estimate sensitivity and specificity, it is essential to have a training dataset and a testing dataset. The training dataset is to build a statistical model and the testing dataset is to evaluate the fitted model. Please specify the training and the testing data. Response: Thank you very much for the raised question. Usually the prediction of classes for data classification are based on finding the optimum boundary between classes. For this case where we used an accuracy with cut-off=0.5, we don’t see the need of training data. After data imputation and engendering feature the third step was to split data into train and test. This was carried out by the software. The built model shows that access to treatment and age are the only important predictors. Please explain the lack of importance of social and economic predictors in the built model. Response: Thank you very much for the question. Several studies indicated that the major causes of malaria occurrence are the climatic conditions specially temperature bellow 20oC the sporogony cease, and humidity below 50 and over 90 %. The built model shows a coefficient (1.289) lacking a variable. Please revise. Response: Thank you very much for the observation. This was revised, the variable is Age category (5 to 14 years). RDT based on HRP2 has issues to detect falciparum lacking HRP2 genes. This is an important limitation and indicates that the estimates of prevalence may be underestimated. Response: This is true and a limitation of the current HRP2 based RDTs. There are limited data on HRP2 deletions throughout Mozambique and specifically in Manica Province. However, in a study published in 2019 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711899/) the authors found very few cases of HRP2 deletion and impacts on the efficacy of the current RDTs. Of those infections not detected by the RDTs, not all were P. falciparum. It is unlikely in our study setting that HRP2 deletions impacted the efficacy of the RDT and biased our prevalence estimates. In data source, please include labels to the variables’ levels per variable, i.e., 1=, 0=,II) Conclusions have several issues: “Recent diagnosis and treatment, population density and age category were found to be significant predictors”. Issue: pop density was not significant predictor. Response: Thank you for the observation. Rescaled to 3 decimal places its significant. This was corrected in table. “The model accuracy was 72.3% implying that the model is robust”. Issue: it depends on the approach that it was calculated. Response: Thanks for the observation. “This model indicates that 13.5% of malaria cases can be attributed to sociodemographic factors while previous studied indicated that environmental conditions are attributed to approximately 73% of malaria cases”. Issue: be specific of which sociodemographic factor, and environmental conditions were not studied in this study. Response: Thank you very much for the observation. In the manuscript, more text was added to address this issue."
}
]
}
] | 1
|
https://f1000research.com/articles/11-185
|
https://f1000research.com/articles/11-497/v1
|
05 May 22
|
{
"type": "Systematic Review",
"title": "Effects of exercise training on cardiotoxicity in cancer survivors. A systematic review",
"authors": [
"Ravindra Reddy C",
"Stephen Samuel",
"Vijay Pratap Singh",
"Sourjya Banerjee",
"Ravindra Reddy C",
"Vijay Pratap Singh",
"Sourjya Banerjee"
],
"abstract": "Background: Cardiotoxicity is a major long-term complication of anti-cancer drugs such as anthracycline and androgen deprivation therapy (ADT). These drugs also impact the quality of life, reduced functional capacity, and life expectancy. Exercise attenuates the cardiotoxic effects of anticancer treatments, as indicated by a growing body of evidence.\n\nMethods: Studies for this review were retrieved from databases PubMed, SCOPUS, EMBASE, COCHRANE, and Web of Science and were restricted only to clinical trials. Study results were screened and synchronized to Mendeley. Studies that met the eligibility criteria were extracted into the spreadsheet, summarizing information regarding the site and cancer stages, adjuvant therapy, various exercise interventions, and outcome measures. Risk of bias quality analysis was done in accordance with the National Heart Lung Blood Institute. Results:\n\nIn this systematic review, 9021 articles were screened. After the exclusion criteria, seven articles were included for qualitative analysis. Outcome measures analyzed were measures of cardiotoxicity such as left ventricular ejection fraction (LVEF), cardiac biomarkers, and global longitudinal strain. Conclusion: Although a structured exercise protocol including aerobic and resistance training has been found to improve, the functional capacity is an indirect measure of cardiotoxicity. There is a lack of data in terms of improvement seen in direct measurements of cardiotoxicity such as LVEF and cardiac biomarkers. A lack of evidence regarding the effects of exercise on the direct measurement of cardiotoxicity encourages the need for further research.",
"keywords": [
"Exercise",
"Cardiotoxicity",
"Cancer Survivors",
"Rehabilitation"
],
"content": "Abbreviations\n\nBNP: B-type natriuretic peptide\n\nCG: Control Group\n\nGLS: global longitudinal strain\n\nHER: human epidermal growth factor receptor\n\nIG: Interventional group\n\nLVEF: left ventricle ejection fraction,\n\nMET: Metabolic equivalent\n\nPRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses\n\nRCT: Randomized control trial\n\nROS: Reactive oxygen species\n\nRVEF: right ventricular ejection fraction\n\n\nIntroduction\n\nGlobally cancer and cardiovascular diseases cause morbidity and mortality. Despite various advances in cancer treatments, the detrimental effects of these treatment forms cause a significant burden to cancer survivors. The three most prevalent cancers are prostate, colorectal, and melanoma among males, and breast, uterine corpus, and colorectal cancer among females.1 The most common types of childhood cancer are leukemia, brain cancer, lymphoma, and solid tumors.2 Early screening for cancer helps slow down its progress and, if accompanied by appropriate treatment, can result in a significant decline in the mortality rate.3\n\nOne of the primary treatment strategies in cancer treatment involves chemotherapeutic drugs such as anthracycline, doxorubicin, Paclitaxel, Cyclophosphamide, and Trastuzumab used alone or in combination with radiation therapy.4–6 Despite the therapeutic effects of these drugs, cancer survivors have been found to have long-term adverse side effects such as cardiotoxicity, fatigue, cancer-related pain, sleep disorders, and psychological stress, which contribute to morbidity and mortality amongst them.7\n\nCardiotoxicity is considered a significant concern and severe issue in clinical practice patients receiving chemotherapy. Cardiotoxicity is damage to the heart manifested by either symptomatic or asymptomatic decline in left ventricular ejection fraction (LVEF).8 Although the mechanism of cardiotoxicity is poorly understood, the most agreed upon fact remains the increase of reactive oxygen species (ROS), activating cardiac autophagy and apoptotic pathways.9–12 Studies have defined cardiotoxicity as a decrease in LVEF of >10% points to a value of <53%(reference value).13 Echocardiography-LVEF, myocardial strain imaging, and cardio biomarkers are the standard marker or parameters for measuring the early and late cardiotoxic effects.11,13–18\n\nThe proposed strategies to reduce the cardiotoxic effects are: 1) anthracycline dose reduction, 2) altogether avoiding the radiotherapy/blockade of exposure to other areas, 3) usage of iron chelation, 4) treating the preexisting cardiovascular risk factors, 5) using other interventions such as exercise to alleviate its effects.\n\nExercise training, a most reliable and non-pharmacological option, brings positive outcomes and improves physical fitness by restoring physical function, enhancing the quality of life, and reducing cancer-related fatigue in cancer survivors. This training can be implemented before, during, and after cancer treatments,19–23 thus nullifying the cardiotoxic effects. Exercise interventions, including aerobic exercises such as treadmill walking, running, cycling, and resistance training such as weight training, strength training using Thera Band, and weight cuffs, are safe and feasible for all cancer populations. Over the past decade, steady growth in the body of evidence supports the importance of exercise in attenuating or mitigating the cardiotoxic effects induced by chemotherapeutic drugs.7,19,21,22,24–27 However, several outcome measures, such as VO2 max (maximum amount of oxygen utilized during exercise) and metabolic equivalent (MET), are used in measuring cardiotoxicity; the standard direct predictors are LVEF and cardiac biomarkers.\n\nTo the best of our knowledge, there is no systematic review on the effects of exercise training on cardiotoxicity in cancer survivors; this review aims to synthesize evidence regarding the role of exercise training on cardiotoxicity and identify potential knowledge gaps in terms of research in this area.\n\n\nMethods\n\nThis systematic review of clinical trials on the Effects of exercise training on cardiotoxicity in cancer survivors is reported according to the PRISMA guidelines (See Reporting Guidelines).28\n\nA detailed data search was performed on databases PUBMED, SCOPUS, EMBASE, COCHRANE, and WEB OF SCIENCE from August 2009 to March 2021. The search terms used were cancer, carcinoma, neoplasm (MeSH), cancer survivors (MeSH), adult cancer survivors, and pediatric cancer survivors. For intervention, search terms were exercise training, exercise therapy, prehabilitation, rehabilitation, aerobic training, resistant training, endurance training, treadmill, cycle ergometry, swimming, walking, running, free weights, manual, kettlebell exercises, dumbbell exercises, Pilates, yoga, flexibility training, stretching exercises, high-intensity interval training. For cardiotoxicity outcomes, the search terms are Cardiotoxicity, Cardiopulmonary fitness, functional capacity, left ventricle ejection fraction, heart failure, cardiovascular reserve capacity, coronary vascular disease, and physical fitness. The Boolean operator ‘AND’ or ‘OR ‘combined the search terms. Potentially relevant studies were included from the reference list of the included articles. The search for clinical trials was limited to those involving human participants and those published in English. Two investigators, RR and SRS, independently searched the databases mentioned above. The studies were further screened by RR and SRS based on the preset inclusion criteria. A discussion with VPS sorted any further discrepancies.\n\nType of participant: All kinds of cancer survivors who received chemotherapy.\n\nType of study design: Only clinical trials.\n\nStudies that use other interventions rather than exercise such as Music therapy and Cognitive behavioral therapy, Nordic Walking, speech therapy qualitative studies, Cross-sectional studies, and Systematic review.\n\nRR and SRS performed full-text screening for the included articles independently, and any disagreements were sorted after discussion with VPS. Information on the objectives, site and cancer stages, adjuvant treatment, intervention details, comparator, outcome measures, study design, sample size, adverse events, and critical findings of the included studies were mentioned in the data extraction sheet.\n\nThe included studies underwent the risk of bias assessment performed independently by RR and SRS using the National Heart Lung Blood Institute (NHLBI).29 The NIH checklist for each study type measures 14 unique questions and was scored to assess studies' internal validity. The studies were scored under each query related to randomization, allocation concealment, blinding of participants and assessors, baseline characteristics, dropouts, intervention adherence, outcome data, and other biases. Studies were marked as ‘good,’ ‘fair,’ and ‘poor’ if they met 10-14, 5–9, and ≤4 scores accordingly (See Underlying data).28 Discussions with VPS sorted disagreements in the marking system of the studies between the two reviewers.\n\n\nResults\n\nIn this review, 9021 articles were retrieved from a comprehensive search of the following databases; PubMed-611, web of science-1728, Scopus-4058, Embase-1069, Cochrane-1555. A total of 6089 articles were found after merging duplicates. Based on the title and abstract screening, 13 articles were eligible for full-text screening. Out of the 13 articles, seven met the inclusion criteria and were included in this review (See Underlying data).28\n\nA quality analysis using NHLBI Questionnaire was performed for the included studies interventional studies. Most of the studies were fair to good in quality, and few studies had missing data, smaller sample sizes, dropouts, and differences in baseline characteristics. Among seven studies, one was a single-arm pre-post intervention design; four were randomized controlled trials (RCTs); two were non-RCT. In all included studies, the patients were diagnosed with breast cancer; however, only few authors reported their stage. Most of the participants included in the studies were those aged above 18. The outcome measure of all included studies was cardiac function using echocardiography- LVEF, Global longitudinal strain (GLS), and circulating cardiac biomarkers (troponins and N terminal-pro brain natriuretic peptide (NT-proBNP). Most of the patients received anthracycline class drugs such as doxorubicin and trastuzumab as adjuvant therapy.\n\nExercise intervention for the included participants comprised either aerobic or resistance training or a combination of both. Supervised treadmill walking, unsupervised home-based walking, and cycle ergometry were the modalities used in aerobic exercise, and for resistance training, Thera band, dumbbell, and medicine ball were used. Out of seven studies, three studies30–32 used aerobic, and resistance training as their intervention, and the other four studies33–36 used only aerobic training for their patients. The duration of these exercises was around 30-60 min performed in about 9-16 weeks. Two out of seven studies33,34 incorporated exercise bout just 24-hours before the chemotherapy and observed the changes in echocardiographic findings and cardio biomarkers.\n\nThe dropouts were as follows: 11 from Foulkes et al., 21 from Katarzyna Hojan et al., two from Howden et al., three from Kirkham et al., two from Haykowsky et al., six from Zhijun Ma et al., and three from Kirkham et al.\n\nOne study among seven has been published twice in a different journal, and their relevant data has been extracted and presented in Tables 1 and 2.\n\n\nDiscussion\n\nPatients with cancer with underlying cardiovascular complications have reduced life expectancy compared to those with cancer alone. It is expected that the survival rate of the cancer population will increase by 30% by 2022 in the United States alone.37 Modern treatment strategies for cancer have improved their survival rate and costed adverse cardiovascular injury as side effects in their long-term survival period. This study aimed to look for therapeutic strategies to alleviate the side effects.38 A growing body of evidence supports the role of exercise in preventing and managing various treatment-related complications in cancer survivors. Hence, this review was conducted to summarize the available literature and thus evaluate the effects of exercise training on cardiotoxicity in cancer survivors. The studies included in this review used outcome measures that directly measure cardiotoxicity in cancer survivors. The effect of exercise interventions has been discussed in detail under each outcome measure.\n\nCancer therapy-induced cardiac dysfunction is a long-term complication in cancer survivors, with some being symptomatic and others asymptomatic. Heart failure is defined as pump failure, measured in LVEF.39 Exercise training potentially induces ventricular remodeling in patients with heart failure40 by restoring abnormal neurohormonal, autonomic and hemodynamic functions. Among the included studies, five studies30–32,35,36 measured LVEF as a primary outcome measure, and the other two studies33,34 evaluated it as a secondary measure. one36 among seven studies, showed clinically significant improvements in LVEF (P<0.05). In contrast, six other showed negligible changes in left ventricular ejection from baseline to post-chemotherapy. This study incorporated only aerobic exercises for their patients for 16 weeks (3d/week).36\n\nIt is one of the echocardiographic findings and a potential predictor of subclinical cancer therapy-related cardiac dysfunction. It analyzes the subtle changes or deformation occurring in the left ventricle.39,41 Based on research evidence, a greater than 15% change is a strong predictor of cardiotoxicity.41 There a is lack of evidence supporting the role of exercise training in GLS; however, in a trial conducted by Valzania, Cinzia et al., improvements have been seen in GLS values in patients receiving cardio resynchronization therapy during exercise.42 Among seven studies included in this review, two studies35,36 didn’t assess GLS as an outcome measure, while most studies showed slight changes in GLS value. However, a clinical trial conducted by Foulkes et al. demonstrated a considerable decline in GLS value over 16 months (P = 0.015),30 despite providing a combination of aerobic and resistance training.\n\nBiomarkers are one of the best diagnostic predictors of early cardiotoxicity. The test performed during or after the chemotherapy helps anticipate the presence of cardiotoxicity. Troponins and Natriuretic peptides are the significant biomarkers in determining subclinical cardiotoxicity. These biomarkers imply a certainty of cardiac damage due to chemotherapy.39,43 Based on the research literature, it is evident that even prolonged exercise training in healthy individuals can cause an acute elevation in these biomarkers, which are transient.44 However, a trial conducted by Braith et al. on heart failure patients showed that 16-weeks of endurance training helped reduce the baseline values of natriuretic peptides.45 Only five studies30,32–34,36 investigated biomarkers as their outcome and revealed that there is a significant elevation of troponins and natriuretic peptides post-chemotherapy in acute time. Interestingly these values recovered after 12 months in two studies.30,36 Thus, exercise training as an intervention to reduce biomarkers level is unclear and poorly understood.\n\nThus, this systematic review summarizes the effect of exercise training on cardiotoxicity in cancer survivors. Although previous studies summarize the impact of exercise as an intervention on cardiotoxicity measured by VO2 max in cancer survivors, no review synthesizes evidence regarding the direct measure of cardiotoxicity. The inclusion of studies published in English and exclusion of the grey literature are the limitation of this review. Aerobic exercise training was limited to treadmill modality in most of the studies. Recent advances in exercise training like high-intensity interval training have shown clinical benefits in reduced ejection fraction patients suggesting ventricular remodeling, thus improving their functional capacity.46 So, there is a need for an alternate form of exercise to counteract the chemotherapy-induced dysfunction.\n\nIn this review, one out of seven studies36 showed statistically significant improvement in cardiotoxicity-related outcome measures. In comparison, three studies30,32,33 showed that there was no deterioration of the cardiotoxicity related outcome measures. In contrast, the remaining three studies30,32,35 showed a decline in the outcome measures, which was statistically significant.\n\nIndividualized exercise prescription, based on the frequency, intensity, type, and time (FITT) principle, can be recommended based on patients’ baseline characteristics or comorbidities limiting their physical performance. Cancer patients also suffer from sarcopenia,47–49 which reduces their strength; there is a clinical need for resistance training.\n\nThe timing of exercise intervention used before, concomitant, or after chemotherapy has a significant role in providing protective effects. A gap has to be explored for further strengthening of evidence in optimal timing. In most of the included studies, the intervention duration was short, about four months; other studies can implement exercises for the long run and see the clinical changes.\n\nChildhood cancer survivors with Hodgin’s lymphoma, and adult cancer survivors with prostate and colorectal cancer, are common and may also suffer from chemotherapy-related side effects. Predominantly early childhood cancer survivors with a longer life span have to sustain chemotherapy-induced cardiovascular injury affecting their quality of life in the long run. Despite evidence regarding exercise training, no studies are measuring the clinical changes in LVEF, GLS, and biomarkers, which are the direct measures of cardiotoxicity. Therefore, exploring the role of exercises in other cancer survivors is crucial to gather more evidence regarding the direct measurement of cardiotoxicity.\n\n\nConclusion\n\nThis review concludes that exercise has a potential role as an intervention in preventing deterioration of outcome measures that measure cardiotoxicity and improve the same. We recommend further research to ascertain the dose, volume of exercise, and optimal timing to further understand the role of exercise in cardiotoxicity.\n\n\nData availability\n\nOpen Science Framework (OSF): Effects of exercise on cardiotoxicity in cancer survivors. A systematic review’. DOI: 10.17605/OSF.IO/Q4YZM\n\nThis project contains the following underlying data:\n\nReview protocol.docx. (It has information on search strategy, databases, search terms used, and inclusion and exclusion criteria.)\n\nSystematic review.xlsx. (Patients’ characteristics such as site/stage, adjuvant treatments, intervention, results, dropouts)\n\nRisk of bias.docx. (It includes the tables for which risk of bias for studies was done using NIH tool)\n\nData are available under the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nReporting guidelines\n\nOpen Science Framework (OSF): PRISMA checklist and flow chart for ‘Effects of exercise training on cardiotoxicity in cancer survivors. A systematic review’. DOI: 10.17605/OSF.IO/Q4YZM\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAuthor contributions\n\nConceptualization, R.R. AND S.R.S; Methodology, R.R. Investigation, R. R AND S.R.S.\n\nSoftware, R.R. AND S.R.S; Supervision, S.R.S., V.P.S. AND S.B.; Funding Acquisition, S.R.S., V.P.S. AND S.B.; Writing – Original Draft Preparation, Writing – Review & Editing, R. R. AND S.R.S.",
"appendix": "References\n\nMiller KD, Nogueira L, Mariotto AB, et al.: Cancer treatment and survivorship statistics. CA Cancer J Clin. 2019 2019 Sep 1 [cited 2021 May 11]; 69(5): 363–385. Publisher Full Text\n\nLam CG, Howard SC, Bouffet E, et al.: Science and health for all children with cancer. Science. American Association for the Advancement of Science. 2019; 363: 1182–1186. Publisher Full Text\n\nSiegel RL, Miller KD, Jemal A: Cancer statistics. CA Cancer J Clin. 2020 2020 Jan [cited 2021 May 11]; 70(1): 7–30. Publisher Full Text Reference Source\n\nTable 1|Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress. [cited 2021 May 11]. Reference Source\n\nBanfill K, Giuliani M, Aznar M, et al.: Cardiac Toxicity of Thoracic Radiotherapy: Existing Evidence and Future Directions. J Thorac Oncol. Elsevier Inc. 2021; 16: 216–227. Publisher Full Text\n\nKoutroumpakis E, Palaskas NL, Lin SH, et al.: Modern Radiotherapy and Risk of Cardiotoxicity. Chemotherapy. S. Karger AG. 2020; 65: 65–76. Publisher Full Text\n\n2015 Strategic Priorities Symptom Management & Quality of Life Steering Committee (SxQoL SC).\n\nWolf CM, Reiner B, Kühn A, et al.: Subclinical Cardiac Dysfunction in Childhood Cancer Survivors on 10-Years Follow-Up Correlates With Cumulative Anthracycline Dose and Is Best Detected by Cardiopulmonary Exercise Testing, Circulating Serum Biomarker, Speckle Tracking Echocardiography, and Tissue Doppler Imaging. Front Pediatr. 2020 Mar; 8: 8. Publisher Full Text\n\nBhagat A, Kleinerman ES: Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention. Advances in Experimental Medicine and Biology. Springer; 2020; p. 181–192. Publisher Full Text\n\nBabiker HM, McBride A, Newton M, et al.: Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system. Critical Reviews in Oncology/Hematology. Elsevier Ireland Ltd.2018; 126: 186–200. Publisher Full Text\n\nDessalvi CC, Deidda M, Mele D, et al.: Chemotherapy-induced cardiotoxicity: new insights into mechanisms, monitoring, and prevention. J Cardiovasc Med. 2018 Jul 1; 19(7): 315–23. Publisher Full Text\n\nKoutsoukis A, Ntalianis A, Repasos E, et al.: Cardio-oncology: A focus on cardiotoxicity. Eur Cardiol Rev. 2018 Jun 1; 13(1): 64–9. PubMed Abstract | Publisher Full Text\n\nPlana JC, Galderisi M, Barac A, et al.: Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: A report from the American society of echocardiography and the European association of cardiovascular imaging. J Am Soc Echocardiogr. 2014 [cited 2021 May 11]; 27(9): 911–39. PubMed Abstract\n\nCardinale D, Colombo A, Bacchiani G, et al.: Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015 Jun 2; 131(22): 1981–8. PubMed Abstract | Publisher Full Text\n\nSawaya H, Sebag IA, Plana JC, et al.: Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ: Cardiovasc Imaging. 2012; 5(5): 596–603. PubMed Abstract | Publisher Full Text\n\nTocchetti CG, Ragone G, Coppola C, et al.: Detection, monitoring, and management of trastuzumab-induced left ventricular dysfunction: An actual challenge. Eur J Heart Fail. 2012; 14: 130–137. PubMed Abstract | Publisher Full Text\n\nColombo A, Cardinale D: Using cardiac biomarkers and treating cardiotoxicity in cancer. Future Cardiology. 2013; 9: 105–118. Publisher Full Text\n\nCardinale D, Cipolla CM: Assessment of cardiotoxicity with cardiac biomarkers in cancer patients. Herz. 2011; 36: 325–332. Publisher Full Text\n\nMustian KM, Cole CL, Lin PJ, et al.: Exercise Recommendations for the Management of Symptoms Clusters Resulting From Cancer and Cancer Treatments. Seminars in Oncology Nursing. W.B. Saunders. 2016; 32: 383–393. PubMed Abstract | Publisher Full Text\n\nMustian KM, Sprod LK, Janelsins M, et al.: Exercise Recommendations for Cancer-Related Fatigue, Cognitive Impairment, Sleep Problems, Depression, Pain, Anxiety, and Physical Dysfunction—A Review. Oncol Hematol Rev. 2012 [cited 2021 May 11];08(02):81; 08: 81. Publisher Full Text Reference Source\n\nSpeed-Andrews AE, Courneya KS: Effects of exercise on quality of life and prognosis in cancer survivors. Current Sports Medicine Reports. 2009; 8: 176–181. Publisher Full Text\n\nCampbell KL, Winters-Stone KM, Wiskemann J, et al.: Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable. Medicine and Science in Sports and Exercise. 2019 Nov 1; 51(11): 2375–90.\n\nSchmitz KH, Courneya KS, Matthews C, et al.: No Title. Medicine and Science in Sports and Exercise Med Sci Sports Exerc. Jul, 2010; p. 1409–26. PubMed Abstract\n\nTong CKW, Lau B, Davis MK: Exercise Training for Cancer Survivors. Curr Treat Options Oncol. Springer; 2020; Vol. 21. . Publisher Full Text\n\nScott JM, Nilsen TS, Gupta D, et al.: Exercise therapy and cardiovascular toxicity in cancer. Circulation. 2018; 137(11): 1176–1191. PubMed Abstract | Publisher Full Text\n\nKleckner IR, Dunne RF, Asare M, et al.: Exercise for Toxicity Management in Cancer—A Narrative Review. Oncol Hematol Rev. 2018; 14(1): 28–37. PubMed Abstract | Publisher Full Text\n\nChen JJ, Wu PT, Middlekauff HR, et al.: Aerobic exercise in anthracycline-induced cardiotoxicity: A systematic review of current evidence and future directions. Am J Physiol - Hear Circ Physiol. 2017; 312(2): H213–H222. PubMed Abstract | Publisher Full Text\n\nC, R. RSamuel SR, Singh P, et al.: Effects of exercise training on cardiotoxicity in cancer survivors.2022, April 5. Publisher Full Text\n\nStudy Quality Assessment Tools|NHLBI, NIH: [cited 2021 May 23]. Reference Source\n\nFoulkes SJ, Howden EJ, Bigaran A, et al.: Persistent Impairment in Cardiopulmonary Fitness after Breast Cancer Chemotherapy. Med Sci Sports Exerc. 2019 Aug 1 [cited 2020 Nov 29]; 51(8): 1573–1581. PubMed Abstract\n\nHojan K, Procyk D, Horynska-Kestowicz D, et al.: The Preventive Role of Regular Physical Training in Ventricular Remodeling, Serum Cardiac Markers, and Exercise Performance Changes in Breast Cancer in Women Undergoing Trastuzumab Therapy-An REH-HER Study. J Clin Med. 2020 May; 9(5). PubMed Abstract | Publisher Full Text\n\nHowden EJ, Bigaran A, Beaudry R, et al.: Exercise as a diagnostic and therapeutic tool for the prevention of cardiovascular dysfunction in breast cancer patients. Eur J Prev Cardiol. 2019 Feb 1; 26(3): 305–315. PubMed Abstract | Publisher Full Text\n\nKirkham AA, Eves ND, Shave RE, et al.: The effect of an aerobic exercise bout 24 h prior to each doxorubicin treatment for breast cancer on markers of cardiotoxicity and treatment symptoms: A. Breast Cancer Res Treat. 2018 Nov 6; 167(3): 719–29. PubMed Abstract | Publisher Full Text\n\nKirkham AA, Shave RE, Bland KA, et al.: Protective effects of acute exercise prior to doxorubicin on cardiac function of breast cancer patients: A proof-of-concept RCT. Int J Cardiol. 2017; 245: 263–270. PubMed Abstract | Publisher Full Text\n\nHaykowsky MJ, Mackey JR, Thompson RB, et al.: Adjuvant Trastuzumab Induces Ventricular Remodeling Despite Aerobic Exercise Training. Clin Cancer Res. 2009 Aug; 15(15): 4963–4967. PubMed Abstract | Publisher Full Text\n\nMa Z: Effect of anthracycline combined with aerobic exercise on the treatment of breast cancer. Pak J Pharm Sci. 2018 May; 31(3(Special)): 1125–1129. PubMed Abstract\n\nCancer Statistics - National Cancer Institute: [cited 2022 Apr 12]. Reference Source\n\nBlackwell: Cardiotoxicity of Anticancer Treatments: Epidemiology, Detection, and Management CONTINUING MEDICAL EDUCATION ACCREDITATION AND DESIGNATION STATEMENT.\n\nBloom MW, Hamo CE, Cardinale D, et al.: Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging. Circ Hear Fail. 2016 Jan 1 [cited 2021 Jun 13]; 9(1). Publisher Full Text Reference Source\n\nHaykowsky MJ, Liang Y, Pechter D, et al.: A Meta-Analysis of the Effect of Exercise Training on Left Ventricular Remodeling in Heart Failure Patients. The Benefit Depends on the Type of Training Performed. J Am Coll Cardiol. 2007; 49(24): 2329–2336. PubMed Abstract | Publisher Full Text\n\nOikonomou EK, Kokkinidis DG, Kampaktsis PN, et al.: Assessment of Prognostic Value of Left Ventricular Global Longitudinal Strain for Early Prediction of Chemotherapy-Induced Cardiotoxicity: A Systematic Review and Meta-analysis. JAMA Cardiology. 2019; 4(10): 1007–1018. PubMed Abstract | Publisher Full Text\n\nValzania C, Gadler F, Boriani G, et al.: Changes in global longitudinal strain during rest and exercise in patients treated with cardiac resynchronization therapy. Clin Physiol Funct Imaging. 2012 Jul [cited 2021 Jun 15]; 32(4): 310–6. PubMed Abstract\n\nAnanthan K, Lyon AR: The Role of Biomarkers in Cardio-Oncology. J Cardiovasc Transl Res. 2020; 13(3): 431–450. PubMed Abstract | Publisher Full Text\n\nEijsvogels TMH, Fernandez AB, Thompson PD: Are there deleterious cardiac effects of acute and chronic endurance exercise?. Physiol. Rev. 2016; 96(1): 99–125. PubMed Abstract | Publisher Full Text\n\nBraith RW, Welsch MA, Feigenbaum MS, et al.: Neuroendocrine activation in heart failure is modified by endurance exercise training. J Am Coll Cardiol. 1999; 34(4): 1170–1175. PubMed Abstract | Publisher Full Text\n\nGomes Neto M, Durães AR, Conceição LSR, et al.: High intensity interval training versus moderate intensity continuous training on exercise capacity and quality of life in patients with heart failure with reduced ejection fraction: A systematic review and meta-analysis. Int J Cardiol. 2018 Jun 15 [cited 2021 Jun 19]; 261: 134–41. PubMed Abstract\n\nNipp RD, Fuchs G, El-Jawahri A, et al.: Sarcopenia Is Associated with Quality of Life and Depression in Patients with Advanced Cancer. Oncologist. 2018 Jan; 23(1): 97–104. PubMed Abstract | Publisher Full Text\n\nChindapasirt J: Sarcopenia in cancer patients. Asian Pac J Cancer Prev. Asian Pacific Organization for Cancer Prevention; 2016; 16. : 8075–8077. Publisher Full Text\n\nDavis MP, Panikkar R: Sarcopenia associated with chemotherapy and targeted agents for cancer therapy. Vol. 8, Annals of Palliative Medicine. AME Publishing Company; 2019; 86–101."
}
|
[
{
"id": "140895",
"date": "01 Jul 2022",
"name": "Sharon F. Kramer",
"expertise": [
"Reviewer Expertise Systematic review methods including meta-analyses and data synthesis",
"risk of bias assessment",
"clinical trials and exercise"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to review this manuscript of a systematic review investigating the effect of exercise on cardiotoxicity outcomes in cancer patients receiving chemotherapy and/or radiotherapy.\nThe rationale for the review is clearly stated. The background is missing some details regarding definitions of the main concepts addressed in this review for example: cardiotoxicity and details about how this is measured (this information is reported in the discussion and could be moved to the background and methods) and exercise and what is the potential underlying mechanisms of exercise on cardiotoxicity.\nMethods:\nSeveral sections are missing in the methods.\n\nWhat criteria are used regarding study design? i.e., randomised controlled trail, non-randomised controlled trials, pre-post studies?\n\nWhat was the process of screening title and abstract?\n\nWhat comparisons were of interest? i.e., exercise A vs exercise B, exercise vs no exercise etc.\n\nI suggest providing more background about why these tools were developed as I was not aware of these tools and maybe other readers might not be either. For example, it is not clear that there are several tools that were developed for different study types. Specify which tools were used.\n\nAdd a section to the methods about the outcomes of interest including: timing of outcome measurement of interest (post intervention and FU), how these outcomes are/should be measures, and how the outcome measure should be interpreted higher value is greater toxicity? (some of the details are reported in discussion and could be moved to methods section).\n\nAlthough no meta-analyses were performed, the methods still need a section about how the data was summarised/synthesised. Please provide information abut how the results were structured by study design, by population, by outcome.\nResults:\nThe main results regarding toxicity are reported in the discussion and should be moved to the results section. I suggest restructuring or adding a table with just the results outcomes and consider how this could be structured (see suggestions above by study design, outcome or population).\n\nAvoid vote counting i.e. 1 out of seven studies showed a significant result. Reporting 95%CI is more informative and helps the reader to interpret data better instead of reporting just the p -value.\nConclusion:\nThe conclusion currently doesn’t reflect what is reported in the results. Currently there doesn’t seem to be any strong evidence to suggest that exercise mitigates the cardiotoxic effects of chemo/radiotherapy in cancer patients.\nI suggest revisiting the PRISMA guidelines to help with structuring the manuscript and adding missing information/sections.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? No\n\nIs the statistical analysis and its interpretation appropriate? No\n\nAre the conclusions drawn adequately supported by the results presented in the review? No",
"responses": []
},
{
"id": "180450",
"date": "12 Jul 2023",
"name": "Quentin Jacquinot",
"expertise": [
"Reviewer Expertise Exercise physiology and supportive care"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAbbreviations section (page 3)\nHarmonize the writing. For example: Capitalize the first only or capitalize first letter for each word.\n\nWrite the meaning of MET in full. Add \"of Task\".\n\nIntroduction section (page 3)\n\nAdd a reference for the first sentence.\n\nChange the order of the sentences in the writing of the first paragraphs of the introduction for more logic. For example: Start with the incidence (ref 1 and 2), then the notion of mortality (ref 3) then the sentences of references 4-6 and finally the first two sentences of the introduction and the reference.\n\nWeight your comments regarding the sentence \"This training can be implemented before, during, and after cancer treatments,19–23 thus nullifying the cardiotoxic effects\". Modify \"can be\" by \"could be\" and \"nullifying\" by a less \"strong\" term because it contradicts the results of your article.\n\nRegarding VO2, specify that it is an \"indirect\" reflection of cardiotoxicity.\n\nMethods section\nCite reference 28 (See Underlying data) earlier and in each subsections of the method section because currently it comes too late, whereas these informations are important.\n\nsubsection \" Search strategy and selection criteria\"\nAdd the words MESH for all categories (intervention, cardiotoxicity, etc...) as done for neoplasm and cancer survivors.\n\nsubsection \"Inclusion criteria\"\nSpecify the type of study design (RCT, observational, etc.)\n\nsubsection \"Exclusion criteria\"\nSpecify that pre-clinical studies are excluded.\n\nWhy Nordic walking is excluded whereas selected studies offered unsupervised walking or the treadmill (cf : Supervised treadmill walking, unsupervised home-based walking in results section)?\n\nResults section\nSubsection \"Characteristics of the studies\"\nMaybe add the flowchart in the body text and not in the supplementary data?\n\nIn the first sentence put the number in brackets like this: PubMed (n=6).\n\nAdd \"®\" to Thera band® as it's a brand or change by \"resistance bands\". In table 2: Write in the \"results\" column \"usual\" and \"training\" at the top and not only in the first line. This will make it possible to harmonize the wording to facilitate reading on the 2 pages.\n\nSame comment: Harmonize the wording of the \"outcomes measures\" column because sometimes it writes echo* - sometimes echography in full then sometimes no information on the method (as for Katarzyna et al).\n\nSame comment for the \"outcomes measure\" column: Sometimes there are deadlines, sometimes not. You must harmonize the wording and be more rigorous in the wording and organization of the paragraphs so that they are written in the same way for all the studies.\n\nLast sentence of the result part, please add the reference of the study.\n\nDiscussion section\nFirst sentence of the discussion part, please add a reference.\n\nSpecify within the limits that the data presented relates only to breast cancer.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "168414",
"date": "11 Sep 2024",
"name": "Sheetal Kalra",
"expertise": [
"Reviewer Expertise Physical health",
"fitness",
"sports injuries",
"sports rehabilitation",
"women health",
"exercise interventions"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting article. The authors have synthesized the evidence regarding role of exercises on cardiotoxicity. Certain observations are: 1. In Abstract it would be justified to include a line or rationale of study , may be in background or as separate heading 2. Methodology section can be improved by including information under PICOS framework 3. The PRISMA flowchart should include reasons for exclusion of 6076 articles in screening section. 4. Also records identified does not give complete information. Should be re-written. 5. How was the review Question1 \"What are the effects of exercise training in preventing cardiotoxicity in cancer survivors\" mentioned in study protocol addressed in study?\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Yes\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/11-497
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.